Glyutazon

General characteristics. Structure:

Active ingredient: pioglitazone; 1 tablet contains a pioglitazon a hydrochloride is equivalent to a pioglitazon of 15 mg or 30 mg, or 45 mg.

Auxiliary veshchestva:laktoza monohydrate, hydroxypropyl cellulose, calcium carboxymethylcellulose, magnesium stearate.

Pharmacological properties:

Pharmacodynamics. Глютазон® – peroral hypoglycemic drug of a tiazolidindionovy row. Action of a pioglitazon depends on insulin presence. The high-selection agonist of γ-receptors, which are activated by a peroksisomny proliferator (γ-PPAR). γ-PPAR-retseptora are found in fatty, muscular fabrics and in a liver. Activation of nuclear receptors of PPAR-γ modulates a transcription of the genes sensitive to insulin which take part in control of level of glucose and metabolism of lipids. Глютазон® reduces insulin resistance in peripheral fabrics and in a liver, as a result of it the consumption of insulin-dependent glucose increases and emission of glucose from a liver decreases. Unlike sulphonylurea derivatives, пиоглитазон does not stimulate insulin secretion with pancreas β-cells.
At a diabetes mellitus of the II type reduction of insulin resistance under the influence of a pioglitazon leads to decrease in concentration of glucose in blood, to decrease in level of insulin in a blood plasma and A1C hemoglobin (glikozilirovanny hemoglobin, HbA1C). In combination with sulphonylurea derivatives, Metforminum or insulin drug improves glycemic control.
At patients at use of a pioglitazon thanks to stimulation also the PPAR alpha happens to disturbance of lipidic exchange activation of a catabolism of mediators of an inflammation, thickness of an internal wall of arteries due to elimination of inflammatory and proliferative processes decreases, fibrinogen level in a blood plasma decreases, and also the level of triglycerides decreases and the LPVP level (lipoproteids of high density) increases, at the same time the LPNP level (lipoproteids of low density) and the general cholesterol do not change.

Pharmacokinetics. Absorption. After intake пиоглитазон it is quickly soaked up; the maximum concentration in a blood plasma of not changed pioglitazon usually are reached in 2 hours after reception. Proportional increase in concentration in plasma was observed for doses from 2 to 60 mg. The stable state is reached after administration of drug within 4 - 7 days. Reusable use does not lead to cumulation of drug or its metabolites. Meal does not influence absorption. Absolute bioavailability of a pioglitazon exceeds 80%.
Distribution. The settlement volume of distribution at the person makes 1,25 l/kg. Pioglitazon and all his active metabolites extensively contact proteins of plasma (> 99%).
Metabolism. Pioglitazon is extensively metabolized in a liver by a hydroxylation of aliphatic methylene groups. Usually it is carried out with the participation of enzyme 2C8 of system of P450 cytochrome, though other isoenzymes can be involved to a lesser extent. 3 of 6 identified metabolites are active (M - ІІ, M - ІІІ and M-IV). Considering activity, concentration and communication with proteins, пиоглитазон and its metabolite M - ІІІ equally influence efficiency. On the basis of it the contribution of M-IV to efficiency approximately three times exceeds a contribution of a pioglitazon whereas the relative contribution of M - ІІ is minimum.
The researches in vitro did not reveal any certificates that пиоглитазон any subtype of system of P450 cytochrome oppresses. The person has no induction of the main isoenzymes of system of P450 1A cytochrome, 2C8,9 and 3A4.
Allocation. 55% of a pioglitazon are excreted with excrements and 45% – with urine. The average elimination half-life of not changed pioglitazon makes 5 - 6 hours, and for all its active metabolites – from 16 to 23 hours.
Patients of advanced age. Pharmacokinetic parameters at patients aged from 65 years are also more senior and at young patients are similar.
Patients with renal failures. Patients with renal failures have a concentration of a pioglitazon and its active metabolites in plasma is lower, than at patients з normal function of kidneys, but the clearance of parent connection is similar. Thus, concentration of a free (untied) pioglitazon is invariable.
Patients with abnormal liver functions. The general concentration of a pioglitazon in plasma is invariable, but at the increased distribution volume the clearance is reduced along with the increased fraction of an untied pioglitazon.

Indications to use:

Treatment of a diabetes mellitus ІІ type:
As monotherapy
– to patients (especially to patients with excess body weight) both contraindications and intolerance of Metforminum in case of inadequate control of level of sugar in blood a diet and physical exercises;
in the form of a double combination therapy with
– Metforminum to patients (especially to patients with excess body weight) with insufficient glycemic control, despite use of the most tolerable dose of Metforminum;
– sulphonylurea derivatives only at patients з intolerance and to contraindications to Metforminum at insufficient glycemic control, despite use of the most tolerable dose of derivatives of sulphonylurea;
in the form of a triple combination therapy with
– Metforminum and derivatives of sulphonylurea at patients (especially to patients with excess body weight) with insufficient glycemic control, despite use of a double combination therapy.
Глютазон® it is shown also in a combination with insulin at a diabetes mellitus ІІ type to patients with insufficient glycemic control at use of insulin to whom Metforminum is contraindicated or there is an intolerance of Metforminum.

Route of administration and doses:

Глютазон® adults orally 1 time a day irrespective of meal accept. The dose of drug is selected individually. The initial dose of a pioglitazon makes 15 mg or 30 mg, if necessary the dose can be raised to 30 - 45 mg of 1 times a day.
The maximum daily dose – 45 mg.
At a combination therapy of a pioglitazon with insulin the dose of insulin remains same or at the message of the patient on a hypoglycemia decreases.
Patients of advanced age.
Dose adjustment of a pioglitazon is not required to patients of advanced age.
Patients with renal failures.
Dose adjustment of a pioglitazon to patients with renal failures (clearance of creatinine> of 4 ml/min.) is not required. Pioglitazon is not recommended to apply to patients who are on dialysis.
Patients with abnormal liver functions.
Pioglitazon patients should not apply with disturbances of functions of a liver.

Features of use:

Delay of liquid and heart failure.
Pioglitazon can become the liquid delay reason that can strengthen heart failure. Treatment of patients who have at least one risk factor of development of chronic heart failure (for example, a myocardial infarction in the anamnesis) should be begun with the minimum dose with the subsequent its gradual increase. This group of patients should be controlled constantly concerning signs and symptoms of heart failure, increase in body weight or emergence of hypostases, especially patients with a reduced diastolic reserve. As insulin and пиоглитазон is associated with a liquid delay, their simultaneous use can strengthen risk of hypostases. Patients who accept a combination of these drugs have to be controlled carefully concerning manifestations of symptoms of heart failure, increase in body weight or emergence of hypostases. At any deterioration in the cordial status пиоглитазон it is necessary to cancel.
At use of a pioglitazon for patients 75 years are more senior it is necessary to show care owing to limited experience of use in this age group.

Monitoring of function of a liver. Before an initiation of treatment pioglitazony it is necessary to check the level of activity of liver enzymes at all patients. It is not necessary to appoint пиоглитазон to patients in the presence of clinical displays of a disease of a liver in an active phase and at the increased ALT level more than is 2,5 times higher than the upper bound of norm. At moderate increase in activity of enzymes of a liver it is necessary to begin or continue with care treatment pioglitazony. During treatment pioglitazony patients with pathology of a liver or at development of symptoms of dysfunction of a liver (nausea, anorexia, pain in a stomach, fatigue) need to control the level of liver enzymes regularly. At increase in level of activity of enzymes (ALT) by 3 times or development of jaundice treatment pioglitazony should be stopped.

Increase in body weight. There are data on dozozavisimy increase in body weight. Visceral fat significantly decreased while ekstraabdominalny fatty weight increased. Similar changes in distribution of fatty weight in an organism at reception of a pioglitazon were followed by improvement of sensitivity to insulin. In certain cases increase in body weight can be associated with a liquid delay, the baht a symptom of heart failure therefore it is necessary to control body weight carefully can. Patients are recommended to control food caloric content strictly.

Hematology. During treatment pioglitazony small lowering of the level of hemoglobin (relative decrease in 4%) and a hematocrit (relative decrease in 4,1%) owing to increase in volume of a blood plasma was observed. Similar changes were observed for Metforminum (relative decrease in hemoglobin – 3-4%, a hematocrit – 3,6-4,1%) and to a lesser extent for drugs of group of sulphonylurea (relative decrease in hemoglobin – 1-2%, a hematocrit – 1-3,2%).

Hypoglycemia. As a result of hypersensitivity of fabrics to insulin patients who accept пиоглитазон in the form of double or triple therapy with sulphonylurea drugs with insulin can have the increased risk of development of a hypoglycemia. At risk of a gipoklikemiya the dose decline of drugs of sulphonylurea or insulin can be necessary.

Disturbances from organs of sight. At disturbance of visual acuity macular hypostasis can develop. Consultation of the ophthalmologist is in that case necessary.

Others. The risk of changes at women at therapy is possible pioglitazony that needs to be considered at prolonged treatment.
Owing to increase in sensitivity of fabrics to insulin updating of an ovulation can be result of treatment pioglitazony women with a syndrome of polycystic ovaries. Such patients risk to become pregnant. Patients should be warned about a possibility of pregnancy. If pregnancy already occurred, пиоглитазон it is necessary to otemnit.
Глютазон® monohydrate therefore patients should not appoint it with such rare hereditary diseases as intolerance of a galactose, deficit of lactase of Lapp or disturbance of absorption of glucose galactose contains lactoses.

Ability to influence speed of response at control of motor transport or work with other mechanisms. At use of drug emergence of side reactions which can influence ability to manage motor transport or work with other mechanisms is possible.

Side effects:

Side reactions are listed on frequency: very widespread (> 1/10); extended (> 1/100, <1/10); not widespread (> 1/1000, <1/100); seldom meeting  (> 1/10 000,  <1/1000); very seldom meeting (<1/10 000); it is unknown (frequency cannot be estimated according to the available data).
Monotherapy pioglitazony:
- from organs of sight: extended – vision disorders;
infections: extended – upper respiratory tract infections; not widespread – sinusitis;
- from a nervous system: extended – a gipoyesteziya; not widespread – sleeplessness;
- others: extended – increase in body weight.
Pioglitazon in a combination therapy with Metforminum:
- from circulatory system: extended – anemia;
- from organs of sight: extended – vision disorders;
- from a digestive tract: extended – a meteorism;
- from a musculoskeletal system: extended – arthralgias;
- from a nervous system: extended – a headache;
- from an urinary system: extended – a hamaturia;
- from reproductive system: extended – erectile dysfunction;
- others: extended – increase in body weight.
Pioglitazon in a combination therapy with sulphonylurea derivatives:
- from a vestibular mechanism: not widespread – вертиго;
- from organs of sight: extended – vision disorders;
- from a digestive tract: extended – a meteorism;
- general disturbances: not widespread – fatigue;
- metabolic frustration: not widespread – the increased appetite, a hypoglycemia;
- from a nervous system: extended – dizziness; not widespread – a headache;
- from an urinary system: extended – a glycosuria, a proteinuria;
- from skin: not widespread – the increased sweating;
- others: extended – increase in body weight; not widespread – increase in a lactate dehydrogenase.
Pioglitazon in a triple combination therapy with Metforminum and derivatives of sulphonylurea:
- metabolic frustration: very widespread – a hypoglycemia;
- from a musculoskeletal system: extended – arthralgias;
- others: extended – increase in body weight, increase in a kreatinfosfokinaza in a blood plasma.
Pioglitazon in a combination therapy with insulin:
- metabolic frustration: very widespread – a hypoglycemia;
- general disturbances: very widespread – hypostasis;
- infections: extended – bronchitis;
- from a musculoskeletal system: extended – arthralgias, a dorsodynia;
- from respiratory system: extended – an asthma (диспноэ);
- from cardiovascular system: extended – heart failure;
- others: extended – increase in body weight.

Interaction with other medicines:

Researches of interaction proved what пиоглитазон significantly does not influence pharmacokinetics and a pharmacodynamics of digoxin, warfarin, a fenprokumon and Metforminum. Simultaneous use of a pioglitazon with derivatives of sulphonylurea does not influence pharmacokinetics of these drugs. Researches at the person do not assume induction of the main enzymes of system of P450 1A cytochrome, 2C8/9 and 3A4. Therefore, it is possible to expect lack of interaction with substances which are metabolized by these enzymes, for example, oral contraceptives, cyclosporine, blockers of calcium channels and inhibitors of GMKA-KOA reductase.
There were messages that simultaneous use of a pioglitazon з gemfibrozily (inhibitor of enzyme 2C8 of system of P450 cytochrome) is led to increase in the area under a curve by "concentration time" (AUC) of a pioglitazon by 3 times. As there is a potential for increase in risk of development of dozozavisimy by-effects, the dose decline of a pioglitazon at simultaneous use can be necessary with gemfibrozily.
Simultaneous use of a pioglitazon with rifampicin (the inductor of enzyme 2C8 of system of P450 cytochrome) leads to decrease by 54% of AUC of a pioglitazon. Increase in a dose of a pioglitazon at simultaneous use з rifampicin on condition of careful monitoring of glycemic control can be necessary.

Contraindications:

Hypersensitivity to active ingredient or to any other component of drug.
Heart failure (stages І - the IV NYHA), heavy disturbances of functions of a liver, diabetic ketoacidosis, a diabetes mellitus like І.

Use during pregnancy or feeding by a breast. Due to the lack of clinical data use of a pioglitazon during pregnancy or feeding by a breast is not recommended.

Children. Data on use of a pioglitazon by children are absent therefore this age category of patients should not appoint drug.

Overdose:

The maximum dose about which it was reported, – 120 mg a day for 4 days and further – 180 mg a day for 7 days – was not associated with any symptoms.
The hypoglycemia can be observed at use of a combination of a pioglitazon with derivatives of sulphonylurea or insulin.
Treatment: symptomatic and maintenance therapy.

Storage conditions:

To store at a temperature not above 25 °C in dry, protected from light and the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 14 tablets in the blister; on 2 blisters in a cardboard box.
On 10 tablets in the blister; on 3 blisters in a cardboard box.