Avandamet - instructions for use, dose, side effects, contraindications

Active substanceMetformin + rosiglitazoneMetformin + rosiglitazone

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Dosage form: & nbspfilm coated tablets

Composition:

Component	The content in one tablet in mg, dosage:
	1 mg / 500 mg			2 mg / 500 mg
NUCLEUS TABLETS:
*Rosiglitazone granules:*
Active substance:
Rosiglitazona	1.33 mg			2.65 mg
maleate *
Excipients:
Sodium carboxymethyl starch	0.5 mg			1.0 mg
Hypromellose, 3cR	0.5 mg			1.0 mg
Cellulose microcrystalline kaya	2.0 mg			4.0 mg
Lactose monohydrate	5.67 mg			11,35 mg
Total:
Granulated concentrate rosiglitazone	10.0 mg			20.0 mg
*Metformin granules:*
Active substance:
Metformin		500,0			500,0
hydrochloride		mg			mg
Excipients:
Povidone 29-32		15.0 mg			15.0 mg
Hypromellose, 3cR		20.0 mg			20.0 mg
Total:
Granulated		535,0			535,0
metformin concentrate		mg			mg
hydrochloride
*Other excipients;*
Cellulose microcrystalline and I			30.0 mg			29.1 mg
Magnesium stearate			3.0 mg			2.9 mg
Theoretical mass of the core of the tablet:			578.0 mg			587.0 mg
CASING OF THE TABLET:
Opadry I*** yellow (Oradgu I Yellow (03B22409)			17 mg			-
Opapray I pink (Oradgu I Rink (03B24658)			-			17 mg
The theoretical mass of the tablet shell:			17.0 mg			17.0 mg
Theoretical tablet weight:			595.0 mg			604.0 mg

Notes

* - 1.33 mg and 2.65 mg of rosiglitazone maleate are equivalent respectively 1 mg and 2 mg rosiglitazone base.

** - EF - European Pharmacopoeia, current edition.

*** - The "OUADRAY I" tablet shell contains:

Component	The content in one tablet in mg, dosage:
- Hypromellose 6cR	10.63 mg	10.63 mg
- Titanium dioxide	5.21 mg	5.30 mg
- Macrogol 400	1.06 mg	1.06 mg
- Iron oxide yellow	0.10 mg	-
- Iron oxide red	-	0.02 mg

Description:

Tablet 1 mg / 500 mg: Oval-shaped tablets coated with a yellow film membrane, on one side of which are engraved with the letters "gsk", on the other side - "1/500"

Tablet 2 mg / 500 mg: Tablets of the oval form, covered with a film shell of light pink color, on one side of which engraved the letters '' gsk '', on the other side - "2/500"

Pharmacotherapeutic group:Hypoglycemic agent for oral administration

ATX: & nbsp

A.10.B.D Combination of biguanides and sulfonylurea derivatives

A.10.B.D.03 Metformin and rosiglitazone

Pharmacodynamics:

Mechanism of action

The composition of Avandamet includes two hypoglycemic active ingredients with complementary mechanisms of action,which improve glycemic control in patients with type 2 diabetes mellitus: rosiglitazone maleate, a class of thiazolidinediones, and metformin hydrochloride, a representative of the biguanide class. The mechanism of action of thiazolidinediones consists mainly in enhancing the sensitivity of tissues targets to insulin, whereas biguanides act mainly by reducing the production of endogenous glucose in the liver.

Rosiglitazone

A selective and potent agonist of the PRAK-gamma receptor core, belonging to hypoglycemic drugs of the thiazolidinedione class. It improves glycemic control by increasing the insulin sensitivity of key target tissues such as adipose tissue, skeletal muscle and liver. It is known that insulin resistance plays an important role in the pathogenesis of type 2 diabetes. Therefore, rosiglitazone improves metabolic control by reducing blood glucose, circulating insulin and free fatty acids. Due to different but complementary mechanisms of action, combined therapy with rosiglitazone and a derivative of sulfonylureas or metformin leads to a synergistic improvement in glycemic control in patients with type 2 diabetes mellitus.

Metformin

Biguanide with anti-hyperglycemic action, which reduces both basal and postprandial glucose concentrations in plasma. It does not stimulate the secretion of insulin and therefore does not cause hypoglycemia.

There are three possible mechanisms of action of metformin:

■ reduction of glucose production in the liver by suppression of gluconeogenesis and glycogenolysis;

■ increased sensitivity of muscle tissue to insulin, improved consumption and utilization of glucose by peripheral tissues;

■ delayed absorption of glucose in the intestine.

Pharmacodynamic effects

Rosiglitazone

Hypoglycemic activity of rosiglitazone is demonstrated in experimental models of type 2 diabetes mellitus in animals. Rosiglitazone retains the function of beta cells, as evidenced by an increase in the mass of the islets of Langerhans pancreas and an increase in the content of insulin in them, and also prevents the development of severe hyperglycemia. It is also established that rosiglitazone significantly slows the development of renal dysfunction and systolic hypertension. Rosiglitazone did not stimulate the secretion of insulin by the pancreas and did not cause hypoglycemia in rats and mice.In accordance with the mechanism of action rosiglitazona, improving glycemic control is accompanied by a clinically significant decrease in serum insulin concentration. The concentrations of insulin precursors, which are generally believed to be risk factors for cardiovascular diseases, also decrease. One of the key results of treatment with rosiglitazone is a significant reduction in the concentrations of free fatty acids.

Metformin

Stimulates intracellular synthesis of glycogen, activating the enzyme glycogen synthase. It enhances the activity of all types of transmembrane glucose transporters. People, regardless of their effect on glycemia, metformin improves lipid metabolism. This has been demonstrated with the use of therapeutic doses of metformin in medium and long-term clinical trials: metformin reduces the concentration of total cholesterol, low-density lipoprotein cholesterol and triglycerides.

Pharmacokinetics:

Suction

Avandamet

The bioequivalence study of Avandamet (4 mg / 500 mg) showed that both components of the drug, rosiglitazone and metformin, were bioequivalent to the simultaneous use of rosiglitazone maleate tablets of 4 mg and tablets of metformin hydrochloride, 500 mg each. This study also demonstrated the proportionality of doses of rosiglitazone in the combined preparation of 1 mg / 500 mg and 4 mg / 500 mg.

Eating does not affect the area under the concentration-time curve (AUC) rosiglitazona and metformin. At the same time, simultaneous intake of food leads to a decrease in the maximum concentration (C_m_Oh): 209 ng / ml vs. 270 ng / ml rosiglitazone and 762 ng / ml versus 909 ng / ml metformin; and an increase in the time to reach the maximum concentration (T_m_Oh) - 2.56 h against 0.98 h for rosiglitazone and 3.96 h against 3.00 h for metformin.

Rosiglitazone

Absolute bioavailability of rosiglitazone after ingestion of 4 or 8 mg is about 99%. FROM_m_Oh rosiglitazona is reached approximately in 1 hour after its reception inside. In the range of therapeutic doses, rosiglitazone concentrations in plasma are approximately proportional to its dose. Reception rosiglitazona with food does not change AUC, but in comparison with reception on an empty stomach there is a slight decrease in Cm(by about 20-28%) and an increase in T_m_Oh(1.75 hours). These small changes are clinically insignificant, in connection with which rosiglitazone can be taken regardless of food. The increase in pH of gastric contents does not affect the absorption of rosiglitazone.

Metformin

After oral metformin T_m_Ohis about 2.5 hours, and the absolute bioavailability after ingestion of 500 or 850 mg of metformin in healthy people is approximately 50-60%. After oral administration, the unabsorbed fraction found in the stool was 20-30% of the dose.

After ingestion, metformin absorption is saturable and incomplete. It is assumed that the absorption of metformin is nonlinear. With conventional metformin doses and the usual dosing regimen, equilibrium plasma concentrations are achieved within 24-48 hours and are generally less than 1 μg / ml. In controlled clinical trials, C_m_Oh metformin does not exceed 4 μg / ml, even after taking the maximum doses of this drug. Simultaneous food intake reduces the absorption of metformin and somewhat reduces the rate of absorption. After oral administration of 850 mg of metformin while eating it C_m_Oh decreases by 40% and AUC - by 25%, and T_m_Oh increases by 35 min. The clinical significance of these changes is not known.

Binding to blood plasma proteins and distribution

Rosiglitazone

The volume distribution of rosiglitazone is approximately 14 liters, and the total plasma clearance is about 3 liters / h. High degree of binding to plasma proteins - about 99.8%, does not depend on the concentration and age of the patient. At present, there is no data on the unexpected cumulation of rosiglitazone when taken once or twice a day.

Metformin

The binding of metformin to plasma proteins is negligible. Metformin penetrates into the red blood cells. FROM_m_Oh in the blood below C_m_Oh in plasma and achieved about the same time. Erythrocytes, most likely, are a secondary distribution compartment. Average volume of distribution (Vd) varies from 63 to 276 liters.

Metabolism

Rosiglitazone

It is subject to intensive metabolism, it is excreted in the form of metabolites. The main ways of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. Metabolites rosiglitazona not have pharmacological activity. Research in vitro showed that rosiglitazone is metabolized predominantly by the enzyme CYP2C8 and, to a much lesser extent, by the enzyme CYP2C9.

In conditions in vitro rosiglitazone does not have a significant inhibitory effect on the enzymes CYP1A2, CYP2A6, CYP2C19, CYP206, CYP2E1, CYP3A and CYP4A, and therefore it is unlikely that in vivo he will enter into significant metabolic interactions with drugs that are metabolized by these enzymes of the cytochrome P450 system. In vitro rosiglitazone moderately inhibits the enzyme CYP2C8 (IC₅₀ is 18 μmol) and weakly inhibits the enzyme CYP2C9 (IC₅₀ is 50 μmol). The study of the interaction of rosiglitazone with warfarin in vitro showed that rosiglitazone does not interact with substrates of the enzyme CYP2C9.

Metformin is not metabolized and is excreted unchanged in kidneys. No metformin metabolites have been identified in humans.

Excretion

Rosiglitazone

The total plasma clearance of rosiglitazone is about 3 l / h, and the final half-life of it is about 3-4 hours. There is currently no data on the unexpected cumulation of rosiglitazone once or twice a day. About two-thirds of the dose of rosiglitazone taken internally is excreted by the kidneys, about 25% is excreted by the intestine. Unchanged, it is not found in urine or feces.The final half-life is about 130 hours, which indicates a very slow excretion of metabolites. When you re-ingest rosiglitazona not excluded the cumulation of its metabolites in the plasma, in particular the main metabolite (para-hydroxysulfate), the concentration of which, presumably, can increase by 5 times.

Metformin

It is excreted by glomerular filtration and tubular secretion. The renal clearance of metformin is more than 400 ml / min. After oral administration, the apparent terminal half-life of metformin is approximately 6.5 hours. In patients with impaired renal function, renal clearance decreases

in proportion to the decrease in creatinine clearance, and, consequently, the half-life increases, resulting in increased concentrations of metformin in the plasma.

Peculiarities of pharmacokinetics rosiglitazona in different groups of patients

■ Floor

There were no significant differences in the pharmacokinetics of rosiglitazone in men and women.

■ Elderly patients

There were no significant differences in the pharmacokinetics of rosiglitazone in elderly and uninhabited patients.

■ Patients with impaired renal function There was no significant difference in the pharmacokinetics of rosiglitazone in patients with impaired renal function, as well as in chronic dialysis.

■ Patients with impaired hepatic function

In patients with moderate to severe hepatic impairment (on the Child-Pugh B / C scale) C_m_Oh and AUFROM were 2-3 times higher, which was the result of increased binding to plasma proteins and a decrease in rosiglitazone clearance. The use of the drug Avandamet is contraindicated in the case of a violation of the liver, regardless of the degree of its violation.

Indications:

■ Diabetes mellitus type 2

Azandameth is prescribed for glycemic control in patients with ineffective diet or monotherapy with thiazolidinedione or metformin. as well as patients who have already received combined preparations of thiazolidinedione and metformin.

■ Avandamet can be used in combination with sulfonylurea derivatives (a three-component combination) for glycemic control.

Contraindications:

■ Hypersensitivity to any of the components of the drug;

■ Heart failure of NYHA functional class I-IV;

■ Acute or chronic diseases leading to tissue hypoxia (eg, cardiac or respiratory failure, recent myocardial infarction, shock);

■ Liver failure;

■ Alcoholism, acute alcohol intoxication;

■ Diabetic ketoacidosis or diabetic precoma;

■ Renal failure (at a serum creatinine concentration greater than 135 μmol / L in men and more than 110 μmol / L in women) and / or creatinine clearance less than 70 ml / min;

■ Acute conditions with a risk of developing kidney failure (dehydration, severe infections, shock);

■ Intravascular injection of iodine-containing radiocontrast agents;

■ Simultaneous introduction of insulin.

Pregnancy and lactation:

Pregnancy

It is known that rosiglitazone penetrates through human placenta and is found in the tissues of the fetus.

There is insufficient data to justify the use of the combination rosiglitazone + metformin in pregnant women. Patients with diabetes mellitus during pregnancy recommended the use of insulin. Applying a combination rosiglitazone + metformin during pregnancy is contraindicated.

Breastfeeding period

There is insufficient data to justify the application of the combination rosiglitazone + metformin in the period of breastfeeding. It is not known whether the combination rosiglitazone + metformin in breast milk during breastfeeding. As a rule, patients with diabetes recommended the use of insulin during breastfeeding. Applying a combination rosiglitazone + metformin during the period of breastfeeding is contraindicated.

Dosing and Administration:

The dosage regimen is selected and set individually. The drug Avandamet can be taken regardless of food intake. Taking Avandameth during or after a meal can reduce unwanted reactions from the gastrointestinal tract caused by metformin.

Adults

The recommended initial dose of the combination rosiglitazone + metformin is 4 mg / 1000 mg. Daily combination dose rosiglitazone + metformin can be increased to maintain individual control of glycemia in the patient. Increase in the dose should be gradual up to a maximum daily doses 8 mg rosiglitazona + 2000 mg metformin.A slow increase in the dose may weaken unwanted reactions from the gastrointestinal tract (caused mainly by metformin). The dose should be increased in increments of 2-4 mg per day for rosiglitazone and / or 500 mg per day for metformin. The interval between dose adjustments should be selected individually, depending on the patient's response to therapy. The therapeutic effect after dose adjustment may not appear for 6-8 weeks for rosiglitazone and for 1 -2 weeks for metformin. When switching from other oral hypoglycemic drugs to combination rosiglitazone + metformin It is necessary to take into account the activity and duration of action previous hypoglycemic drugs. When switching from combination therapy rosiglitazone + metformin for separate taking of drugs, the initial doses of rosiglitazone and metformin should correspond to the already taken doses of each of the two active substances. Correction of the doses of one of the components of the drug Avandamet, rosiglitazone or metformin, may be required when combined with other drugs.

Special patient groups

Children

Currently, there is no data on the use of Avandamet in children under 18 years of age, so the use of the drug in this age group is not recommended.

Elderly patients

Metformin is excreted by the kidneys, so the initial and maintenance doses of Avandamet in elderly patients should be adequately adjusted due to a very likely decrease in kidney function in this group of patients. Any dose adjustment should be based on data on kidney function that should be monitored continuously.

Patients with impaired renal function

The drug Avandamet is contraindicated for the treatment of patients with renal insufficiency (with a serum creatinine concentration of more than 135 μmol / L in men and more than 110 μmol / L in women) and / or creatinine clearance less than 70 ml / min.

Patients with impaired hepatic function

In patients with mild liver function disorder (6 points or less on the Child-Pugh scale, class A), correction of the dosage regimen of rosiglitazone is not required. However, since impaired liver function is one of the risk factors for lactic acidosis in the treatment of metformin, the use of combination rosiglitazone + metformin in patients with impaired liver function of any severity is not recommended. Simultaneous application of the combination rosiglitazone + metformin with sulfonylurea derivatives in patients receiving rosiglitazone

and metformin in patients receiving a combination rosiglitazone + metformin with derivatives of sulfonylureas, the initial dose of rosiglitazone should be 4 mg per day. Increase

the dose of rosiglitazone to 8 mg per day is necessary with caution and after a proper clinical assessment of the risk of the patient developing unwanted reactions associated with fluid retention.

Side effects:The undesirable phenomena presented below are listed according to the anatomical and physiological classification and frequency occurrence. Frequency is determined as follows: Often (>1/10), often (>1/100 and <1/10), infrequently (>1/1 000 and <1/100), rarely (>1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

In clinical studies, the safety profile of the rosiglitazone-metformin combination was consistent with the profile of the individual components.

Rosiglitazone

Data from clinical trials

From the hematopoiesis and lymphatic system
Anemia*
Rosiglitazone (compared with placebo)		Often
Rosiglitazone + metformin (in comparison with metformin)		Often
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)		Often
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)		Often
Rosiglitazone + insulin (compared with insulin)		Often
Leukopenia
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)	Often

Thrombocytopenia
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)	Often


Granulocytopenia
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)	Often

* - often dose-dependent, from mild to moderate severity.


From the side of metabolism
Hypercholesterolemia *
Rosiglitazone (compared with placebo)	Often
Rosiglitazone + metformin (in comparison with metformin)	Rarely
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)	Often

Rosiglitazone + derivatives	Often
sulfonylureas + metformin (in comparison with the derivatives sulfonylureas + metformin)
Rosiglitazone + insulin (compared with insulin)	Often
Hypertriglyceridemia
Rosiglitazone (compared with placebo)			Often
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)			Often


Hyperlipidemia
Rosiglitazone (compared with placebo)			Often
Rosiglitazone + metformin (in comparison with metformin)			Often
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)			Often

Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)			Often

Weight gain **
Rosiglitazone (compared with placebo)			Often

Rosiglitazone + metformin (by compared with metformin)			Often
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)			Often
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)			Often
Rosiglitazone + insulin (compared with insulin)			Often
Increased appetite
Rosiglitazone (compared with placebo)				Sometimes
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)				Sometimes
Rosiglitazone + insulin (compared with insulin)				Sometimes
Hypoglycemia ***
Rosiglitazone + metformin (in comparison with metformin)				Often
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)				Often
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)				Often
Rosiglitazone + insulin (compared with insulin)				Often

* - total cholesterol increased simultaneously with increase high-density lipoprotein (HDL) and low-density lipoprotein (LDL) concentrations, the cholesterol / HDL ratio remained unchanged.

** - weight gain, mainly dose-dependent. Perhaps due to fluid retention and the accumulation of fatty deposits.

*** - hypoglycemia, mostly moderate or mild, dose-dependent in combination treatment with sulfonylurea or insulin.

From the nervous system
Dizziness
Rosiglitazone + metformin (in comparison with metformin)	Often
Rosiglitazone + derivatives of sulfonylureas (by compared with derivatives of sulfonylurea)	Often
Headache
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)	Often

From the side of the cardiovascular system
From the side of the cardiovascular system
Heart failure / pulmonary edema *
Rosiglitazone + derivatives of sulfonylureas (in comparison with metformin + derivatives of sulfonylureas)	Often
	Often
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)	Often
	Often
Rosiglitazone + metformin (in comparison with metformin + derivatives of sulfonylureas)	Often
	Often
Rosiglitazone monotherapy (in comparison with derivatives of sulfonylurea or metformin)	Sometimes
	Sometimes
Rosiglitazone + insulin (compared with insulin)	Often
Myocardial ischemia **
Rosiglitazone (compared with placebo)	Often
Rosiglitazone + metformin (in comparison with metformin)	Often
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)	Often
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)	Often
Rosiglitazone + insulin (compared with insulin)	Often

* - Heart failure / pulmonary edema. An increase in the incidence of heart failure was observed with the addition of rosiglitazone to regimens based on the use of insulin or sulfonylurea derivatives. The number of observations does not allow to make an unambiguous conclusion about the connection with the dose of the drug, however, the frequency of cases is higher for a daily dose of rosiglitazone 8 mg compared with a daily dose of 4 mg.

Symptoms of myocardial ischemia were more often observed with the appointment of rosiglitazone to patients on insulin therapy.

** - A higher incidence of events associated with myocardial ischemia was observed in patients receiving insulin therapy when rosiglitazone was added. Data on the possibility of rosiglitazone to increase the risk of myocardial ischemia are inadequate. A retrospective analysis of 42 short-term clinical trials suggests a relationship between rosiglitazone intake and the risk of developing myocardial ischemia in placebo-controlled studies, but not in comparison with active drugs.The risk of developing myocardial ischemia has not been confirmed in some large-scale, longer-term studies. It is particularly important that there was no increased risk in a prospective clinical study of cardiovascular outcomes (mean follow-up of 5.5 years) comparing rosiglitazone with metformin and sulfonylurea. The relationship between rosiglitazone and the development of myocardial ischemia has not been established.

In the retrospective analysis described above, an increase in the incidence of serious adverse events associated with myocardial ischemia was noted in patients who received rosiglitazone, compared with other groups that also used nitrates. A small number of patients who received nitrate therapy in these studies made it difficult to interpret this observation.

In a long-term randomized prospective study with verified cardiovascular outcomes, there was no difference in the primary outcome: death or hospitalization for cardiovascular reasons in a small number of patients who initially received nitrate therapy.

Rosiglitazone is not recommended for patients,receiving concomitant therapy with nitrates.

From the gastrointestinal tract
Constipation *
Rosiglitazone (compared with placebo)	Rarely
Rosiglitazone + metformin (in comparison with metformin)	Often
Rosiglitazone + derivatives of sulfonylureas (in comparison with derivatives of sulfonylurea)	Rarely
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)	Often



Rosiglitazone + insulin (compared with insulin)	Sometimes
* Constipation usually was mild or moderate.
From the musculoskeletal system
Fractures of bones *
Rosiglitazone (compared with metformin)		Often
Rosiglitazone (in comparison with glibencl amide)		Often
Rosiglitazone + metformin (in comparison with sulfonylurea + metformin)		Often
Rosiglitazone + derivatives of sulfonylureas (in comparison with metformin + derivatives of sulfonylureas)		Often
Myalgia
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)		Often
* - most of the reports concerned fractures of the upper limbs and fractures of the distal sections of the lower extremities.
From the body as a whole
Peripheral edema *
Rosiglitazone (compared with placebo)		Often
Rosiglitazone + metformin (in comparison with metformin)		Often
Rosiglitazone + derivatives of sulfonylureas (by compared with derivatives of sulfonylurea)		Often
Rosiglitazone + sulfonylurea derivatives + metformin (in comparison with the derivatives sulfonylureas + metformin)		Often
Rosiglitazone + insulin (compared with insulin)		Often
* - In general, dose-dependent, from mild to moderate severity, were more often observed with combined treatment with sulfonylurea derivatives or insulin.

The undesirable phenomena that occur when taking Avandamet can be caused by both active components that make up the drug.

AT post-registration period the following undesirable events have been registered:

From the immune system

Highly rarely: Anaphylactic reactions

From the liver and biliary tract

Rarely were there reports of liver function abnormalities accompanied by an increase in hepatic enzyme activity, but a causal relationship between rosiglitazone treatment and liver dysfunction was not established.In patients with diabetes mellitus, there are often violations of the liver.

From the skin and subcutaneous fat

Highly rarely: Angioedema, urticaria, rash, itchy skin

From the side of the organ of vision

Highly rarely: Macular edema

Metformin

Data obtained in clinical trials and post-registration period.

From the gastrointestinal tract:

Highly often: Dyspeptic phenomena (nausea, vomiting, diarrhea, abdominal pain, decreased appetite);

Basically, they occur when high doses are prescribed and at the beginning of treatment, in most cases they pass by themselves.

From the side of metabolism

Rarely: Lactic acidosis, Vitamin B12 deficiency

From the nervous system

Often: Metal smack

From the skin and subcutaneous fat:

Highly rarely: Erythema

It was found in people with hypersensitivity, mostly mild.

Overdose:

Currently, there is no evidence of an overdose of Avandamet. In clinical studies, volunteers well tolerated single oral doses of rosiglitazone up to 20 mg.

Treatment:

An overdose of metformin (or concomitant risk factors for lactic acidosis) can lead to the development of lactic acidosis,which is an urgent medical condition and requires treatment in a hospital.

In case of an overdose, it is recommended that appropriate maintenance therapy be conducted, guided by the clinical condition of the patient.

To remove lactate and metformin from the body, hemodialysis should be used, however rosiglitazone is not removed by hemodialysis (has a high degree of binding to proteins).

Interaction:

There were no separate studies concerning drug interactions with Avandamet. The data below reflects the available information on the interactions of individual

active substances Avandamet (rosiglitazone and metformin). Rosiglitazone

In studies n vitro it was shown that rosiglitazone is metabolized, mainly, with the participation of the enzyme CUR2C8, and only a small part is metabolized with the participation of the enzyme СUR2С9.

Simultaneous application rosiglitazone with inhibitors of the enzyme СUR2С8 (for example, gemfibrozil) led to an increase in the concentration rosiglitazona in blood plasma. Due to the increased risk of developing dose-dependent undesirable

reactions with simultaneous the use of inhibitors of the enzyme СУР2С8 may require a reduction in the dose of rosiglitazone. Simultaneous application rosiglitazona with inducer СУР2С8 (for example, rifampicin) led to a decrease in the concentration rosiglitazona in blood plasma. Thus, with simultaneous use with inducers of the enzyme СUR2С8 it is necessary to carry out a thorough control of glycemia and it is necessary to consider the possibility of correcting the regimen for the treatment of diabetes mellitus. Clinical researches testify that, what rosiglitazone did not have a clinically significant effect on the pharmacokinetics S(-) - warfarin (the substrate of the enzyme СUR2С9).

Rosiglitazone had no effect on the equilibrium pharmacokinetics digoxin or warfarin and did not change anticoagulant activity warfarin.

Rosiglitazone at therapeutic doses had no clinically significant effect on the pharmacokinetics and pharmacodynamics simultaneously applied to other oral hypoglycemic drugs, including metformin, glibenclamide, glimepiride and acarbose. There were no clinically significant interactions as rosiglitazone and nifedipine or oral contraceptives (consisting of ethinyl estradiol and norethisterone), while the application,which confirms the low probability of interaction rosiglitazona with drugs that are metabolized by the enzyme SURZA4.

Metformin

Avandamet should be avoided during application use of alcohol and medicines, containing ethanol.

In acute alcohol intoxication on the background of treatment with a combination rosiglitazone + metformin increased risk of lactic acidosis, caused by metformin. Cationic preparations, which are excreted by renal tubular secretion (including cimetidine) can interact with metformin, competing for a common transport system in the tubules of the kidneys. Careful monitoring is necessary glycemia and, if necessary, change scheme treatment diabetes mellitus with the simultaneous use of cationic drugs, excreted by renal tubular secretion.

Drugs, combined use with which requires special precautions

Glucocorticosteroids (systemic and topical), β₂-Agonists, diuretics can

cause hyperglycemia. More frequent monitoring of blood glucose concentration is required, especially at the beginning of treatment.If necessary, adequately adjust the dose of hypoglycemic drugs, including when you cancel drugs.

ACE inhibitors may reduce concentration glucose at blood. If necessary, adequately adjust the dose of hypoglycemic drugs.

Special instructions:

Type 1 diabetes mellitus

Combination rosiglitazone + metformin is effective only in the presence of insulin, and should not be used to treat diabetic patients 1 type.

Patients in the pre-menopausal period with anovulation

Due to increased sensitivity to insulin, treatment with a combination of rosiglitazone + metformin premenopausal women with anovulation and isisulin resistance (for example, patients with polycystic ovary syndrome) may lead to the resumption of ovulation. For this group of patients, there is a risk of pregnancy.

Fertility

In clinical trials, these women in pre-menopausal women received rosiglitazone. Despite the fact that in preclinical studies there was a violation of the hormonal balance, during treatment with rosiglitazone, there were no significant undesirable effects associated with from violations menstrual cycle. When An unforeseen occurrence of a menstrual irregularity should consider the benefits of continuing therapy.

Lactic acidosis

This is a rare but serious metabolic complication that can occur as a result of the cumulation of metformin. Cases of lactic acidosis in patients receiving metformin, appeared mainly in the group of patients with diabetes mellitus with clinically significant renal dysfunction. Before starting treatment with metformin and, therefore, a combination of rosiglitazone + metformin, it is necessary to assess concomitant risk factors for lactic acidosis, for example, insufficiently controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, liver failure and any diseases accompanied by tissue hypoxia. If you suspect a lactic acidosis, you must cancel the combination rosiglitazone + metformin and immediately hospitalize the patient.

Impaired renal function

There are limited data on the treatment with rosiglitazone patients with severe renal failure. Metformin is excreted by the kidneys, therefore, before starting treatment with Avandamet and further with regular intervals, it is necessary to determine the serum creatinine concentration. Particular attention should be given to patients with an increased risk of developing kidney failure, such as the elderly or someone who is in a condition that can reduce kidney function (eg, dehydration, severe infection, or shock). Avandamet should not be administered to patients with a serum creatinine concentration greater than 135 μmol / L in men or 110 μmol / L in women.

Impaired liver function

Have patients with mild liver function disorder (6 points or less on the Child-Pugh scale, class A), the dose of rosiglitazone should not be reduced. However, given that impaired liver function is a risk factor for development lactic acidosis associated with metformin, a combination of rosiglitazone + metformin not it is recommended to appoint patients with impaired liver function.

Cardiovascular diseases

Rosiglitazone, like others thiazolidinediones, in some patients may cause or worsen the course of heart failure.After starting therapy with a combination rosiglitazone + metformin, and also after a dose increase, careful medical monitoring of the patient's condition, in particular, symptoms and signs of heart failure (including rapid and excessive weight gain, shortness of breath, swelling) is necessary. When symptoms of heart failure appear, therapy should be prescribed in accordance with current standards for the treatment of heart failure. In addition, it is necessary to consider the possibility of canceling the drug or reducing the dose of the combination rosiglitazone + metformin. Combination rosiglitazone + metformin is contraindicated in patients with heart failure of I-IV functional class according to NYON.

Patients with acute coronary syndrome (ACS) were not included in the clinical studies. Since the development of ACS increases the risk of cardiovascular complications, Considering the possibility of developing heart failure with rosiglitazone, Avandamet is not recommended in patients with ACS. When developing ACS, consider the possibility of canceling a combination rosiglitazone + metformin. There are contradictory data on the ability rosiglitazona increase the risk of myocardial ischemia. A retrospective analysis of 42, mostly short-term clinical trials, suggests a relationship between rosiglitazone intake and the risk of developing myocardial ischemia in placebo-controlled trials, but not in comparison with active drugs. An increased risk of developing myocardial ischemia was observed in patients who were in clinical trials with basic nitrate therapy. The risk of developing myocardial ischemia was not confirmed at individual large-scale, longer-term studies. It is particularly important that there is no increased risk in a prospective clinical trial cardiovascular outcomes (mean follow-up period 5.5 years), in which a combination rosiglitazone + metformin and sulfonylurea derivatives.

Causal and investigative the relationship between rosiglitazone intake and the development of myocardial ischemia has not been established. There is also no reliable comparative data on the effect on cardiovascular risks and the comparative advantages of taking oral hypoglycemic drugs, including thiazolidinediones, in patients with type 2 diabetes mellitus. A small number of phenomena associated with myocardial ischemia were observed in patients receiving insulin therapy when rosiglitazone was added. The incidence of these events was higher with combined treatment (2.77%) compared with insulin monotherapy (1.36%). The use of the drug Avandamet together with insulin therapy is contraindicated.

Diabetes mellitus type 2 is one of the main risk factors for the development of coronary heart disease and adverse outcomes of myocardial ischemia. Therefore, regardless of the choice of a hypoglycemic drug, this disease requires evaluation of risk factors for cardiovascular adverse events and, if possible, correction hypoglycemic therapy. Disturbances from the side of the eye In post-marketing reports, when Avandamet is used there are very few reports of the development or deterioration of diabetic macular edema with reduced visual acuity. Many of these patients had peripheral edema. In some cases, such violations were resolved after the abolition of therapy.It should be borne in mind the possibility of developing this complication if the patient has complaints of reduced visual acuity.

Hypoglycaemia

Patients taking Avandamet in a triple combined therapeutics with derivatives sulfonylureas, may have a risk of dose-dependent hypoglycemia. You may need to reduce the dose of the concomitant drug.

Surgical intervention

Metformin and, therefore, the drug Avandamet must be discontinued 48 hours before the scheduled operation with general anesthesia and resumed no earlier than 48 hours after the operation.

The use of contrast agents containing iodine

Intravenous administration of iodine-containing contrast agents in X-ray studies can cause kidney failure. Taking this into account, Avandamet as a preparation containing metformin, should be canceled before or during a radiologic examination, and it can be resumed only after confirmation of normal kidney function.

Effect on the condition of bone tissue

In a comparative study of glycemic control lasting 4-6 years ("ADORT "-" Examining the outcome of diabetes mellitus ") using monotherapy in patients who had not previously received treatment, who was recently diagnosed with type 2 diabetes, there was an increase in the frequency of bone fractures in women taking rosiglitazone. During the 4-6 year period, the incidence of fractures in women taking rosiglitazone, was 9.3% (60/645) compared with 3.5% (21/605) in women taking glibenclamide, and from 5.1% (30/590) in women taking metformin. This increase in frequency was noted after the first year of treatment and persisted throughout the study.

Most registered messages in the rosiglitazone group concerned fractures of the upper limbs and fractures of the distal sections of the lower limbs. This localization of fractures differs from that usually observed in postmenopausal osteoporosis (for example, proximal femur or spine). Other studies show that the risk of bone fractures can also exist in men. Nevertheless, the risk of fractures in women is obviously higher than that of men.

In women, an increase in the incidence of fractures was recorded after the first year of use and subsequent application for a long period. When rosiglitazone is prescribed, especially for women, a possible increase in the risk of fractures should be taken into account. It is necessary to monitor bone mineral density (BMD).

In several studies in men and women taking rosiglitazone, cases of a slight decrease in BMD in the spine and femur were recorded. Correlations between changes in BMD and Risk of fractures is not established.

Simultaneous use with other drugs (see also section "Interaction with other medicinal products")

When used simultaneously with inhibitors or inducers of enzyme CYP2C8 and with the simultaneous use of cationic drugs, derived by renal tubular secretion, requires careful monitoring of blood glucose concentrations and dosage adjustment of rosiglitazone or metformin.

Effect on the ability to drive transp. cf. and fur:Rosiglitazone and metformin Do not affect the driving of cars and the work with mechanisms.

Form release / dosage:Film-coated tablets, 500 mg + 1 mg, 500 mg + 2 mg.

Packaging:For 14 tablets in PVC / A1 blister. For 1, 2. 4 or 8 blisters together with the instruction for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000079

Date of registration:29.05.2007

Expiration Date:Unlimited

Date of cancellation:2017-12-14

The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia

Manufacturer: & nbsp

GLAXO WELLCOME, S.A. Spain

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp14.12.2017

Illustrated instructions

Instructions

Avandamet (Avandamet)