2010/06/24

Avandamet

Composition, structure and packing

Tablets, film-coated yellow, oval, engraved with the "gsk" on one side and "1 / 500" - on the other.
1 tab. rosiglitazone maleate (pellets) 1.33 mg, including rosiglitazone;
1 mg of metformin hydrochloride (pellets) 500 mg.

Excipients: karboksimetilkrahmal, gipromelloza 3sR, microcrystalline cellulose, lactose monohydrate (pellet rosiglitazona), povidone 29-32, gipromelloza 3sR, microcrystalline cellulose, magnesium stearate (for granules metformin).

The composition of the shell: Opadry I yellow (gipromelloza 6sR, titanium dioxide, macrogol 400, iron oxide yellow).

Tablets, film-coated pink, oval, engraved with "gsk" on one side and "2 / 500" - on the other.
1 tab. rosiglitazone maleate (pellets) 2.65 mg, including rosiglitazone;
2 mg of metformin hydrochloride (pellets) 500 mg.

Excipients: karboksimetilkrahmal, gipromelloza 3sR, microcrystalline cellulose, lactose monohydrate (pellet rosiglitazona), povidone 29-32, gipromelloza 3sR, microcrystalline cellulose, magnesium stearate (for granules metformin).

The composition of the envelope: Opadry I pink (gipromelloza 6sR, titanium dioxide, macrogol 400, iron oxide red).

Generic international title, as recommended by WHO, in Russia decided to write an international name - rosiglitazon.

Clinico-pharmacological group: oral hypoglycemic drug.

Pharmacological action

Combined hypoglycemic drug for oral administration.

The structure Avandameta includes two active ingredients with complementary mechanisms of action, which improves glycemic control in patients with diabetes mellitus type 2: rosiglitazona maleate belongs to a class of thiazolidinedione and metformin hydrochloride, a representative class of biguanide.

The mechanism of action of thiazolidinedione is mainly to enhance the sensitivity of target tissues to insulin, while biguanide operate mainly by reducing the production of endogenous glucose in the liver.

Rosiglitazon - selective agonist of PPARγ (peroxisomal proliferator activated gamma) receptors of the nucleus, referring to the hypoglycemic drugs of the thiazolidinedione group. Improves glycemic control by improving insulin sensitivity of key target-tissues, as adipose tissue, skeletal muscles and liver. It is known that insulin resistance plays an important role in the pathogenesis of type 2 diabetes mellitus.

Rosiglitazon improves metabolic control by lowering blood glucose, circulating insulin and free fatty acids. Rosiglitazona demonstrated hypoglycemic activity in experimental studies on models of type 2 diabetes mellitus in animals. Rosiglitazon retains the function of β-cells, as evidenced by the increase in mass islets of Langerhans of the pancreas and increase insulin content in them, and prevents the development of marked hyperglycemia. It was also established that rosiglitazon significantly slows down the development of renal dysfunction and systolic hypertension. Rosiglitazon does not stimulate the secretion of insulin by the pancreas and does not cause hypoglycemia in rats and mice. Improved glycemic control associated with significant decrease in the concentration of insulin in the blood serum. Also decreased the concentration of precursors of insulin, which, as is commonly believed, are risk factors for cardiovascular disease. One of the key results of treatment rosiglitazonom a significant decrease in the concentrations of free fatty acids.

Metformin is a representative of the biguanide class, which act mainly by reducing the production of endogenous glucose in the liver. Metformin lowers both basal and postprandial glucose concentrations in plasma. He does not stimulate insulin secretion and therefore does not cause hypoglycemia. Known 3 possible mechanism of action of metformin: reducing glucose in the liver through inhibition of gluconeogenesis and glycogenolysis, the sensitivity of the muscle tissue to insulin, increasing consumption and glucose utilization by peripheral tissues; delay absorption of glucose from the intestines. Metformin stimulates intracellular glycogen synthesis by activating the enzyme glikogensintazu. It increases the activity of all types of transmembrane carriers of glucose. In humans, regardless of its effect on glycaemia, metformin improves lipid metabolism. When using metformin at therapeutic doses in the medium and long-term clinical studies have shown that metformin reduces the concentration of total cholesterol, LDL cholesterol and TG.

Due to different but complementary mechanisms of action of combined therapy rosiglitazonom and metformin leads to a synergistic improvement of glycemic control in patients with diabetes mellitus type 2.

Pharmacokinetics

Absorption

Avandamet

Investigation of bioequivalence Avandameta (4 mg/500 mg) showed that both components of the drug, rosiglitazon and metformin tablets were bioequivalent rosiglitazona maleate 4 mg and metformin hydrochloride tablets 500 mg in their simultaneous application. This study also demonstrated dose proportionality rosiglitazona in Combination Therapies 1 mg/500 mg and 4 mg/500 mg. Eating does not alter the AUC rosiglitazona and metformin. However, simultaneous ingestion leads to a decrease in Cmax rosiglitazona - 209 ng / ml, compared with 270 ng / ml, and reduce the Cmax of metformin - 762 ng / ml, compared with 909 ng / ml, and an increase in Tmax rosiglitazona - 2.56 h compared with 0.98 h and metformin - 3.96 h, compared to 3 hours

Rosiglitazon

Once inside rosiglitazona in doses of 4 mg or 8 mg rosiglitazona absolute bioavailability is about 99%. Cmax rosiglitazona reached about 1 h after its ingestion. In the range of therapeutic doses rosiglitazona concentrations in plasma approximately proportional to dose. Receiving rosiglitazona with food does not alter the AUC, but compared with the reception on an empty stomach was a slight decrease in Cmax (approximately 20-28%) and an increase in Tmax (1.75 h). These small changes are clinically insignificant, so rosiglitazon can be taken irrespective of food intake. Increasing the pH of gastric contents did not affect the absorption rosiglitazona.

Metformin

After oral administration of metformin Tmax of about 2.5 h, at doses of 500 mg or 850 mg absolute bioavailability in healthy people is about 50-60%. The absorption of metformin is saturable and incomplete. Once inside neabsorbirovavshayasya fraction detectable in the feces accounted for 20-30% of the dose. It is assumed that the absorption of metformin is nonlinear. In the application of metformin in normal doses, and the usual dosing regimen Css in plasma are achieved within 24-48 hours and are usually less than 1 ug / ml. In controlled clinical studies of metformin Cmax not exceed 4 mg / ml, even after taking the maximum doses. Simultaneous food intake reduces the absorption of metformin and slightly reduces the rate of absorption. After oral administration of metformin at a dose of 850 mg while eating his C max decreased by 40% and AUC - 25%, Tmax is increased by 35 min. The clinical significance of these changes is not known.

Distribution

Rosiglitazon

Vd rosiglitazona is about 14 liters, while the total plasma clearance - about 3 l / h. The high degree of plasma protein binding - about 99.8%, does not depend on the concentration and age of the patient. There is currently no data on the unexpected accumulation rosiglitazona at his reception 1-2 times / day.

Metformin

The binding of metformin to plasma proteins is negligible. Metformin penetrates the red blood cells. Cmax in the blood is lower than the Cmax in the plasma and achieved approximately the same time. Red blood cells, most likely, are secondary compartments of distribution. The average Vd varies from 63 to 276 liters.

Metabolism

Rosiglitazon

Subjected to intensive metabolism, appears in the form of metabolites. The main routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. Metabolites rosiglitazona not possess pharmacological activity. Studies in vitro have shown that rosiglitazon metabolized predominantly isoenzyme CYP2C8 and to a much lesser extent - isoenzyme CYP2C9. In the in vitro rosiglitazon does not significantly inhibitory effect on isozymes CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A and CYP4A, so it is unlikely that in vivo, it shall enter into clinically relevant metabolic interactions with drugs that are metabolized by these isoenzymes cytochrome P450 . In vitro rosiglitazon moderately inhibited CYP2C8 (IC50 - 18 uM) and weakly inhibited CYP2C9 (IC50 - 50 uM). Investigation of interaction rosiglitazona with warfarin in vivo showed that rosiglitazon does not interact with substrates CYP2C9. Metformin is not subject to metabolism and is excreted unchanged in the kidneys. A person not identified any metabolites of metformin.

Withdrawal

Rosiglitazon

Total plasma clearance rosiglitazona is about 3 l / h, and its final T1 / 2 of approximately 3-4 h. There is currently no data on the sudden accumulation rosiglitazona at his reception 1-2 times / day. About 2 / 3 of the oral dose rosiglitazona output kidneys, approximately 25% eliminated through the intestines. Unchanged rosiglitazon not detected in the urine or in feces. Final T1 / 2 of metabolites is about 130 h, indicating a very slow their breeding. Repeated ingestion rosiglitazona not excluded accumulation of its metabolites in plasma, in particular the major metabolite (paragidroksisulfata), the concentration of which, presumably, could increase by 5 times.

Metformin

Excreted unchanged in the kidneys by glomerular filtration and tubular secretion. Renal clearance of metformin is more than 400 ml / min. Once inside the final T1 / 2 of metformin is approximately 6.5 hours

Pharmacokinetics in special clinical situations

There have been no significant differences in the pharmacokinetics rosiglitazona depending on gender, age. There have been no significant differences in the pharmacokinetics rosiglitazona in patients with impaired renal function, as well as in chronic dialysis. In patients with moderate and severe hepatic impairment (classes B and C on the scale of Child-Pugh) Cmax and AUC were 2-3 times higher, the result of increased plasma protein binding and decreased clearance rosiglitazona. In patients with renal renal clearance decreased proportionally reduce the spacecraft, and, consequently, increased T1 / 2, as a result of the increased concentration of metformin in plasma.

Statement

Diabetes mellitus type 2:
for glycemic control with diet or ineffectiveness of monotherapy with metformin or thiazolidinediones derivatives, or with previous combination therapy with metformin and thiazolidinedione (two-component therapy);
for glycemic control in combination with sulfonylureas derivatives (triple therapy).

Dosage regimen

The drug is prescribed for adults. Dosage regimen is selected and installed individually. Avandamet may be taken irrespective of food intake.

Receiving Avandameta during or after a meal reduces the unwanted reaction from the digestive system caused by metformin.

The recommended starting dose for adults combinations rosiglitazon / metformin is 4 mg/1000 mg. Daily dose combination rosiglitazon / metformin may be increased to maintain individual control of glycemia. The dose should increase gradually to the maximum - 8 mg rosiglitazona/2000 mg of metformin in the day. The slow increase in dose may reduce the adverse reactions of the digestive system (caused mainly metformin). The dose should be increased in increments of 4 mg / day for rosiglitazona and / or 500 mg daily for metformin. The therapeutic effect after a dose adjustment can not occur within 6-8 weeks for rosiglitazona and within 1-2 weeks for metformin.

In the transition from oral hypoglycemic agents other to a combination of rosiglitazona and metformin should take into account the activity and the duration of the previous drugs.

In the transition from therapy rosiglitazon + metformin monotherapies as a treatment Avandametom initial dose combinations rosiglitazona and metformin should be based on already taken doses rosiglitazona and metformin. Correction doses of one of the components Avandameta, rosiglitazona or metformin, may require the combined use with other drugs.

In elderly patients the initial and maintenance dose Avandameta be adequately adjusted, taking into account the likely decrease in renal function. Any dose adjustment should be based on renal function, which must be constantly monitored.

Patients with hepatic impairment Mild (Class A / 6 points or less / scale Child-Pugh) do not require correction dosing regimen rosiglitazona. Since the abnormal liver function is a risk factor laktatsidoza the treatment with metformin, rosiglitazona combination with metformin is not recommended to be considered in patients with disorders of the liver in patients receiving Avandamet in combination with sulfonylureas, the initial dose rosiglitazona when receiving Avandameta should be 4 mg / day. Increasing doses rosiglitazona up to 8 mg / day should be taken with caution when assessing the risk of adverse reactions associated with water retention.

Side effect

The frequency of adverse reactions submitted in accordance with the following scale: very often (≥ 1 / 10), frequently (≥ 1 / 100, <1 / 10), sometimes (≥ 1 / 1000, <1 / 100), rare (≥ 1 / 10 000, <1 / 1000), is very rare (<1 / 10 000).

The combination rosiglitazon + metformin

Adverse reactions occurring while taking the drug Avandamet may be due to the two active ingredients comprising the drug.

Rosiglitazon

Frequency categories are defined in comparison with the frequency of unwanted reactions in the treatment of placebo or drug comparison, and not absolute values for those adverse reactions that may be associated with rosiglitazonom. For dose-dependent adverse reactions the frequency category reflects the maximum dose rosiglitazona. Categories of frequency do not account for other factors, including differences in study duration, antecedent conditions and the initial characteristics of patients. Categories of frequency of undesirable reactions are based on clinical studies and may not reflect the frequency of adverse reactions in normal clinical practice.

Increasing the number of cases of congestive heart failure was observed in accession rosiglitazona to therapy, based on sulfonylureas or insulin. Number of observations does not allow a clear conclusion about the connection with the drug dose, but the incidence is higher for a daily dose rosiglitazona 8 mg, compared with a daily dose of 4 mg. Symptoms of myocardial ischemia were more frequent in the appointment rosiglitazona patients who are on insulin therapy. Data on the ability rosiglitazona increase the risk of myocardial ischemia insufficient. Retrospective analysis of mostly short-clinical studies with placebo, but no comparison with the drug, said the relationship between the intake rosiglitazona and risk of myocardial ischemia. These findings are not supported by long clinical studies with drugs comparison (metformin and / or sulfonylureas), and the relationship between rosiglitazonom and the risk of ischemia is not installed. Increased risk of ischemic myocardial damage was observed in patients who were in clinical research on the basal nitrate therapy. Rosiglitazon not recommended in patients receiving concomitant therapy with nitrates.

In the postmarketing period reported the following adverse reactions

Allergic reactions: very rare - anaphylactic reactions.

Since the cardiovascular system: rarely - Chronic heart failure / pulmonary edema. Reports on the development of these adverse reactions were obtained for rosiglitazona, used as monotherapy and in combination with other hypoglycemic means. It is known that the risk of heart failure significantly increased in patients with diabetes compared with patients without diabetes.

On the part of the digestive system: rarely reported complaints of violations of the liver, accompanied by increasing concentrations of liver enzymes, but the causal link between treatment rosiglitazonom and liver dysfunction is not installed. Allergic reactions: seldom - angioedema, urticaria, rash, itchy skin.

On the part of the organ of vision: a very rare - macular edema.

Metformin

These clinical trials and postmarketing period, the part of the digestive system: very often - dyspepsia (nausea, vomiting, diarrhea, abdominal pain, anorexia). Mainly developed in the appointment of the drug in high doses and at the beginning of treatment, in most cases are on their own. Often - metallic taste in the mouth.

Dermatological reactions: very rare - erythema.

Was observed in patients with hypersensitivity and was mostly mild. Other: very rarely - laktatsidoz, deficiency of vitamin B12.

Contraindications
Heart failure (I-IV functional classes classification NYHA);
acute or chronic diseases that lead to tissue hypoxia (eg cardiac or respiratory failure, recent myocardial infarction, shock);
hepatic impairment;
alcoholism, acute alcohol intoxication;
diabetic ketoacidosis;
diabetic precoma;
renal impairment (Serum creatinine over 135 umol / l in men and more than 100 mmol / l in women and / or the CC less than 70 ml / min);
acute condition and the risk of renal failure (dehydration, severe infection, shock);
intravascular injection of radiopaque iodine;
simultaneous insulin;
Hypersensitivity to the drug's components.

Pregnancy and lactation

There is currently no sufficient data on the application of the drug in pregnant women. Reported the ability rosiglitazona cross the placenta in humans and is found in fetal tissues. During pregnancy, women with diabetes is usually recommended to appoint insulin. Pregnant women Avandamet may be granted only in cases when the expected benefit to the patient outweighs the potential risk to the fetus.

Currently there are no sufficient data on the use Avandameta in nursing women. It is not known whether Avndamet penetrate into breast milk. Lactating women suffering from diabetes, insulin is usually recommended to appoint. Avandamet lactating women can be given only if the expected benefit outweighs the potential risk to the child.

Application for violations of liver function

Since the abnormal liver function is one of the risk factors of lactic acidosis with metformin treatment, Avandamet is not recommended to be considered in patients with hepatic impairment.

Application for violations of renal function

Metformin is displayed by the kidneys, so before starting treatment Avandametom continue at regular intervals is necessary to determine the concentration of creatinine in serum. Particular attention should be given to patients with an increased risk of renal failure, for example, elderly patients or patients whose condition may be accompanied by a decrease in renal function (dehydration, severe infection or shock). Avandamet should not be prescribed to patients with serum creatinine over 135 umol / l in men or 110 mol / l in women.

The drug contraindications in renal impairment (Serum creatinine over 135 umol / l in men and more than 100 mmol / l in women) and / or the CC less than 70 ml / min.

Cautions

The combination rosiglitazon + metformin, including Avandamet, effective only while maintaining the production of endogenous insulin, the drug should not be appointed for the treatment of patients with diabetes mellitus type 1. Because of increasing sensitivity to insulin treatment combination rosiglitazon + metformin in premenopausal women with anovulation and insulin resistance (eg, patients with polycystic ovary syndrome) can lead to the resumption of ovulation. Such patients may become pregnant. Women predmenopauznogo children receive rosiglitazon during clinical studies. Hormone imbalance observed in the experiment, but during the treatment of women rosiglitazonom no significant adverse reactions, involving violations of the menstrual cycle. In the case of menstrual disorders should critically evaluate the appropriateness of continuing treatment Avandametom.

Due to accumulation of metformin in rare cases, there is a serious metabolic complication - laktatsidoz, mainly in patients with diabetes with clinically significant renal dysfunction. Before treatment with metformin and, therefore, a combination of rosiglitazon + metformin, it is necessary to evaluate associated risk factors of lactic acidosis, such as insufficiently controlled diabetes, ketosis, prolonged fasting, excessive alcohol consumption, liver dysfunction (including hepatic failure) and any diseases accompanied by tissue hypoxia. If you suspect that laktatsidoz Avandamet should be lifted immediately and hospitalized patients. There are limited data on the treatment rosiglitazonom patients with renal failure and severe.

Metformin is displayed by the kidneys, so before starting treatment Avandametom continue at regular intervals is necessary to determine the concentration of creatinine in serum. Particular attention should be given to patients with an increased risk of renal failure, for example, elderly patients or patients whose state can be accompanied by a decrease in renal function (dehydration, severe infection or shock). Avandamet should not be prescribed for patients with serum creatinine over 135 umol / l in men or 110 mol / l in women.

Patients with hepatic impairment Mild (6 points or less on the scale of Child-Pugh) rosiglitazona lower dose is not necessary. However, given that the dysfunction of the liver is a risk factor for the development laktatsidoza associated with metformin, rosiglitazona combination with metformin is not recommended to be considered in patients with hepatic impairment.

Derivatives of thiazolidinediones, including rosiglitazon can cause or worsen chronic heart failure. After initiation of therapy rosiglitazonom and during dose titration, careful medical monitoring of the patient in respect of the following signs and symptoms of heart failure: a rapid and excessive weight gain, shortness of breath, swelling. With the development of symptoms of heart failure should consider reducing the dose or withdrawal Avandameta and assign therapy in accordance with current standards of treatment of heart failure. Do not use a combination of rosiglitazon + metformin in patients with symptomatic heart failure. The drug is contraindicated in patients with congestive heart failure I-IV functional class according to the classification NYHA. Patients with acute coronary syndrome (ACS) are not included in clinical studies. Since the development of acute coronary syndrome increases the risk of heart failure, not recommended for use rosiglitazon patients with ACS. Data on the ability rosiglitazona increase the risk of myocardial ischemia insufficient. Retrospective analysis of mostly short-clinical studies with placebo, but no comparison with the drug, said the relationship between the intake rosiglitazona and risk of myocardial ischemia. These findings are not supported by long clinical studies with drugs comparison (metformin and / or sulfonylureas), and the relationship between rosiglitazonom and the risk of ischemia is not installed. Increased risk of ischemic myocardial damage was observed in patients who were in clinical research on the basal nitrate therapy.

Also, there is no reliable data on the impact of receiving oral hypoglycemic drugs, including thiazolidinedione group on the status of large vessels in patients with diabetes mellitus type 2. Rosiglitazon not recommended in patients receiving concomitant therapy with nitrates. There are rare reports of the development or worsening diabetic macular edema with reduction of visual acuity. At the same patients are often reported on the development of peripheral edema. In some cases, these violations were resolved after discontinuation of therapy. Keep in mind the possibility of this complication in patients' complaints to reduce visual acuity.

Patients receiving Avandamet in the ternary combination with sulfonylureas may be at risk of developing dose-dependently hypoglycemia. You may need dose reduction while taking drugs.

Metformin and, consequently, Avandamet you must cancel 48 hours before elective surgery with general anesthesia and resume therapy not earlier than 48 h after surgery. In / to the introduction of iodine contrast medium in radiological investigations can cause kidney failure. Given this, Avandamet as a preparation containing metformin, should be lifted to contrast radiographic examination or during it, admission may resume only after confirmation of normal renal function.

In the long term study of monotherapy with type 2 diabetes mellitus patients not previously treated with oral hypoglycemic agents, it was observed an increase in the incidence of fractures for women in the group rosiglitazona (9.3%, 2.7 cases per 100 patients-years) compared with metformin group (5.1%, 1.5 cases per 100 patient-years) and gliburida / glibenclamide (3.5%, 1.3 cases per 100 patient-years). Most of the cases registered in the group concerned rosiglitazona fracture of forearm, hand and foot. Possible increased risk of fractures should take into account when appointing rosiglitazona, especially women. Required monitoring of bone and maintenance of bone health in accordance with the standards of therapy.

In case of simultaneous appointment with inhibitors or inducers of CYP2C8 and when used with cationic drugs that are derived through the renal glomerular secretion, requires careful control of blood glucose and correction doses rosiglitazona or metformin.

Use in Pediatrics

Currently, no data on the use of the drug in children and adolescents under the age of 18 years, so the use of the drug in this age group is not recommended. Effects on ability to drive vehicles and management mechanisms Rosiglitazon and metformin does not affect the ability to drive vehicles and to work with mechanisms.

Overdose

There is currently no data on overdose Avandameta. In clinical studies, volunteers are well-tolerated single oral doses rosiglitazona to 20 mg. Symptoms: Overdose of metformin (or associated risk factors laktatsidoza) can lead to the development laktatsidoza.

Treatment: laktatsidoz an urgent medical condition and requires treatment in hospital. It is recommended that maintenance therapy, monitoring the clinical condition of the patient.

For the excretion of lactate and metformin should be used hemodialysis, but rosiglitazon not removed by hemodialysis (due to the high degree of protein binding).

Drug Interactions

Specific studies on the interaction Avandameta were launched. The following data reflect the information available about the interactions of individual active components Avandameta (rosiglitazona and metformin).

Rosiglitazon

Gemfibrozil (an inhibitor of CYP2C8) in a dose of 600 mg 2 times / day increased the Css rosiglitazona 2 times. This increase in concentration rosiglitazona associated with risk of dose-dependent side effects, so in the combined use with inhibitors of CYP2C8 Avandameta may require dose reduction rosiglitazona. Other inhibitors of CYP2C8 caused a slight increase in systemic concentrations rosiglitazona. Rifampin (inductor CYP2C8) in a dose of 600 mg / day reduced the concentration of rosiglitazona by 65%. Therefore, patients who receive both rosiglitazon and inducers of enzyme CYP2C8, should involve careful control of blood glucose and change if necessary dose rosiglitazona.

Readmission rosiglitazona increases the Cmax and AUC of methotrexate in 18% (90% CI: 11% - 26%) and 15% (90% CI: 8% - 23%), respectively, compared with the same dose of methotrexate in the absence of rosiglitazona. Rosiglitazon in therapeutic doses did not exert clinically significant effect on the pharmacokinetics and pharmacodynamics simultaneously used other oral hypoglycemic drugs, including metformin, glibenclamide, glimepirid and acarbose.

It was shown that rosiglitazon has no clinically significant effect on the pharmacokinetics of S (-)-warfarin (substrate of the enzyme CYP2C9).

Rosiglitazon not affect the pharmacokinetics and pharmacodynamics of digoxin or warfarin and does not alter the anticoagulant activity of the latter.

There were no clinically significant interactions also rosiglitazona and nifedipine or oral contraceptive (ethinyl estradiol and consisting of norethisterone), while the application, which confirms the low probability of interaction rosiglitazona with drugs that are metabolized by involving CYP3A4.

Metformin

In acute alcohol intoxication on the background of treatment with a combination rosiglitazon + metformin increased risk of laktatsidoza due to metformin. Cationic drugs that are derived through the renal glomerular secretion (including cimetidine) may interact with metformin by competing for the overall system removal (should conduct a careful monitoring of blood glucose and change when necessary treatment when used with cationic drugs that are shown by renal glomerular secretion). In / to the introduction of X-ray contrast agents contain iodine, can cause kidney failure, which could result in accumulation of metformin and development laktatsidoza (use of metformin should be removed prior to imaging, may be resumed taking metformin at least 48 hours after the X-ray and positive re- evaluation of renal function).

Preparations for the application of which requires special care

GCS (systemic and topical), β2-adrenoceptor agonists, diuretics may cause hyperglycemia, so if you need simultaneous application with Avandametom require more frequent monitoring of blood glucose, especially at the beginning of treatment, may require dosage adjustment Avandameta, including remove the drug.

ACE inhibitors can reduce blood glucose levels. If necessary, the simultaneous use or drug withdrawal should be properly adjusted dose Avandameta.

Terms and Conditions of storage

The drug should be stored out of reach of children at or above 25 ° C. Shelf life - 2 years.