INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MANINIL® 3.5

Composition:

Active substance: glibenclamide;

1 tablet contains glibenclamide (micronized form) 3.5 mg;

Excipients: lactose monohydrate, potato starch, colloidal anhydrous silicon dioxide, methylhydroxyethylcellulose, magnesium stearate, Ponceau 4R dye (E 124).

Pharmaceutical form. Tablets.

Main physicochemical properties: flat, parallel-sided pink tablets with bevelled edges and a dividing line on one side.

The tablet can be divided into equal doses.

Pharmacotherapeutic group.

Digestive system and metabolism. Antidiabetic medicinal products. Antihyperglycemic agents, excluding insulins. Sulfonylurea. Glibenclamide. ATC code A10BB01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. The medicinal product Maninil® 3.5 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 II, IIDM). This effect is glucose concentration-dependent in the environment surrounding β-cells.

When blood glucose concentration is very high, at which glucose-induced stimulation of insulin secretion is maximal, additional large-scale insulin release due to glimepiride intake is not expected. The clinical relevance of this observation, made in healthy volunteers, for diabetic patients taking glimepiride has not been established.

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

Pharmacokinetics.

Absorption. The medicinal product Maninil® 3.5 is rapidly and almost completely absorbed after oral administration. Concomitant food intake does not significantly affect glimepiride absorption.

Distribution. Plasma protein binding of the medicinal product Maninil® 3.5 exceeds 98%. Maximum serum concentration is reached within 1–2 hours and is approximately 100 ng/mL after a 1.75 mg dose of glimepiride. After 8–10 hours, serum concentration decreases to 5–10 ng/mL, depending on the administered dose.

The elimination half-life from serum after intravenous administration is about 2 hours, and after oral administration – 2–5 hours. However, some studies indicate that in diabetic patients it may be prolonged up to 8–10 hours.

Metabolism. Glimepiride is completely metabolized in the liver. The main metabolite is 4-trans-hydroxyglimepiride; the second metabolite is 3-cis-hydroxyglimepiride. Metabolites do not significantly contribute to the glucose-lowering effect of glimepiride.

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

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

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

Preclinical safety data.

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

Furthermore, in vitro studies provided no evidence of mutagenic potential.

Regular long-term carcinogenicity studies have not been conducted.

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

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the active substance, Ponceau 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 cases of diabetes mellitus requiring insulin: insulin-dependent diabetes mellitus type I, complete secondary failure of glimepiride therapy in type II diabetes mellitus, metabolic acidosis, diabetic precoma or coma, post-pancreatectomy state;
severe impairment of liver function;
severe impairment of kidney function;
pregnancy and lactation (also see section "Use during pregnancy or breastfeeding");
patients treated with bosentan must not take the medicinal product Maninil® 3.5.

Interaction with other medicinal products and other forms of interactions.

Concomitant use of other medicinal products may enhance or reduce the effect of Maninil® 3.5; therefore, they 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 considered when glimepiride is used concomitantly with inducers or inhibitors of CYP 2C9.

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

Awareness 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 with concomitant use of: acetazolamide, β-blockers, barbiturates, diazoxide, diuretics, glucagon, isoniazid, corticosteroids, laxatives (in chronic abuse, see section "Special precautions for use"), nicotinic acid, phenothiazine derivatives, phenytoin, rifampicin, thyroid hormones, female sex hormones (gestagens, estrogens), sympathomimetics.

H2-receptor antagonists, clonidine, and reserpine may cause either reduction or enhancement of the blood glucose-lowering effect of Maninil® 3.5.

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

In patients receiving glimepiride concomitantly with bosentan, an 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 likely enhance its toxicity; therefore, when both substances are used concomitantly, measures for 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 forms of interactions. Acute or chronic alcohol consumption may unpredictably enhance or reduce the blood glucose-lowering effect of the medicinal product Maninil® 3.5.

Special precautions for use.

The patient should be informed that if other disorders occur during therapy with Maninil® 3.5, he or she must immediately consult the treating physician, and when changing physicians, must inform the new physician about the existing diabetes mellitus (e.g. during hospitalization, after an accident, or if illness occurs during vacation).

Hypoglycemia.

The patient should be made aware of the risk of hypoglycemia during therapy 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 patients who do not follow the physician's recommendations generally have a higher risk of hypoglycemia.

Medicinal products acting on the central nervous system, β-adrenoreceptor blockers, as well as autonomic neuropathies, 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 be controlled only briefly with usual amounts of sugar, require immediate treatment (see section "Overdose").

Hyperglycemia.

If the treatment regimen is not followed, if the glucose-lowering effect of Maninil® 3.5 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 dryness of the skin, fungal infections, or skin infections, as well as reduced performance.

In exceptional stressful situations (e.g. trauma, surgery, infections accompanied by fever), metabolic control may deteriorate, leading to hyperglycemia, which may require temporary insulin therapy.

Laxatives.

Chronic abuse of laxatives may lead to impaired metabolism.

Alcohol.

Acute or chronic alcohol consumption may unpredictably enhance or reduce the glucose-lowering effect of Maninil® 3.5.

Impaired liver and kidney function and endocrine disorders.

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

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

In patients with G6PD deficiency, treatment with sulfonylurea drugs may cause hemolytic anemia. Since glibenclamide belongs to the chemical class of sulfonylureas, it should be used with caution in patients with G6PD deficiency, and consideration should be given to switching to alternative non-sulfonylurea derivatives.

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 drugs with a shorter duration of action should be preferred.

Maninil® 3.5 contains lactose.

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

The drug is contraindicated in patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy.

Maninil® 3.5 is contraindicated during pregnancy. Since oral antidiabetic drugs do not control blood glucose levels as reliably as insulin, they are not suitable for treating diabetes during pregnancy.

Insulin therapy is the treatment of choice during pregnancy. If possible, oral antidiabetic drugs should be discontinued and replaced with insulin before planned pregnancy.

Breastfeeding.

Since it is unknown whether Maninil® 3.5 passes into breast milk, it is contraindicated during breastfeeding. Breastfeeding patients should be treated with insulin to control diabetes, or they 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 hypo- or hyperglycemia, attention and reaction speed may be impaired, especially at the beginning of therapy, 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 hypoglycemia warning symptoms. In such cases, the appropriateness of driving should be re-evaluated.

Dosage and Administration

Dosage

Dose adjustment of Maninil® 3.5 should be performed only by a physician, along with dietary adjustments. The dosage depends on the results of metabolic monitoring (blood and urine glucose levels).

Treatment should be initiated with the lowest possible dose, especially in patients particularly prone to hypoglycemia or with body weight less than 50 kg. It is important to note that glyburide in Maninil® 3.5 is in micronized form; therefore, the recommended doses of Maninil® 3.5 differ from those of preparations containing non-micronized glyburide.

Initiation of treatment. Dosage should be increased gradually, starting with the lowest possible dose:

½ (up to 1) tablet of Maninil® 3.5 (corresponding to 1.75–3.5 mg of glyburide) per day.

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

maximum 3 tablets of Maninil® 3.5 (corresponding to 10.5 mg of glyburide) per day.

Switching from other antidiabetic medications. Transition from another oral glucose-lowering agent to Maninil® 3.5 should be done cautiously, starting with:

½ (up to 1) tablet of Maninil® 3.5 (corresponding to 1.75–3.5 mg of glyburide) per day.

Dose adjustment. In elderly patients, debilitated or malnourished individuals, and 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 antidiabetic agents. Maninil® 3.5 may be used as monotherapy or in combination with metformin. In justified cases, for patients intolerant to metformin, thiazolidinediones (e.g., pioglitazone) may be additionally prescribed.

Maninil® 3.5 may also be combined with oral antidiabetic agents that do not stimulate insulin release (e.g., guar gum or acarbose).

In cases of secondary failure to glyburide therapy, combination therapy with insulin may be attempted. When complete loss of endogenous insulin secretion occurs, insulin monotherapy is indicated.

Elderly patients. For 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 as needed (see section "Special Warnings and Precautions for Use").

Administration

Tablets should be taken before meals, without chewing, and swallowed with sufficient liquid (preferably a glass of water).

When the daily dose exceeds 2 tablets of Maninil® 3.5, the total dose should be divided into morning and evening doses in a 2:1 ratio.

It is important to take the medication at the same time every day. Dosing errors, such as missed doses, must never be compensated by taking a higher dose later.

Duration of treatment depends on the course of the disease. Metabolic control should be monitored at regular intervals as recommended.

In particular, blood and urine glucose concentrations should be regularly monitored. Additionally, HbA1c and/or fructosamine levels, as well as other parameters (e.g., blood lipid levels), are recommended for periodic assessment.

Children

The safety and efficacy of Maninil® 3.5 in children and adolescents have not been established; therefore, this medicinal product should not be used for the treatment of children and adolescents.

Overdose

Acute, significant overdose of Maninil® 3.5, such as prolonged administration of slightly increased doses, may lead to severe, prolonged hypoglycemia, which can be life-threatening. After suspected overdose, 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. Substantial overdose and severe reactions, such as loss of consciousness and other serious neurological disturbances, should be considered medical emergencies requiring immediate treatment and hospitalization.

Symptoms of overdose

In cases of intentional overdose, prolonged hypoglycemia with possible relapses after several days of initially successful treatment may occur. In patients with impaired consciousness, hypoglycemic coma may rapidly develop, characterized by loss of consciousness, tachycardia, moist skin, hyperthermia, motor agitation, hyperreflexia, paresis, and a positive Babinski reflex.

Treatment measures in case of overdose

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

In accidental intoxications and when contact with the patient is possible (in the absence of seizure predisposition), after intravenous glucose administration, vomiting should be induced or gastric lavage performed.

For patients in a state of unconsciousness, 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).

Subsequently, 1 mg of glucagon may be administered intramuscularly or intravenously. If the patient does not regain consciousness, this measure may be repeated; further intensive therapy may be necessary.

Particularly in children who have accidentally ingested Maninil® 3.5, glucose solution must be administered cautiously to avoid dangerous hyperglycemia, followed by careful monitoring of blood glucose levels.

Patients who have ingested life-threatening amounts of Maninil® 3.5 require detoxification by gastric lavage and administration of activated charcoal, provided the drug was taken recently.

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

Adverse reactions.

Adverse reactions occurred with the following 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 during glibenclamide treatment and may lead to severe hypoglycaemia with coma, which can be life-threatening. In cases of very subtle hypoglycaemia, particularly in patients with autonomic neuropathy or 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 section "Special warnings and precautions for use".

Hypoglycaemia is defined as a drop in blood glucose levels below approximately 50 mg/dL. Symptoms that may signal an excessive drop in blood glucose levels to the patient or to those nearby include: sudden sweating, palpitations, tremor, hunger, anxiety, tingling sensation around the mouth, pallor of the skin, headache, drowsiness, sleep disturbances, feeling of fear, unsteadiness, 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 usually have cold, clammy skin and may experience seizures.

Patients with diabetes can manage mild hypoglycaemia by consuming sugar or foods or drinks containing a high amount of sugar. Therefore, they should always carry 20 grams of glucose with them.

If hypoglycaemia cannot be corrected immediately, a physician must be contacted without delay.

Other adverse reactions.

Disorders of the blood and lymphatic system.

Rare: thrombocytopenia.

Very rare: leukopenia, erythropenia, granulocytopenia up to the development of 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: possible cross-allergy with sulfonamides, sulfonamide derivatives, and probenecid.

Disorders of metabolism and nutrition.

Common: weight gain.

Very rare: hyponatraemia, disulfiram-like reaction.

Disorders of the visual system.

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

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 and ALT, alkaline phosphatase, drug-induced hepatitis, intrahepatic cholestasis, possibly due to a hyperergic allergic reaction of the liver tissue.

These liver function disorders are reversible after discontinuation of Maninil® 3.5, 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 are hypersensitivity reactions that are usually reversible, but very rarely may progress to life-threatening conditions associated with dyspnoea and decreased arterial blood pressure, potentially leading to shock.

Very rare: life-threatening allergic vasculitis, generalized hypersensitivity reactions including skin rash, arthralgia, fever, proteinuria, and jaundice. 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 medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should 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 in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Berlin-Chemie AG.

Manufacturer's address and place of business.

Glienicker Weg 125, 12489 Berlin, Germany.