Глюкованс®

General characteristics. Structure:

Dosage of 2,5 mg +500 mg:

Active components: Glibenclamidum - 2,5 mg, Metforminum a hydrochloride - 500 mg.

Auxiliary components:

Kernel: croscarmellose sodium - 14,0 mg, povidone To 30 - 20,0 mg, cellulose microcrystallic - 56,5 mg, magnesium stearate - 7,0 mg.

Cover: опадрай OY-L-24808 pink - 12,0 mg: lactoses monohydrate - 36,0%, a gipromelloza 15 Wednesday - 28,0%, titanium dioxide - 24,39%, a macrogoal - 10,00%, ferrous oxide yellow - 1,30%, ferrous oxide red - 0,3%, ferrous oxide black - 0,010%; the water purified - q.s.

Dosage of 5 mg +500 mg:

Active components: Glibenclamidum - 5 mg, Metforminum a hydrochloride - 500 mg.

Auxiliary components:

Kernel: croscarmellose sodium - 14,0 mg, povidone To 30 - 20,0 mg, cellulose microcrystallic - 54,0 mg, magnesium stearate - 7,0 mg.

Cover: опадрай 31-F-22700 yellow - 12,0 mg: lactoses monohydrate - 36,0%, a gipromelloza 15 Wednesday - 28,0%, titanium dioxide - 20,42%, a macrogoal - 10,00%, dye quinoline yellow - 3,00%, ferrous oxide yellow - 2,50%, ferrous oxide red - 0,08%; the water purified - q.s.

Description
Dosage of 2,5 mg +500 mg: kapsulovidny biconvex tablets, film coated light orange color, with an engraving "2,5" on one party.
Dosage of 5 mg +500 mg: kapsulovidny biconvex tablets, film coated yellow color, with an engraving "5" on one party.

Pharmacological properties:

Глюкованс® represents the fixed combination of two peroral hypoglycemic means of various pharmacological groups: Metforminum and Glibenclamidum.

Metforminum concerns to group of guanyl guanidines and reduces the content of both basal, and postprandialny glucose in a blood plasma. Metforminum does not stimulate secretion of insulin and in this regard does not cause a hypoglycemia. Has 3 mechanisms of action:
• reduces production of glucose liver at the expense of inhibition of a gluconeogenesis and a glycogenolysis;
• increases sensitivity of peripheral receptors to insulin, consumption and utilization of glucose cells in muscles;
• absorption of glucose in digestive tract detains.

Drug also has favorable effect on lipidic composition of blood, reducing the level of the general cholesterol, lipoproteins of the low density (LPNP) and triglycerides.

Glibenclamidum concerns to group of derivatives of sulphonylurea II of generation. Content of glucose at reception of Glibenclamidum decreases as a result of insulin secretion stimulation by pancreas b-cells.

Metforminum and Glibenclamidum have various mechanisms of action, but mutually supplement hypoglycemic activity of each other. The combination of two hypoglycemic means has synergy effect in decrease in content of glucose.

Pharmacokinetics
Glibenclamidum. At intake absorption makes more than 95% of digestive tract. Glibenclamidum which is a part of the drug Glyukovans® is micronized. The peak of concentration in plasma is reached approximately in 4 hours, distribution volume - about 10 l. Communication with proteins of plasma makes 99%. Almost it is completely metabolized in a liver with formation of two inactive metabolites which are removed by kidneys (40%) and with bile (60%). An elimination half-life – from 4 to 11 hours.

Metforminum after intake is absorbed from digestive tract rather fully, the peak of concentration in plasma is reached within 2,5 hours. About 20-30% of metformin are removed through digestive tract in an invariable look. Absolute bioavailability makes from 50 to 60%.

Metforminum is quickly distributed in fabrics, practically does not contact proteins of plasma. Is exposed to metabolism in very weak degree and it is removed by kidneys. The elimination half-life averages 6,5 hours. At a renal failure, the renal clearance decreases as well as the clearance of creatinine, at the same time an elimination half-life increases that leads to increase in concentration of Metforminum in a blood plasma. The combination of Metforminum and Glibenclamidum in one dosage form has the same bioavailability, as at reception of the tablets containing Metforminum or Glibenclamidum separately. On bioavailability of Metforminum in combination with Glibenclamidum meal, as well as does not influence bioavailability of Glibenclamidum. However the speed of absorption of Glibenclamidum increases at meal.

Indications to use:

Diabetes mellitus 2 types at adults:
• at inefficiency of a dietotherapy, physical exercises and the previous monotherapy by Metforminum or derivatives of sulphonylurea;
• for substitution of the previous therapy by two drugs (Metforminum and to sulphonylurea derivatives) at patients with the stable and well controlled level of a glycemia.

Route of administration and doses:

The dose of drug is defined by the doctor individually for each patient depending on glycemia level.

The initial dose makes 1 tablet of the drug Глюкованс® 2,5 of mg of +500 mg or Глюкованс® 5 mg +500 mg once a day. In order to avoid a hypoglycemia the initial dose should not exceed a day dose of Glibenclamidum (or an equivalent dose of other earlier accepted sulphonylurea drug) or Metforminum if they were applied as therapy of the first line. It is recommended to increase a dose no more than by 5 mg of Glibenclamidum + 500 mg of Metforminum a day each 2 or more weeks for achievement of adequate control of content of glucose in blood.

Substitution of the previous combination therapy Metforminum and Glibenclamidum: the initial dose should not exceed a day dose of Glibenclamidum (or an equivalent dose of other drug of sulphonylurea) and Metforminum, accepted earlier. Each 2 or more weeks after an initiation of treatment adjust a dose of drug depending on glycemia level.

The maximum daily dose makes 4 tablets of the drug Глюкованс® 5 of mg of +500 mg or 6 tablets of the drug Глюкованс® 2,5 of mg of +500 mg.

Dosing mode:
The mode of dosing depends on individual appointment:

For dosages of 2,5 mg +500 mg and 5 mg +500 mg
• Once a day, in the morning during a breakfast, at purpose of 1 tablet in day.
• Twice a day, in the morning and in the evening, at purpose of 2 or 4 tablets in day.

For a dosage of 2,5 mg +500 mg
• Three times a day, in the morning, in the afternoon and in the evening, at purpose of 3, 5 or 6 tablets in day.

For a dosage of 5 mg +500 mg
• Three times a day, in the morning, in the afternoon and in the evening, at purpose of 3 tablets in day.

Pill should be taken during food. Each administration of drug has to be followed meal with rather high content of carbohydrates for prevention of emergence of a hypoglycemia.

Elderly patients
The dose of drug is selected proceeding from a condition of function of kidneys. The initial dose should not exceed 1 tablet of the drug Глюкованс® 2.5 of mg of +500 mg. It is necessary to carry out regular assessment of function of kidneys.

Children
The drug Glyukovans® is not recommended for use for children.

Features of use:

Against the background of treatment by the drug Glyukovans® it is regularly necessary to control glycemia level on an empty stomach and after food.

Lactoacidosis
Lactoacidosis is extremely rare, but serious (high mortality in the absence of urgent treatment) a complication which can arise because of Metforminum cumulation. Lactoacidosis cases at the patients receiving Metforminum arose generally at patients with a diabetes mellitus with the expressed renal failure.

It is necessary to consider also other interfaced risk factors, such as badly controlled diabetes, ketosis, long starvation, alcohol overconsumption, liver failure and any state connected with the expressed hypoxia.

It is necessary to consider risk of development of lactoacidosis at emergence of nonspecific signs such as the muscular spasms which are followed by dispepsichesky frustration, an abdominal pain and strong indisposition. In hard cases an atsidotichesky asthma, a hypoxia, a hypothermia and a coma can be noted.

Diagnostic laboratory indicators are: the low indicator рН blood, concentration of a lactate in plasma is higher than 5 mmol/l, the raised anion interval and a ratio lactate/pyruvate.

Hypoglycemia
As Glyukovans® contains Glibenclamidum, administration of drug is followed by risk of emergence of a hypoglycemia at the patient. Gradual titration of a dose after an initiation of treatment can prevent emergence of a hypoglycemia. This treatment can be appointed only to the patient adhering to the mode of regular meal (including a breakfast). It is important that consumption of carbohydrates was regular as the risk of development of a hypoglycemia increases at the late meal insufficient or unbalanced consumption of carbohydrates. Development of a hypoglycemia is most probable at a hypocaloric diet, after an intensive or long exercise stress, at alcohol intake or at reception of a combination of hypoglycemic means.

Because of the compensatory reactions caused by a hypoglycemia there can be a perspiration, fear, tachycardia, hypertensia, heartbeat, stenocardia and arrhythmia. The last symptoms can be absent if the hypoglycemia develops slowly, in case of vegetative neuropathy or at a concomitant use of beta adrenoblockers, a clonidine, Reserpinum, a guanetidin or sympathomimetics.

At patients with a diabetes mellitus the headache, hunger, nausea, vomiting, the expressed fatigue, frustration of a dream, the excited state, aggression, disturbance of concentration of attention and psychomotor reactions, a depression, confusion of consciousness, disturbance of the speech, a vision disorder, a shiver, paralysis and paresthesia, dizziness, a delirium, spasms, a somnolention, unconsciousness, shallow breathing and bradycardia can be other symptoms of a hypoglycemia.

Careful purpose of drug, selection of a dose and appropriate instructions for the patient are important for decrease in risk of development of a hypoglycemia. If at the patient hypoglycemia attacks which are either heavy, or connected with ignorance of symptoms repeat, it is necessary to consider the possibility of treatment by other hypoglycemic means.

The factors promoting development of a hypoglycemia:
• Simultaneous alcohol intake, especially at starvation,
• Refusal or (especially concerns elderly patients) inability of the patient to interact with the doctor and to follow the recommendations stated in the application instruction
• Bad food, irregular meal, starvation or changes in a diet,
• An imbalance between an exercise stress and reception of carbohydrates,
• Renal failure,
• Heavy liver failure,
• Drug Glyukovans® overdose,
• Separate endocrine disturbances: insufficiency of function of a thyroid gland, hypophysis and adrenal glands,
• Concomitant use of separate medicines.

Renal and liver failure
The pharmacokinetics and/or pharmacodynamics can change at patients with a liver failure or a heavy renal failure. The hypoglycemia arising at such patients can be long, in this case the corresponding treatment has to be begun.

Instability of content of glucose in blood
In case of surgical intervention or other reason of a decompensation of diabetes, it is recommended to provide temporary transition to an insulin therapy. Symptoms of a hyperglycemia are the speeded-up urination, the expressed thirst, a xeroderma.

In 48 hours prior to planned surgical intervention or intravenous administration of iodinated X-ray contrast means administration of drug of Glyukovans® should be stopped. Treatment is recommended to be resumed in 48 hours, and only after function of kidneys was estimated and recognized as normal.

Function of kidneys
As metformin is removed by kidneys, before an initiation of treatment, and is regular in the subsequent, it is necessary to define clearance of creatinine and/or content of creatinine in blood serum: at least once a year at patients with normal function of kidneys, and 2-4 times a year at elderly patients, and also at patients with clearance of creatinine on the upper bound of norm.

It is recommended to observe extra care in cases when function of kidneys can be broken, for example, at elderly patients, or in case of the beginning of anti-hypertensive therapy, reception of diuretics or non-steroidal anti-inflammatory drugs (NPVP).

Other precautionary measures
The patient has to report to the doctor about emergence of a bronchopulmonary infection or infectious disease of urinogenital bodies.

Influence on ability to drive the car and to work with mechanisms
Patients have to be informed on risk of emergence of a hypoglycemia and have to observe precautionary measures during the driving and work with the mechanisms demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

 the treatment course the following side effects can be observed by the drug Glyukovans®.

Frequency of side effects of drug is regarded as follows:
Very frequent: ≥ 1/10
Frequent: ≥ 1/100, <1/10
Infrequent: ≥ 1/1000, <1/100
Rare: ≥ 1/10 000, <1/1000
Very rare: <1/10 000
Single: cannot be estimated at the available data.

Disbolism:
Hypoglycemia (See. "Overdose", "Special instructions").
Seldom: Attacks of a hepatic porphyria and skin porphyria.
Very seldom: lactoacidosis (See. "Special instructions").

The decrease in absorption of B12 vitamin which was followed by decrease in its concentration in blood serum at prolonged use of Metforminum. At detection of megaloblastny anemia it is necessary to consider a possibility of such etiology.

Disulfirampodobny reaction at alcohol intake.

Laboratory indicators:
Infrequently: Increase in concentration of urea and creatinine in blood serum from average to moderate degree.
Very seldom: Hyponatremia.

Circulatory and lymphatic systems:
These undesirable phenomena disappear after drug withdrawal.
Seldom: Leukopenia and thrombocytopenia.
Very seldom: Agranulocytosis, hemolitic anemia, aplasia of marrow and pancytopenia.

Nervous system:
Often: Taste disturbance (metal smack in a mouth).

Sight:
In an initiation of treatment there can be a temporary vision disorder because of decrease in content of glucose in blood.

Gastrointestinal disturbances:
Very often: nausea, vomiting, diarrhea, abdominal pains and lack of appetite. These symptoms meet in an initiation of treatment more often and in most cases pass independently. For prevention of development of the specified symptoms it is recommended to accept drug in 2 or 3 receptions; slow increase in a dose of drug also improves its portability.

Skin and hypodermic cellulose:
Seldom: skin reactions such as itch, urticaria, makulopapulezny rash.
Very seldom: skin or visceral allergic vasculitis, polymorphic erythema, exfoliative dermatitis, photosensitization.

Immunological reactions:
Very seldom: Acute anaphylaxis.

Reactions of cross hypersensitivity to sulfonamides and their derivatives can meet.

Gepato-biliarnye frustration:
Very seldom: The disturbance of indicators of function of a liver or hepatitis demanding the treatment termination.

Interaction with other medicines:

Contraindicated combinations

Connected using Glibenclamidum
Miconazolum can provoke development of a hypoglycemia (up to development of a coma).

Connected using Metforminum
Iodinated contrast means: Depending on function of kidneys administration of drug should be stopped in 48 hours prior to or after intravenous administration of iodinated contrast means.

Not recommended combinations

Connected using sulphonylurea derivatives

Alcohol: Antabusny reaction (intolerance of alcohol) at a concomitant use of alcohol and Glibenclamidum is very seldom observed.

Alcohol intake can increase hypoglycemic action (by means of inhibition of compensatory reactions or a delay of its metabolic inactivation) that can promote development of a hypoglycemic coma. During treatment by the drug Glyukovans® it is necessary to avoid the alcohol intake and medicines containing alcohol.

Phenylbutazone increases hypoglycemic effect of derivatives of sulphonylurea (replacing sulphonylurea derivatives in places of protein-binding and/or reducing their elimination). It is preferable to use other anti-inflammatory drugs finding smaller interactions or to warn the patient about need of independent control of level of a glycemia; if necessary, it is necessary to correct a dose at combined use of anti-inflammatory drug and after its termination.

Connected using Glibenclamidum

Bozentan in a combination with Glibenclamidum increases risk of a hepatotoxic action. It is recommended to avoid a concomitant use of these drugs. Also the hypoglycemic effect of Glibenclamidum can decrease.

Connected using Metforminum

Alcohol: The risk of development of lactoacidosis amplifies at an acute drunkenness, especially in case of starvation, either bad food, or a liver failure. During treatment by the drug Glyukovans® it is necessary to avoid the alcohol intake and medicines containing alcohol.

The combinations demanding care

Connected using all hypoglycemic means

Chlorpromazinum: in high doses (100 mg/days) causes increase in level of a glycemia (reducing insulin emission).

Precautionary measures: it is necessary to warn the patient about need of independent control of content of glucose for blood; if necessary, correct a dose of hypoglycemic means during simultaneous use of a neuroleptic and after the termination of its use.

Glucocorticosteroids (GKS) and тетракозактид: the increase in blood of content of glucose which sometimes is followed by a ketosis (GKS cause decrease in tolerance to glucose).

Precautionary measures: it is necessary to warn the patient about need of independent control of content of glucose for blood; if necessary, it is necessary to correct a dose of hypoglycemic means during simultaneous use of GKS and after the termination of their use.

Danazol has hyper glycemic effect. In need of treatment danazoly and at the termination of reception of the last dose adjustment of the drug Glyukovans® under control of level of a glycemia is required.

b2-adrenomimetik: due to stimulation of b2-adrenoceptors increase concentration of glucose in blood.

Precautionary measures: it is necessary to warn the patient and to establish control of content of glucose in blood, transfer into an insulin therapy is possible.

Diuretics: increase in content of glucose in blood. Precautionary measures: it is necessary to warn the patient about need of independent control of content of glucose for blood; dose adjustment of hypoglycemic means can be required during simultaneous use with diuretics and after the termination of their use.

Inhibitors of an angiotensin-converting enzyme (APF) (captopril, enalapril): use of APF inhibitors promotes decrease in content of glucose in blood. If necessary it is necessary to correct a drug Glyukovans® dose during simultaneous use with APF inhibitors and after the termination of their use.

Connected using Metforminum

Diuretics: The lactoacidosis arising at reception of Metforminum against the background of the functional renal failure caused by reception of diuretics, in particular loopback.

Connected using Glibenclamidum

b-adrenoblockers, clonidine, Reserpinum, гуанетидин and sympathomimetics mask some symptoms of a hypoglycemia: heartbeat and tachycardia; the majority of non-selective beta adrenoblockers increase the frequency of development and weight of a hypoglycemia.

It is necessary to warn the patient about need of independent control of content of glucose for blood, especially in an initiation of treatment.

Flukonazol: Increase in an elimination half-life of Glibenclamidum with possible emergence of manifestations of a hypoglycemia. It is necessary to warn the patient about need of independent control of content of glucose for blood; correction of a dose of hypoglycemic drugs can be required during simultaneous treatment flukonazoly and after the termination of its use.

Other interactions: combinations which should be taken into account:

Connected using Glibenclamidum

Desmopressin: Глюкованс® can reduce antidiuretic effect of desmopressin.

Antibacterial HP from group of streptocides, ftorkhinolona, anticoagulants (coumarin derivatives), MAO inhibitors, chloramphenicol, пентоксифиллин, hypolipidemic HP from group of fibrat, Disopyramidum - risk of development of a hypoglycemia against the background of Glibenclamidum use.

Contraindications:

• hypersensitivity to Metforminum, Glibenclamidum or other derivatives of sulphonylurea, and also to excipients;
• diabetes mellitus of 1 type;
• diabetic ketoacidosis, diabetic prekoma, diabetic coma;
• renal failure or renal failure (clearance of creatinine less than 60 ml/min.);
• acute states which can lead to change of function of kidneys: dehydration, a heavy infection, shock, intravascular introduction of iodinated contrast means (see. "Special instructions");
• acute or chronic diseases which are followed by a hypoxia of fabrics: heart or respiratory failure, recently postponed myocardial infarction, shock;
• liver failure;
• porphyria;
• pregnancy, breastfeeding period;
• concomitant use of Miconazolum;
• extensive surgeries;
• alcoholism, acute drunkenness;
• lactoacidosis (including in the anamnesis);
• observance of a hypocaloric diet (less than 1000 кал / days);

It is not recommended to use drug at persons 60 years performing hard physical activity that is connected with the increased risk of development of lactoacidosis at them are more senior.

Глюкованс® contains lactose therefore its use is not recommended to patients with the rare hereditary diseases connected with intolerance of a galactose, deficit of lactase or a syndrome of glyukozo-galaktozny malabsorption.

With care: a feverish syndrome, adrenal insufficiency, hypofunction of a front share of a hypophysis, a disease of a thyroid gland with noncompensated disturbance of its function.

Use during pregnancy and during breastfeeding
Use of drug is contraindicated during pregnancy. The patient has to be warned that during treatment by the drug Glyukovans® it is necessary to inform the doctor on the planned pregnancy and on pregnancy approach. When planning pregnancy, and also in case of approach of pregnancy during administration of drug of Glyukovans®, drug has to be cancelled, and treatment is appointed insulin.

Глюкованс® it is contraindicated when breastfeeding as there are no data on its ability to get into breast milk.

Overdose:

At overdose development of a hypoglycemia because of existence derivative sulphonylurea as a part of drug is possible (see. "Special instructions").

Easy and moderate symptoms of a hypoglycemia without loss of consciousness and neurologic manifestations can be corrected by immediate consumption of sugar. It is necessary to execute correction of a dose and/or to change a diet. Emergence of heavy hypoglycemic reactions demands rendering emergency medical service from the patients with a diabetes mellitus who are followed by a coma, a paroxysm or other neurologic frustration. Intravenous administration of solution of a dextrose right after establishment of the diagnosis or emergence of suspicion on a hypoglycemia, before hospitalization of the patient is necessary. After recovery of consciousness it is necessary to give to the patient the food rich with digestible carbohydrates (in order to avoid repeated development of a hypoglycemia).

The long overdose or existence of the interfaced risk factors can provoke development of lactoacidosis as Metforminum (is a part of drug see. "Special instructions").

Lactoacidosis is the state demanding emergency medical service; treatment of lactoacidosis has to be carried out in clinic. The most effective method of treatment allowing to remove a lactate and Metforminum is the hemodialysis.

The clearance of Glibenclamidum in a blood plasma can increase at patients with liver diseases. As Glibenclamidum actively contacts blood proteins, drug does not eliminirutsya at dialysis.

Storage conditions:

List B. To store at a temperature not above 30 °C. To store in the place, unavailable to children. Term godnosti3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets are film coated, 2,5 mg +500 mg and 5 mg +500 mg.
Packaging: On 15 in PVC / the blister Is scarlet. On 2 blisters together with the application instruction place in a cardboard pack.
The M symbol for protection against falsification is applied on the blister and a cardboard pack.