Glibofor

General characteristics. Structure:

Active ingredients: metformin, glibenclamide;

1 tablet contains Metforminum of a hydrochloride 500 mg, Glibenclamidum of 5 mg;

excipients: sodium krakhmalglikolit (type A), povidone (K-30), silicon dioxide colloid anhydrous, magnesium stearate;

structure of a film cover: Opadry Yellow 04G82949 (gipromeloza, talc, titanium dioxide (Е 171), polyethyleneglycol 6000, propylene glycol, ferrous oxide yellow (Е 172), quinolinic yellow (Е 104)).

Pharmacological properties:

Pharmacodynamics. Glibofor – the combined drug of two peroral hypoglycemic means of different pharmacological groups: Metforminum and Glibenclamidum.

Metforminum reduces a hyperglycemia, does not lead to development of a hypoglycemia. Unlike sulphonylurea does not stimulate secretion of insulin and does not render hypoglycemic effect at healthy volunteers. Reduces in plasma both the initial level of glucose, and glucose level after meal.

Metforminum works in three ways:

- causes decrease in production of glucose in a liver at the expense of inhibition of a gluconeogenesis and a glycogenolysis;

- improves capture and utilization of peripheral glucose in muscles due to increase in sensitivity to insulin;

- slows down absorption of glucose in intestines.

Metforminum stimulates intracellular synthesis of a glycogen, influencing a glikogensintetaza.

Increases the transport volume of all types of membrane carriers of glucose (GLUT).

Irrespective of the action on a glycemia Metforminum renders positive effect on metabolism of lipids: reduces the content of the general cholesterol, lipoproteins of low density and triglycerides.

Glibenclamidum – derivative sulphonylurea of the second generation. Causes decrease in level of glucose in blood, stimulates production of insulin with a pancreas. This action depends on existence of the functioning beta cells (Langergants's islands).

Metforminum and Glibenclamidum possess different mechanisms a deysviya, however their actions complementary. Glibenclamidum stimulates a pancreas to production of insulin, and Metforminum increases sensitivity of peripheral receptors to insulin and glucose utilization by cells. Brakes a gluconeogenesis in a liver. Slows down absorption of carbohydrates in intestines.

Pharmacokinetics. Absorption. After reception of a peroral dose of Metforminum time of achievement of the maximum concentration (Tmax) makes 2,5 hours. Absolute bioavailability of Metforminum for tablets of 500 mg or 850 mg makes about 50-60% at healthy people. After intake Metforminum is absorbed from a digestive tract, 20-30% are removed with excrements.

Distribution. Linkng with proteins of plasma insignificant. Metforminum gets into erythrocytes. The maximum concentration in blood below the maximum concentration in plasma, is also reached practically at the same time. Erythrocytes most likely represent the second camera of distribution. The average volume of distribution (Vd) fluctuates in the range of 63-276 l.

Metabolism. Metformin is removed in not changed view with urine. Metabolites at the person are not revealed.

Removal. The renal clearance of Metforminum makes> 400 ml/min., it indicates that metformin is removed due to glomerular filtering and canalicular secretion. After reception of a dose inside the elimination half-life makes about 6,5 hours. At an impaired renal function the renal clearance decreases in proportion to clearance of creatinine and therefore the elimination half-life increases that leads to increase in level of Metforminum in plasma.

Glibenclamidum. After intake absorption makes    48-84% of digestive tract. Time of achievement of the maximum concentration – 1-2 hours, distribution volume –      9-10 l. Linkng with proteins of plasma makes 95%. Almost the second is completely metabolized in a liver with formation of two inactive metabolites, one of which is brought by kidneys, and – bile. An elimination half-life – from 3 to 10-16 hours.
Pharmaceutical characteristic

Main physical and chemical properties: tablets of the extended form with a biconvex surface of yellow color, film coated, with a text on one party of "U 24".

Indications to use:

Treatment of a diabetes mellitus of the II type at adults, for substitution of the previous therapy by Metforminum combination with Glibenclamidum at patients with stable and well controlled glycemia.

Route of administration and doses:

Apply inside during meal. The dose is defined by the doctor individually depending on glycemia level.

At substitution of a combination therapy with Metforminum and Glibenclamidum treatment by drug Glibofor is begun in doses according to the previous dosage. Each 2 weeks after an initiation of treatment adjust a dose of drug depending on results of measurements of level of a glycemia.

Gradual increase in a dose promotes decrease in side effects from a digestive tract and prevents development of a hypoglycemia.

The maximum recommended dose makes 3 tablets of Glibofor a day.

In individual cases the dose can be raised to 4 tablets a day.

The mode of dosing depends individually on indications:
1 tablet a day: during a breakfast;
2 or 4 tablets a day: in the morning and in the evening;
3 tablets a day: in the morning, in the afternoon and in the evening.

For prevention of emergence of hypoglycemic episodes it is necessary to eat  food rich with vuglevoda.

Glibofor with insulin is not present data on joint therapy of drug.

At patients of advanced age the dosage of drug is adjusted depending on parameters of function of kidneys, it is regularly necessary to carry out assessment of function of kidneys (see the section "Features of Use").

Features of use:

Use during pregnancy or feeding by a breast

Data on use of drug during pregnancy are absent.

When planning pregnancy, and also in case of its approach during drug use, Glibofor it is necessary to cancel, notify the doctor and to appoint an insulin therapy.

Data on a priniknoveniya of Metforminum and Glibenclamidum in breast milk are absent therefore drug is contraindicated to use during feeding by a breast.
Children

Do not apply in pediatric practice.

Lactacidemia – the rare, but heavy metabolic complication resulting from hydrochloride Metforminum cumulation. Cases of emergence of a lactacidemia at patients with a diabetes mellitus and a liver failure of heavy degree are registered. Risk factors of emergence of a lactacidemia: badly adjustable diabetes mellitus, a ketosis, long starvation, excessive alcohol intake, a liver failure or any state connected with a hypoxia.

The lactacidemia is characterized by muscular spasms, an atsidozny asthma, abdominal pains and a hypothermia, development of a coma is possible further. At suspicion on a lactacidemia it is necessary to stop use of drug and to immediately hospitalize the patient.

Hypoglycemia. Drug Glibofor contains sulphonylurea therefore the patients applying this medicine, podverdzhena to risk of development of a hypoglycemia. After the beginning of therapy titration of a dose of drug can prevent development of a hypoglycemia. Drug is appointed to patients who adhere to the regular schedule of meal (including a breakfast). The regular use of carbohydrates is an important factor as the risk of development of a hypoglycemia increases in case of untimely meal, the insufficient or unbalanced use of carbohydrates. The hypoglycemia most often arises at patients who are on a low-calorie diet, after intensive or long exercises, at alcohol intake or at a combination therapy hypoglycemic means.

Hypoglycemia symptoms: headache, feeling of hunger, nausea, vomiting, strong fatigue, sleep disorders, concern, attacks of aggression, disturbance of concentration and reactions, depression, confusion of consciousness, defects of the speech, vision disorder, shiver, paralysis, paresthesia, dizziness, delirium, spasms, drowsiness, loss of consciousness, shallow breathing, bradycardia.

At moderate symptoms of a hypoglycemia without loss of consciousness or neurologic manifestations it is necessary to accept sugar at once. It is necessary to provide dose adjustment of drug and/or to otkorregirovat a food allowance. Heavy hypoglycemic reactions with a coma, spasms and other neurologic signs which can cause medical emergencies are possible. It demands the emergency treatment with intravenous administration of glucose at establishment of the diagnosis or suspicion on a hypoglycemia before hospitalization of the patient.

Selection of patients, dose adjustment, and also providing necessary instructions to patients is important for decrease in risk of development of a hypoglycemia. If patients have repeated episodes of a hypoglycemia of heavy degree, it is necessary to consider the possibility of other options of treatment.

The factors promoting emergence of a hypoglycemia:

- a concomitant use of alcohol, especially together with starvation;

- refusal (especially at patients of advanced age) or inability of patients to implement recommendations of the doctor;

- irregular meal, malnutrition, the missed meal, starvation or change of a diet;

- the wrong ratio between physical exercises and the use of carbohydrates;

- renal failure;

- heavy liver failure;

- overdose by drug Glibofor;

- some endocrine disturbances: insufficiency of function of a thyroid gland,   insufficiency of function of a hypophysis and adrenal glands;

- a concomitant use of some drugs (see the section "Vzaimodeystviyesdrugy medicines idrugy types of interactions").

Pochechnaya the liver failure at patients can change pharmacokinetics and/or a pharmacodynamics of drug. If this category of patients has a hypoglycemia, she can become chronic and demands the corresponding treatment.

Glucose level imbalance in blood.

In case of impossibility of administration of drug Glibofor (carrying out surgical interventions or other reasons) it is necessary to provide temporary insulin therapy. Hyperglycemia symptoms: the increased urination, strong thirst, a xeroderma.

Kidneys. As metformin is removed by kidneys, before the beginning and during treatment by drug Glibofor it is necessary to check creatinine level in blood serum, especially at patients with an impaired renal function and at patients of advanced age. It is necessary to show care when function of kidneys, for example, in an initiation of treatment by antihypertensives, diuretics and at the beginning of therapy by non-steroidal anti-inflammatory drugs can be broken.

Yodosoderzhashchy rentgenokontrastnyesredstvo. When carrying out radiological researches using X-ray contrast means it is necessary to stop use of drug in 48 hours prior to carrying out a research and not to renew earlier than in 48 hours after X-ray inspection and assessment of function of kidneys.

The concomitant use of Glibenclamidum with etanolsoderzhashchy medicines, phenylbutazone or danazoly is not recommended (see the section "Vzaimodeystviyes Other Medicines Idrugy Types of Interactions").

Hirurgicheskiyevmeshatelstva. It is necessary to stop Glibofor's use in 48 hours prior to the planned surgical intervention which is carried out under the general, spinal or peridural anesthesia and not to renew earlier than in 48 hours after carrying out operation and assessment of function of kidneys.

Precautionary measures.

Patients need to adhere to a diet, it is correct to distribute the use of carbohydrates for day. Patients with an excess weight need to adhere to a low-calorie diet.

During therapy by drug it is necessary to carry out physical exercises. It is necessary to control laboratory indicators regularly.

Treatment of patients with insufficiency of G6DF using sulphonylurea can lead to development of hemolitic anemia. As Glibenclamidum is included into this chemical class, it is necessary to apply with extra care Glibofor to patients with insufficiency of G6DF.

The patients having rare hereditary intolerance of a galactose, a lactose intolerance or disturbances of absorption of glucose galactose should not use drug.
Ability to influence speed of response at control of motor transport or work with other mechanisms

During treatment by Glibofor it is necessary to manage with extra care motor transport or to work with other mechanisms because of risk of development of a hypoglycemia.

Side effects:

Undesirable effects on the frequency of emergence classify by such categories: very often (≥ 1/10), it is frequent (≥ 1/100 and <1/10), infrequently (≥ 1/1000 and <1/100), is rare (> 1/10000 and <1/1000), is very rare (<1/10000).

Sostorona of a kroviya of lymphatic system. The reversible tests disappearing after the treatment termination.

Seldom: leukopenia, thrombocytopenia.

Very seldom: agranulocytosis, hemolitic anemia, marrow aplasia, megaloblastny anemia, pancytopenia.

From a nervous system.

Often: taste disturbances, metal smack in a mouth.

With стороныглаз. Short-term visual disturbances can arise in an initiation of treatment in connection with decrease in level of a glycemia.

From a storonypishchevaritelny path.

Very often: nausea, vomiting, diarrhea, abdominal pain, meteorism, lack of appetite. Most often these by-effects arise in an initiation of treatment and, as a rule, spontaneously disappear. For the prevention of emergence of by-effects from a digestive tract gradual increase in a dosage and use of drug 2-3 times a day is recommended.

From skin and hypodermic cellulose.

Seldom: skin reactions (itch, urticaria, rozeolezny rash).

Very seldom: skin or visceral allergic vasculitis, multiformny erythema, exfoliative dermatitis, photosensitization, small tortoiseshell.

Metabolism. A hypoglycemia (see the section "Osobennostiprimeneniya").

Infrequently: acute hepatic porphyria, skin porphyria.

Very seldom: lactacidemia.

At prolonged use of drug B12 vitamin absorption can decrease that is followed by decrease in its level in blood serum. It is observed at patients with megaloblastny anemia. Disulfirampodobny reaction at alcohol intake.

From a liver.

Very seldom: the disturbance of indicators of function of a liver or hepatitises demanding the treatment termination.

Laboratory indicators.

Infrequently: moderate increase in level of urea and creatinine in blood serum.

Very seldom: hyponatremia.

Interaction with other medicines:

Interactions which are contraindicated.

In relation to Glibenclamidum.

- Miconazolum (for system use, oral cavity gel) – strengthens hypoglycemic action with possible manifestations of a hypoglycemia or even coma.

Unrecommended interactions.

On отношениюк to sulphonylurea.

- Alcohol - effect of Antabusum (intolerance of alcohol), especially for Chlorproramidum, Glibenclamidum, a glipizid, Tolbutamidum. It is necessary to avoid alcohol intake and use of the medicines containing alcohol.

- Phenylbutazone (for system use) – strengthens effect of sulphonylurea. It is recommended to apply other antiinflammatory medicine having the smaller number of interactions or to warn the patient and to strengthen self-checking. If necessary the dose of drug should be modified during reception and after phase-out of anti-inflammatory drugs.

In relation to all anti-diabetic drugs.

- Danazol – if this combination is obligatory, it is necessary to warn the patient about strengthening of self-checking of indicators of level of glucose in blood. If necessary the dose of drug should be modified during reception and after phase-out of a danazol.

In relation to Metforminum.

- Ethanol – the increased risk of lactoacidosis during an acute drunkenness, especially at starvation, malnutrition or a liver failure.

- Yodosoderzhashchy radiopaque substances – intravascular introduction of contrast means can lead to a renal failure. It can cause accumulation of Metforminum in an organism and lactoacidosis. Drug use Glibofor should be stopped before carrying out radiological researches and not to renew earlier than in 48 hours after X-ray inspection with use of radiopaque substances and after repeated assessment of function of kidneys.

Combinations, which следуетприменятьс care.

In relation to all anti-diabetic drugs.

Chlorpromazinum – at reception of high doses (100 mg of Chlorpromazinum) raises glucose level in blood (decrease in production of insulin). It is necessary to warn the patient and to strengthen self-checking of indicators of level of glucose in blood. Whenever possible the dose of drug should be modified during reception and after phase-out of a hlopromazin.

Glucocorticosteroids and tetrakozaktida (systemic and local action) – increase in level of glucose in blood that sometimes is followed by a ketosis. Whenever possible the dose of drug should be modified during reception and after phase-out of corticosteroids.

β2-симпатомиметики - increase in level of glucose in blood. It is necessary to warn the patient, to strengthen control of level of glucose in blood, whenever possible to transfer the patient to therapy by insulin.

APF inhibitors (for example captopril, enalapril) – can reduce glucose level in blood. If necessary it is necessary to modify Glibofor's dose during reception and after phase-out of APF inhibitors.

In relation to Metforminum.

Diuretics – the development of a lactacidemia owing to use of Metforminum against the background of a functional renal failure connected with reception of diuretics, especially loopback diuretics.

In relation to Glibenclamidum.

β-blockers - - - - - - - - - – mask hypoglycemia symptoms: the accelerated heartbeat and tachycardia. The majority of non-selective β-blockers increase the frequency of emergence and severity of a hypoglycemia. The patient needs to control glucose level in blood, especially in an initiation of treatment.

Flukonazol – lengthening of an elimination half-life of sulphonylurea with possible manifestations of a hypoglycemia. Whenever possible the dose of drug should be modified during reception and after phase-out of a flukonazol.

Bozentan – risk of weakening of effect of glibenclamide as бозентан reduces concentration of Glibenclamidum in a blood plasma. At a concomitant use there is a risk of increase in levels of enzymes of a liver. The patient needs to control glucose level in blood and level of liver enzymes. If necessary it is necessary to modify a dose of anti-diabetic drug.

Interactions which to sleduyetuchityvat.

In relation to Glibenclamidum.

Desmopressin – reduction of antidiuretic action.

Contraindications:

Hypersensitivity to Metforminum, Glibenclamidum, to other components of drug or other derivatives of sulphonylurea, to sulfonamides;
diabetes of the I type; diabetic ketoacidosis, diabetic prekoma;
renal failure (clearance of creatinine <60 ml/min.);
the acute diseases proceeding with risk of development of renal failures: dehydration, serious infectious diseases, shock, intravascular introduction of yodosoderzhashchy contrast means;
acute and chronic diseases which can lead to development of a hypoxia (heart or respiratory failure, an acute myocardial infarction, shock);
liver failure, acute drunkenness, alcoholism;
porphyria;
concomitant use of Miconazolum (see the section "Interaction with Other Medicines and Other Types of Interactions").

Overdose:

The overdose can lead to development of a hypoglycemia as drug contains sulphonylurea. Considerable overdose or existence of concurrent factors of risk can lead to development of a lactacidemia (see the section "Osobennostiprimeneniya") that demands removal from an organism of a lactate and Metforminum by means of a hemodialysis.

Patients can have a long clearance of Glibenclamidum with the broken function of a liver.

Due to dense communication with proteins glibenclamide is not removed during a hemodialysis.

Storage conditions:

Period of validity. 3 years from the date of production of in bulk. Not to use drug after the termination of the period of validity specified on packaging. To store in the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister. On 3, 6 or 10 blisters enclosed in a pack (packaging from the "in bulk" form of USV Limited manufacturing, India).