Maninil^® (Tablets) Instructions for Use

Marketing Authorization Holder

Berlin-Chemie, AG (Germany)

Manufactured By

Menarini-Von Heyden, GmbH (Germany)

Or

Berlin-Chemie, AG (Germany)

Quality Control Release

BERLIN-CHEMIE, AG (Germany)

ATC Code

A10BB01 (Glibenclamide)

Active Substance

Glibenclamide (Rec.INN registered by WHO)

Dosage Forms

	Maninil® 3.5	Tablets 3.5 mg: 120 pcs.
	Maninil® 5	Tablets 5 mg: 120 pcs.

Dosage Form, Packaging, and Composition

Maninil^® 1.75

Tablets pale pink, flat-cylindrical, with beveled edges and a score on one side.

Excipients : lactose monohydrate, potato starch, hydroxyethylcellulose, colloidal silicon dioxide, magnesium stearate, Ponceau 4R dye [Ponso 4R] (E124).

120 pcs. – bottles of colorless glass (1) – cardboard packs.

Maninil^® 3.5

Tablets pink, flat-cylindrical, with beveled edges and a score on one side.

Excipients : lactose monohydrate, potato starch, hypromellose, colloidal silicon dioxide, magnesium stearate, Ponceau 4R dye [Ponso 4R] (E124).

120 pcs. – bottles of colorless glass (1) – cardboard packs.

Maninil^® 5

Tablets pink, flat-cylindrical, with a bevel and a score on one side.

Excipients : lactose monohydrate, potato starch, gelatin, talc, magnesium stearate, Ponceau 4R dye [Ponso 4R] (E124).

120 pcs. – bottles of colorless glass (1) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

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

Pharmacological Action

Oral hypoglycemic drug from the group of second-generation sulfonylurea derivatives.

It stimulates insulin secretion by binding to specific receptors on the membrane of pancreatic beta cells, lowers the threshold for glucose stimulation of pancreatic beta cells, increases insulin sensitivity and the degree of its binding to target cells, increases insulin release, enhances the effect of insulin on glucose uptake by muscles and the liver, thereby reducing blood glucose concentration. It acts in the second phase of insulin secretion. It inhibits lipolysis in adipose tissue. It has a hypolipidemic effect, reduces the thrombogenic properties of blood.

Maninil^® 1.75 and Maninil^® 3.5 in micronized form represent a high-tech, specially milled form of glibenclamide, allowing the drug to be absorbed faster from the gastrointestinal tract. Due to the earlier achievement of C_max of glibenclamide in plasma, the hypoglycemic effect practically coincides in time with the rise in blood glucose concentration after a meal, which makes the drug’s action milder and more physiological. The duration of the hypoglycemic action is 20-24 hours.

The hypoglycemic effect of the drug Maninil^® 5 develops after 2 hours and lasts for 12 hours.

Pharmacokinetics

Absorption

After oral administration of Maninil^® 1.75 and Maninil^® 3.5, rapid and almost complete absorption from the gastrointestinal tract is observed. Complete release of the micronized active substance occurs within 5 minutes.

After oral administration of Maninil^® 5, absorption from the gastrointestinal tract is 48-84%. T_max – 1-2 hours. Absolute bioavailability – 49-59%.

Distribution

Plasma protein binding is more than 98% for Maninil^® 1.75 and Maninil^® 3.5, 95% – for Maninil^® 5.

Metabolism and Excretion

It is almost completely metabolized in the liver to form two inactive metabolites, one of which is excreted by the kidneys and the other with bile.

T_1/2 for Maninil^® 1.75 and Maninil^® 3.5 is 1.5-3.5 hours, for Maninil^® 5 – 3-16 hours.

Indications

• Type 2 diabetes mellitus – as monotherapy or as part of combination therapy with other oral hypoglycemic drugs, except for sulfonylurea derivatives and glinides.

ICD codes

Dosage Regimen

The dose of the drug depends on age, severity of diabetes mellitus, blood glucose concentration on an empty stomach and 2 hours after a meal.

The initial dose of the drug Maninil^® 1.75 is 1-2 tablets (1.75-3.5 mg) once a day. If the effect is insufficient, under medical supervision, the dose of the drug is gradually increased until the daily dose necessary for stabilization of carbohydrate metabolism is achieved. The dose increase should be carried out at intervals from several days to 1 week, until the required therapeutic dose is reached, which should not exceed the maximum. The maximum daily dose of the drug Maninil^® 1.75 is 6 tablets (10.5 mg).

If the daily dose of glibenclamide exceeds 3 tablets of the drug Maninil^® 1.75, it is recommended to use the drug Maninil^® 3.5.

Switching from other hypoglycemic drugs to Maninil^® 1.75 should be started under medical supervision with 1-2 tablets of the drug Maninil^® 1.75 per day (1.75-3.5 mg), gradually increasing the dose to the necessary therapeutic dose.

The initial dose of the drug Maninil^® 3.5 is 1/2-1 tablet (1.75-3.5 mg) once a day. If the effect is insufficient, under medical supervision, the dose of the drug is gradually increased until the daily dose necessary for stabilization of carbohydrate metabolism is achieved. The dose increase should be carried out at intervals from several days to 1 week, until the required therapeutic dose is reached, which should not exceed the maximum. The maximum daily dose of the drug Maninil^® 3.5 is 3 tablets (10.5 mg).

Switching from other hypoglycemic drugs to Maninil^® 3.5 should be started under medical supervision with 1/2-1 tablet of the drug Maninil^® 3.5 per day (1.75-3.5 mg), gradually increasing the dose to the necessary therapeutic dose.

The initial dose of the drug Maninil^® 5 is 1/2-1 tablet (2.5-5 mg) once a day. If the effect is insufficient, under medical supervision, the dose of the drug is gradually increased until the daily dose necessary for stabilization of carbohydrate metabolism is achieved. The dose increase should be carried out at intervals from several days to 1 week, until the required therapeutic dose is reached, which should not exceed the maximum. The maximum daily dose of the drug Maninil^® 5 is 3 tablets (15 mg).

Switching from other hypoglycemic drugs to Maninil^® 5 should be started under medical supervision with 1/2-1 tablet of the drug Maninil^® 5 per day (2.5-5 mg), gradually increasing the dose to the necessary therapeutic dose.

In elderly patients, debilitated patients, patients with malnutrition, patients with severe renal or hepatic impairment, the initial and maintenance dose of the drug Maninil^® should be reduced due to the risk of hypoglycemia.

Maninil^® should be taken before meals, without chewing and with a small amount of liquid. Daily doses of the drug up to 2 tablets are usually taken once a day – in the morning, immediately before breakfast. Higher doses are divided into morning and evening intake.

If one dose of the drug is missed, the next tablet should be taken at the usual time, and a higher dose should not be taken.

Adverse Reactions

Definition of frequency of adverse effects: common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (< 1/10,000), including isolated reports.

From the metabolism common – hypoglycemia (feeling of hunger, hyperthermia, tachycardia, drowsiness, weakness, skin moisture, impaired coordination of movements, tremor, general anxiety, feeling of fear, headache, transient neurological disorders, including visual and speech disorders, appearance of paresis or paralysis or altered perception of sensations); weight gain;

From the digestive system uncommon – nausea, feeling of heaviness in the stomach, belching, vomiting, abdominal pain, diarrhea, metallic taste in the mouth.

From the liver and biliary tract very rare – temporary increase in liver enzyme activity, intrahepatic cholestasis, hepatitis.

From the immune system uncommon – itching, urticaria, purpura, petechiae, increased photosensitivity; very rare – generalized allergic reactions accompanied by skin rash, arthralgia, fever, proteinuria and jaundice; allergic vasculitis; anaphylactic shock.

From the hematopoietic system rare – thrombocytopenia; very rare: leukopenia, erythropenia, agranulocytosis; in isolated cases – pancytopenia, hemolytic anemia.

Other very rare – visual impairment and accommodation disorders, increased diuresis, transient proteinuria, hyponatremia, disulfiram-like reaction when taking alcohol (most common signs of the effect: nausea, vomiting, abdominal pain, sensation of heat in the skin of the face and upper body, tachycardia, dizziness, headache), cross-allergy to probenecid, sulfonylurea derivatives, sulfonamides, diuretic agents containing a sulfonamide group in the molecule.

Contraindications

• Hypersensitivity to glibenclamide and/or components included in the drug;
• Hypersensitivity to other sulfonylurea derivatives, sulfonamides, diuretic agents containing a sulfonamide group in the molecule, and to probenecid, because cross-reactions may occur;
• Type 1 diabetes mellitus;
• Diabetic ketoacidosis, diabetic precoma and coma;
• Condition after pancreatic resection;
• Severe hepatic insufficiency;
• Severe renal failure (creatinine clearance less than 30 ml/min);
• Decompensation of carbohydrate metabolism in infectious diseases, burns, injuries or after major surgical operations, when insulin therapy is indicated;
• Leukopenia;
• Intestinal obstruction, gastric paresis;
• Hereditary lactose intolerance, lactase deficiency or glucose and lactose malabsorption syndrome;
• Glucose-6-phosphate dehydrogenase deficiency;
• Pregnancy;
• Lactation period (breastfeeding);
• Children and adolescents under 18 years of age (efficacy and safety have not been studied).

With caution the drug should be prescribed for thyroid diseases (with impaired function), febrile syndrome, hypofunction of the anterior pituitary gland or adrenal cortex, chronic alcoholism, acute alcohol intoxication, in elderly patients (over 70 years old) due to the risk of hypoglycemia.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and the breastfeeding period.

If pregnancy occurs, the drug should be discontinued.

Use in Hepatic Impairment

The drug is contraindicated in severe hepatic insufficiency.

In patients with severe hepatic impairment, the initial and maintenance dose of the drug Maninil^® should be reduced due to the risk of hypoglycemia.

Use in Renal Impairment

The drug is contraindicated in severe renal failure (creatinine clearance less than 30 ml/min).

In patients with severe renal impairment, the initial and maintenance dose of the drug Maninil^® should be reduced due to the risk of hypoglycemia.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

In elderly patients, the initial and maintenance dose of the drug Maninil^® should be reduced due to the risk of hypoglycemia.

Special Precautions

During treatment with the drug Maninil^®, it is necessary to strictly follow the doctor’s recommendations on diet and self-monitoring of blood glucose concentration.

Long-term abstinence from food, insufficient supply of carbohydrates to the body, intense physical activity, diarrhea or vomiting pose a risk of hypoglycemia.

Concomitant use of drugs that affect the central nervous system, lower blood pressure (including beta-blockers), as well as peripheral neuropathy may mask the symptoms of hypoglycemia.

In elderly patients, the risk of hypoglycemia is somewhat higher, so a more careful selection of the drug dose and regular monitoring of blood glucose concentration on an empty stomach and after meals is necessary, especially at the beginning of treatment.

Alcohol can provoke the development of hypoglycemia, as well as the development of a disulfiram-like reaction (nausea, vomiting, abdominal pain, sensation of heat in the skin of the face and upper body, tachycardia, dizziness, headache), so you should refrain from drinking alcohol during treatment with the drug Maninil^®.

Major surgical interventions and injuries, extensive burns, infectious diseases with febrile syndrome may require discontinuation of oral hypoglycemic drugs and the appointment of insulin.

During treatment, prolonged exposure to the sun is not recommended.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, patients should be cautious when driving vehicles and engaging in other potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Overdose

Symptoms hypoglycemia (feeling of hunger, hyperthermia, tachycardia, drowsiness, weakness, skin moisture, impaired coordination of movements, tremor, general anxiety, feeling of fear, headache, transient neurological disorders (e.g., visual and speech disorders, manifestations of paresis or paralysis or altered perception of sensations). With the progression of hypoglycemia, loss of self-control and consciousness by the patient, development of hypoglycemic coma is possible.

Treatment for mild hypoglycemia, the patient should take a piece of sugar, food or drinks high in sugar (jam, honey, a glass of sweet tea) orally. In case of loss of consciousness, it is necessary to administer glucose intravenously – 40-80 ml of a 40% dextrose (glucose) solution, then infusion of a 5-10% dextrose solution. Then, 1 mg of glucagon can be additionally administered intravenously, intramuscularly or subcutaneously. If the patient does not regain consciousness, this measure can be repeated; further intensive therapy may be required.

Drug Interactions

Enhancement of the hypoglycemic effect of the drug Maninil^® is possible with simultaneous use with ACE inhibitors, anabolic agents and male sex hormones, other oral hypoglycemic agents (e.g., acarbose, biguanides) and insulin, azapropazone, NSAIDs, beta-blockers, quinolone derivatives, chloramphenicol, clofibrate and its analogues, coumarin derivatives, disopyramide, fenfluramine, antifungal drugs (miconazole, fluconazole), fluoxetine, MAO inhibitors, PAS, pentoxifylline (in high doses with parenteral administration), perhexiline, pyrazolone derivatives, phosphamides (e.g., cyclophosphamide, ifosfamide, trophosphamide), probenecid, salicylates, sulfonamides, tetracyclines and tritoqualine.

Urine acidifying agents (ammonium chloride, calcium chloride) enhance the effect of the drug Maninil^® by reducing the degree of its dissociation and increasing its reabsorption.

The hypoglycemic effect of the drug Maninil^® may decrease with simultaneous use of barbiturates, isoniazid, diazoxide, corticosteroids, glucagon, nicotinates (in high doses), phenytoin, phenothiazines, rifampicin, thiazide diuretics, acetazolamide, oral contraceptives and estrogens, thyroid hormone preparations, sympathomimetics, slow calcium channel blockers, lithium salts.

H₂-receptor antagonists can, on the one hand, weaken, and on the other hand, enhance the hypoglycemic effect of the drug Maninil^®.

Pentamidine in isolated cases can cause a strong decrease or increase in blood glucose concentration.

When used simultaneously with the drug Maninil^®, the effect of coumarin derivatives may be enhanced or weakened.

Along with enhancing the hypoglycemic effect, beta-blockers, clonidine, guanethidine and reserpine, as well as drugs with a central mechanism of action, can weaken the sensation of precursors of hypoglycemia symptoms.

Storage Conditions

The drug should be stored out of the reach of children. Tablets 1.75 mg and 3.5 mg should be stored at a temperature not exceeding 30°C (86°F), tablets 5 mg – not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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