Avandamet - instructions for use of the drug, structure, Contraindications
Active material: Metformin, Rosiglitazone
When ATH: A10BD03
CCF: Oral hypoglycemic agents
ICD-10 codes (testimony): E11
Manufacturer: GlaxoSmithKline (Britain)
Avandamet: dosage form, composition and packaging
Pills, Film-coated yellow color, Oval, Engraved “gsk” on one side and “1/500” – another.
| 1 tab. | |
| rosiglitazone * maleate | 1.33 mg, |
| incl. rosiglitazone | 1 mg |
| metformin hydrochloride | 500 mg |
Excipients: carboxymethyl starch, hypromellose 3cP, microcrystalline cellulose, lactose monohydrate (for rosiglitazone granules); povidone 29-32, hypromellose 3cP, microcrystalline cellulose, magnesium stearate (for metformin granules).
The composition of the shell: Opadry I yellow (hypromellose 6cP, Titanium dioxide, macrogol 400, iron oxide yellow).
14 PC. – blisters (1) – cardboard boxes.
14 PC. – blisters (2) – cardboard boxes.
14 PC. – blisters (4) – cardboard boxes.
14 PC. – blisters (8) – cardboard boxes.
Pills, Film-coated Pink colour, Oval, Engraved “gsk” on one side and “2/500” – another.
| 1 tab. | |
| rosiglitazone * maleate | 2.65 mg, |
| incl. rosiglitazone | 2 mg |
| metformin hydrochloride | 500 mg |
Excipients: carboxymethyl starch, hypromellose 3cP, microcrystalline cellulose, lactose monohydrate (for rosiglitazone granules); povidone 29-32, hypromellose 3cP, microcrystalline cellulose, magnesium stearate (for metformin granules).
The composition of the shell: Opadry I pink (hypromellose 6cP, Titanium dioxide, macrogol 400, iron oxide red).
14 PC. – blisters (1) – cardboard boxes.
14 PC. – blisters (2) – cardboard boxes.
14 PC. – blisters (4) – cardboard boxes.
14 PC. – blisters (8) – cardboard boxes.
Pills, Film-coated yellow color, Oval, Engraved “gsk” on one side and “2/1000” – another.
| 1 tab. | |
| rosiglitazone * maleate | 2.65 mg, |
| which corresponds to the content of rosiglitazone | 2 mg |
| metformin hydrochloride | 1000 mg |
Excipients: hypromellose 3cP, sodium carboxymethyl starch, lactose monohydrate, microcrystalline cellulose (for rosiglitazone granules); povidone 29-32, hypromellose 3cP, microcrystalline cellulose, magnesium stearate (for metformin granules).
The composition of the shell: Opadry I yellow (hypromellose 6cP, Titanium dioxide, macrogol 400, iron oxide yellow).
14 PC. – blisters (1) – cardboard boxes.
14 PC. – blisters (2) – cardboard boxes.
14 PC. – blisters (4) – cardboard boxes.
14 PC. – blisters (8) – cardboard boxes.
Pills, Film-coated Pink colour, Oval, Engraved “gsk” on one side and “4/1000” – another.
| 1 tab. | |
| rosiglitazone * maleate | 5.3 mg, |
| which corresponds to the content of rosiglitazone | 4 mg |
| metformin hydrochloride | 1000 mg |
Excipients: hypromellose 3cP, sodium carboxymethyl starch, lactose monohydrate, microcrystalline cellulose (for rosiglitazone granules); povidone 29-32, hypromellose 3cP, microcrystalline cellulose, magnesium stearate (for metformin granules).
The composition of the shell: Opadry I pink (hypromellose 6cP, Titanium dioxide, macrogol 400, iron oxide red).
14 PC. – blisters (1) – cardboard boxes.
14 PC. – blisters (2) – cardboard boxes.
14 PC. – blisters (4) – cardboard boxes.
14 PC. – blisters (8) – cardboard boxes.
* international non-proprietary name, recommended by the WHO – Rosiglitazone.
Avandamet: pharmachologic effect
Combined hypoglycemic drug for oral use. Avandamet contains two active ingredients with complementary mechanisms of action, that improve glycemic control in patients with type 2 diabetes mellitus 2: rosiglitazone maleate, belonging to the class of thiazolidinediones, and metformin hydrochloride, member of the biguanide class. The mechanism of action of thiazolidinediones is mainly to increase the sensitivity of target tissues to insulin., while the biguanides act primarily by reducing endogenous glucose production in the liver.
Rosiglitazone – selective PPARγ agonist (peroxisomal proliferator activated gamma) nucleus receptors, related to hypoglycemic drugs from the group of thiazolidinediones. Improves glycemic control by increasing insulin sensitivity of target tissues key, as adipose tissue, skeletal muscle and liver.
Known, that insulin resistance plays an important role in the pathogenesis of diabetes mellitus type 2. Rosiglitazone improves metabolic control by lowering blood glucose, circulating insulin and free fatty acids.
The hypoglycemic activity of rosiglitazone has been demonstrated in experimental studies on models of type 2 diabetes mellitus. 2 in animals. Rosiglitazone preserves β-cell function, as evidenced by the increase in the mass of the islets of Langerhans of the pancreas and increase insulin content in them, as well as prevent the development of severe hyperglycemia. It was also established, that rosiglitazone significantly slows down the development of kidney dysfunction and systolic arterial hypertension. Rosiglitazone not stimulate the secretion of pancreatic insulin and does not cause hypoglycemia in rats and mice.
Improvement in glycemic control is accompanied by a clinically significant decrease in serum insulin concentration. Also decreases insulin precursor concentration, that, as is commonly believed, are risk factors for cardiovascular disease. One of the key results of treatment with rosiglitazone a significant decrease concentrations of free fatty acids.
Metformin is a member of the biguanide class, which act primarily by reducing endogenous glucose production in the liver. Metformin reduces both basal, and postprandial plasma glucose concentration. It does not stimulate insulin secretion and therefore does not cause hypoglycemia.. There are 3 possible mechanism of action of metformin: decreased glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis; increased sensitivity of muscle tissue to insulin, increased uptake and utilization of glucose by peripheral tissues; delayed absorption of glucose from the intestine.
Metformin stimulates intracellular glycogen synthesis, by activating the enzyme glycogen synthase. It enhances the activity of all types of transmembrane glucose transporters. People, regardless of its effect on glycemia, metformin improves lipid metabolism. When using metformin at therapeutic doses in medium-term and long-term clinical studies,, that metformin lowers total cholesterol concentrations, LDL cholesterol and TG.
Due to the different, However, due to complementary mechanisms of action, combination therapy with rosiglitazone and metformin results in a synergistic improvement in glycemic control in patients with type 2 diabetes mellitus. 2.
Pharmacokinetics
Absorption
Avandamet
Bioequivalence Study of Avandamet (4 mg / 500 mg) found, that both components of the drug, rosiglitazone and metformin, were bioequivalent to rosiglitazone maleate tablets 4 mg and metformin hydrochloride tablets 500 mg with their simultaneous use. This study also demonstrated dose proportionality of rosiglitazone in the combination product. 1 mg / 500 mg i 4 mg / 500 mg.
Meal does not change the AUC of rosiglitazone and metformin. At the same time, simultaneous eating leads to a decrease in Cmax rosiglitazone – 209 ng / ml, compared with 270 ng / ml, and decrease Cmax metformin – 762 ng / ml, compared with 909 ng / ml; and increase Tmax rosiglitazone – 2.56 h compared with 0.98 and metformin – 3.96 no, compared with 3 no.
Rosiglitazone
After oral administration of rosiglitazone at doses 4 mg or 8 mg The absolute bioavailability of rosiglitazone is about 99%. Cmax rosiglitazone reached approximately 1 hours after the intake of. The therapeutic dose range rosiglitazone plasma concentrations are approximately proportional to its dose.
Acceptance of rosiglitazone with food does not alter the AUC, but compared to the fasting state, a slight decrease in Cmax (about 20-28%) and an increase in Tmax (1.75 no).
These small changes are clinically insignificant, therefore, rosiglitazone can be taken with or without food.. An increase in gastric pH does not affect the absorption of rosiglitazone.
Metformin
After oral metformin Tmax is about 2.5 no, at doses 500 mg or 850 mg absolute bioavailability in healthy individuals is approximately 50-60%. Metformin absorption is saturable and incomplete. After oral administration, the unabsorbed fraction, obnaruzhivaemaя in Calais, was 20-30% dose.
Expected, Metformin absorption is non-linear. When using metformin at usual doses and the usual dosing regimen Css in plasma achieved within 24-48 h and make up, usually, less 1 ug / ml. In controlled clinical trials Cmax metformin does not exceed 4 ug / ml, even after taking the highest doses.
Simultaneous food intake reduces the degree of absorption of metformin and slightly reduces the rate of absorption.. After oral administration of metformin at a dose 850 mg while eating it Cmax reduced by 40% и AUC – on 25%, Tmax increases by 35 m. The clinical significance of these changes is not known..
Distribution
Rosiglitazone
Vd rosiglitazone is about 14 l, and the total plasma clearance – about 3 l /. The 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 evidence of unexpected accumulation of rosiglitazone when taking it. 1-2 times / day.
Metformin
Plasma protein binding of metformin is negligible. Metformin enters erythrocytes. Cmax in the blood below, than Cmax in plasma and is reached in about the same time. Red blood cells, probably, are a secondary distribution compartment.
Average Vd It varies between 63 to 276 l.
Metabolism
Rosiglitazone
Subjected to intensive metabolism, is output as metabolites. The main metabolic pathways are N-demethylation and hydroxylation, followed by conjugation with glucuronic acid and sulfate. Metabolites rosiglitazone not possess pharmacological activity.
Studies in vitro have shown, that rosiglitazone metabolized primarily CYP2C8 isoenzyme and to a much lesser extent – izofermentom CYP2C9.
In in vitro conditions rosiglitazone has no significant inhibitory effect on CYP1A2 isozymes, CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A и CYP4A , Therefore, it is unlikely, that in vivo it will enter into clinically significant metabolic interactions with drugs, these are metabolized by cytochrome P450 isozymes system. In vitro, rosiglitazone moderately inhibits CYP2C8 (inhibitory concentration – 18 mmol) and weakly inhibits CYP2C9 (inhibitory concentration – 50 mmol). Investigation of the interaction with warfarin rosiglitazone showed in vivo, that rosiglitazone does not interact with CYP2C9 substrates.
Metformin is not metabolized and is excreted unchanged by the kidneys.. No metabolites of metformin have been identified in humans..
Deduction
Rosiglitazone
Total plasma clearance of rosiglitazone is about 3 l /, and its final T1/2 is approximately 3-4 no. At present, there is no evidence of unexpected accumulation of rosiglitazone when taking it. 1-2 times / day. About 2/3 an oral dose of rosiglitazone excreted by the kidneys, about 25% displayed through the intestines. Unchanged rosiglitazone was not found in the urine., our fortress. The final T1/2 metabolites is approximately 130 no, which indicates a very slow release.. Repeated ingestion of rosiglitazone has not ruled out the cumulation of metabolites in the plasma, in particular the main metabolite (paragidroksisulyfata), a concentration, presumably, may increase 5 time.
Metformin
It is excreted unchanged by the kidneys through glomerular filtration and tubular secretion.. The renal clearance of metformin is more than 400 ml / min. After oral administration, final T1/2 metformin is approximately 6.5 no.
Pharmacokinetics in special clinical situations
There were no significant differences in the pharmacokinetics of rosiglitazone depending on gender., age.
There were no significant differences in the pharmacokinetics of rosiglitazone in patients with impaired renal function., as well as chronic dialysis.
In patients with moderate and severe hepatic impairment (Classes B and C on the Child-Pugh) Cmax and were AUC 2-3 times higher, resulting in increased plasma protein binding and reduced clearance of rosiglitazone.
In patients with impaired renal function, renal clearance decreases in proportion to the decrease in CC., and, Consequently, increases T1/2 , as a result, plasma concentrations of metformin increase.
Avandamet: testimony
Diabetes mellitus type 2:
- for glycemic control with the ineffectiveness of diet therapy or monotherapy with thiazolidinedione derivatives or metformin, or with previous combination therapy with thiazolidinedione and metformin (dual therapy);
- for glycemic control in combination with sulfonylurea derivatives (three-component therapy).
Avandamet: dosing regimen
The drug is prescribed adult.
The dosage regimen is selected and set individually.
Avandamet can be taken with or without food.. Taking Avandamet during or after a meal reduces unwanted reactions from the digestive system, metformin-related.
Recommended starting dose for Adult rosiglitazone/metformin combination is 4 mg / 1000 mg. The daily dose of the rosiglitazone/metformin combination may be increased to maintain individual glycemic control.. The dose should be increased gradually up to the maximum – 8 mg rosiglitazone/2000 mg metformin per day.
Slow dose escalation may reduce adverse reactions from the digestive system (caused mainly by metformin). The dose should be increased in increments 4 mg/day for rosiglitazone and/or 500 mg / day for metformin. Therapeutic effect of dose after correction can not be shown for 6-8 weeks and for rosiglitazone 1-2 weeks for metformin.
When switching from other oral hypoglycemic drugs to a combination of rosiglitazone and metformin, the activity and duration of action of the previous drugs should be taken into account..
When switching from rosiglitazone+metformin alone to treatment with avandamet, the initial dose of the combination of rosiglitazone and metformin should be based on the doses of rosiglitazone and metformin already taken..
Dose adjustment of one of the Avandamet components, rosiglitazone or metformin, may be required when used in combination with other drugs.
In elderly patients the initial and maintenance doses of Avandamet should be adequately adjusted, given the likely decline in kidney function. Any dose adjustment should be made based on renal function., which should be continuously monitored.
In patients with mild hepatic impairment (class A /6 points or less / Child-Pugh) no adjustment of rosiglitazone dosing regimen required. Since liver dysfunction is one of the risk factors for lactic acidosis in the treatment of metformin, The combination of rosiglitazone with metformin is not recommended for patients with hepatic impairment.
Patients, receiving Avandamet in combination with a sulfonylurea, The starting dose of rosiglitazone while taking Avandamet should be 4 mg / day. Increasing the dose of rosiglitazone to 8 mg/day should be used with caution after assessing the risk of adverse reactions, related to fluid retention.
Avandamet: side effects
The frequency of adverse reactions is represented by the following gradation: Often (≥1/10), often (≥1/100, <1/10), sometimes (≥1/1000, <1/100), rarely (≥1/10 000, <1/1000), rarely (<1/10 000).
Rosiglitazone combination + metformin
Adverse reactions, arising from the use of the drug Avandamet, may be due to both active components, members of the drug.
Rosiglitazone
frequency category determined in comparison with the frequency of occurrence of adverse reactions in treatment comparisons of placebo or preparation, rather than absolute values for those adverse reactions, which may be associated with rosiglitazone. For dose-related adverse reactions the frequency category reflects the maximum dose of rosiglitazone. Frequency categories do not account for other factors, including differences in study duration, previous state and baseline characteristics of patients. Categories of frequency of adverse reactions identified through clinical trials and may not reflect the frequency of adverse reactions in clinical practice.
Data, obtained in clinical trials
P – rosiglitazone, M – metformin, FROM – sulifonilmochyevina
| Side effect | P | P + M | P + C | P + FROM + M |
| From the hematopoietic system | ||||
| Anemia | often | often | often | often |
| Leukopenia | often | |||
| Thrombocytopenia | often | |||
| Granulocytopenia | often | |||
| Mild to moderate anemia, often dose dependent | ||||
| Metabolism | ||||
| Hypercholesterolemia | often | often | often | often |
| Hyperglyceridemia | often | often | ||
| Hyperlipidemia | often | often | often | often |
| Weight gain | often | often | often | often |
| Increased appetite | often | sometimes | ||
| Gipoglikemiâ | often | Often | Often | |
| In hypercholesterolemia, total cholesterol increased simultaneously with an increase in HDL and LDL, the ratio cholesterol / HDL cholesterol remained unchanged. Weight gain is dose-dependent and possibly related to fluid retention and fat accumulation. Mild or moderate hypoglycemia, mostly dose-dependent. | ||||
| CNS | ||||
| Dizziness | often | often | ||
| Headache | often | |||
| Cardio-vascular system | ||||
| Heart failure / pulmonary edema | often | often | ||
| myocardial ischemia | often | often | often | often |
| An increase in the incidence of heart failure was observed when rosiglitazone was added to therapy., based on sulfonylurea or insulin. The number of cases does not allow to make an unambiguous conclusion about the relationship to the dose of the drug, however, the incidence of the above daily dose for rosiglitazone 8 mg, compared with a daily dose 4 mg. The symptoms of myocardial ischemia were more frequently observed in the appointment of rosiglitazone patients, with insulin. Data on the ability of rosiglitazone to increase the risk of myocardial ischemia are insufficient. Retrospective analysis of mostly short clinical trials with placebo, but not with the comparator, suggests an association between rosiglitazone and the risk of myocardial ischemia. These data are not confirmed by long-term clinical studies with comparators. (metformin and/or sulfonylurea), and the relationship between rosiglitazone and the risk of ischemia has not been established. An increased risk of developing ischemic myocardial damage was observed in patients, were during clinical trials on basic therapy with nitrates. | ||||
| From the digestive system | ||||
| Constipation (mild to moderate) | often | often | often | often |
| On the part of the musculoskeletal system | ||||
| Fractures | often | |||
| Myalgia | often | |||
| Most reports concerned the forearm fractures, hands and feet of women | ||||
| From the body as a whole | ||||
| Swelling | often | often | Often | Often |
| Swelling of mild to moderate severity, often dose-dependent. | ||||
The following adverse reactions have been reported in the post-marketing period
On the part of the immune system: rarely – anaphylactic reactions.
Cardio-vascular system: rarely – Chronic heart failure / pulmonary edema.
Reports on the development of undesirable reactions data obtained for rosiglitazone, used as monotherapy and in combination with other hypoglycemic agents. Known, that the risk of developing heart failure is significantly increased in patients with diabetes compared to patients, do not have diabetes.
From the digestive system: rarely noted reports of hepatic dysfunction, accompanied by an increase in the concentration of liver enzymes, however, a causal relationship between treatment with rosiglitazone and liver dysfunction has not been established.
Skin and subcutaneous tissue disorders: rarely – angioedema, hives, rash, itching.
On the part of the organ of vision: rarely – macular edema.
Metformin
Data from clinical studies and post-marketing period
From the digestive system: Often – dyspepsia (nausea, vomiting, diarrhea, stomach ache, anorexia). They mainly develop when prescribing the drug in high doses and at the beginning of treatment., in most cases go away on their own. Often – metallic taste in mouth.
Dermatological reactions: rarely – эritema (observed in patients with hypersensitivity and was, primarily, mild).
Other: rarely – Lactic acidosis, vitamin B deficiency12.
Avandamet: Contraindications
- Heart failure (I-IV functional classes according to NYHA classification);
- Acute or chronic disease, leading to tissue hypoxia (eg, cardiac or respiratory failure, recent myocardial infarction, shock);
- Liver failure;
- Alcoholism, acute alcohol intoxication;
- Diabetic ketoacidosis;
- Diabetic precoma;
- Renal failure (of serum creatinine 135 µmol/l in men and more 100 µmol / l in women and / or CC less 70 ml / min);
- acute conditions with a risk of developing renal failure (degidratatsiya, severe infections, shock);
- intravascular injection of iodine-containing radiopaque agents;
- Simultaneous administration of insulin;
- Hypersensitivity to the drug.
Avandamet: Pregnancy and lactation
Currently, there are no sufficient data on the use of the drug in pregnant women.. It reported on the ability of rosiglitazone to cross the placenta in humans and is found in fetal tissues. Women with diabetes are usually advised to take insulin during pregnancy.. Avandamet can be prescribed to pregnant women only if, when the expected benefit to the patient outweighs the potential risk to the fetus.
At the moment, there is not enough data on the use of Avandamet in lactating women.. It is not known whether Avndamet passes into breast milk.. Lactating women, suffering from diabetes, usually it recommended to prescribe insulin. Avandamet lactating women can be prescribed only if, when the expected benefit outweighs the potential risk to the child.
Avandamet: Special instructions
Combination rosiglitazone + metformin, incl. Avandamet, effective only when endogenous insulin production is preserved, therefore, the drug should not be prescribed for the treatment of patients with diabetes mellitus type 1.
Due to increased insulin sensitivity, rosiglitazone+metformin combination treatment in premenopausal women with anovulation and insulin resistance (eg, patients with polycystic ovary syndrome) may lead to the resumption of ovulation. Such patients may become pregnant. Premenopausal women received rosiglitazone during clinical trials. Hormonal imbalance was observed in the experiment, but there were no significant adverse reactions during treatment of women with rosiglitazone, associated with menstrual irregularities. In the event of menstrual irregularities, the advisability of continuing treatment with Avandamet should be critically evaluated..
Due to the accumulation of metformin, in rare cases, a serious metabolic complication occurs. – Lactic acidosis, predominantly in the group of patients with diabetes mellitus with clinically significant impaired renal function. Before starting treatment with metformin and, Consequently, rosiglitazone + metformin combination, it is necessary to evaluate the associated risk factors for lactic acidosis, eg, poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive drinking, abnormal liver function (incl. hepatic failure) and any disease, accompanied by tissue hypoxia. If lactic acidosis is suspected, Avandamet should be discontinued and the patient should be hospitalized immediately..
There are limited data on the treatment of patients with severe renal impairment with rosiglitazone.. Metformin is excreted by the kidneys, therefore, before starting treatment with Avandamet and then at regular intervals, it is necessary to determine the concentration of creatinine in serum. Particular attention should be paid to patients with an increased risk of developing renal failure., eg, elderly patients, or sick, which may be accompanied by a decrease in kidney function (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 mmol / L in women.
In patients with mild hepatic impairment (6 points or less on the Child-Pugh scale) dose reduction of rosiglitazone is not necessary. At the same time, considering, that liver dysfunction is a risk factor for the development of lactic acidosis, associated with metformin, The combination of rosiglitazone with metformin is not recommended for patients with hepatic impairment..
Thiazolidinedione derivatives, incl. rosiglitazone, may cause or worsen chronic heart failure. After initiation of rosiglitazone therapy and during dose titration, careful medical monitoring of the patient's condition is necessary in relation to the following symptoms and signs of heart failure: rapid and excessive weight gain, breathlessness, swelling. With the development of symptoms of heart failure, dose reduction or discontinuation of Avandamet should be considered and therapy should be prescribed in accordance with the current standards for the treatment of heart failure.. The use of the combination rosiglitazone + metformin is not recommended in patients with clinical manifestations of heart failure.. The drug is contraindicated in patients with heart failure I-IV functional class according to the NYHA classification..
Patients with acute coronary syndrome (OKS) They were not included in clinical studies. Since the development of acute coronary syndrome increases the risk of developing heart failure, The use of rosiglitazone in patients with ACS is not recommended.. Data on the ability of rosiglitazone to increase the risk of myocardial ischemia are insufficient. Retrospective analysis of mostly short clinical trials with placebo, but not with the comparator, suggests an association between rosiglitazone and the risk of myocardial ischemia. These data are not confirmed by long-term clinical studies with comparators. (metformin and/or sulfonylurea), and the relationship between rosiglitazone and the risk of ischemia has not been established. An increased risk of developing ischemic myocardial damage was observed in patients, were during clinical trials on basic therapy with nitrates.
There are also no reliable data on the effect of taking oral hypoglycemic drugs., incl. groups of thiazolidinediones on the state of large vessels in patients with diabetes mellitus type 2.
There are rare reports of the development or worsening of diabetic macular edema with decreased visual acuity.. Peripheral edema was frequently reported in the same patients.. In some cases, these disorders resolved after discontinuation of therapy.. It should be borne in mind the possibility of developing this complication when the patient complains of a decrease in visual acuity..
Patients, receiving Avandamet in a three-component combination with a sulfonylurea, may be at risk for dose-dependent hypoglycemia. Maybe, the dose of the concomitantly taken drug will need to be reduced.
Metformin i, Consequently, Avandamet must be canceled for 48 h before elective surgery with general anesthesia and resume therapy no earlier than after 48 hours after surgery.
In / in the introduction of iodine-containing contrast agents in x-ray studies can cause renal failure. Considering this, Avandamet as a drug, containing metformin, should be discontinued before or during contrast radiography, you can resume taking only after confirming normal kidney function.
In a longitudinal study of monotherapy of diabetes mellitus type 2 patients, previously untreated oral hypoglycemic drugs, was an increase in the incidence of fractures in women in the rosiglitazone group (9.3%; 2.7 accidents 100 patients-years) compared with metformin groups (5.1%; 1.5 case of 100 patients-years) and glyburide / glibenclamide (3.5%; 1.3 case of 100 patients-years). Most of the reported reports in the rosiglitazone group were forearm fractures., hand and foot. A possible increase in the risk of fractures should be taken into account when prescribing rosiglitazone., especially women. It is necessary to monitor the condition of the bone tissue and maintain bone health in accordance with accepted standards of therapy.
With simultaneous appointment with inhibitors or inducers of CYP2C8 and with the simultaneous use of cationic drugs, excreted by renal glomerular secretion, requires careful monitoring of blood glucose and dose adjustment of rosiglitazone or metformin.
Use in Pediatrics
There are currently no data on the use of the drug in children and adolescents under the age of 18 years, therefore, the use of the drug in this age group is not recommended..
Effects on ability to drive vehicles and management mechanisms
Rosiglitazone and metformin do not affect the ability to drive vehicles and work with mechanisms.
Avandamet: overdose
There are currently no data on Avandamet overdose.. In clinical trials, volunteers tolerated single oral dose of rosiglitazone to 20 mg.
Symptoms: metformin overdose (or associated risk factors for lactic acidosis) can lead to the development of lactic acidosis.
Treatment: lactic acidosis is a medical emergency and requires hospital treatment. Supportive care recommended, monitoring the clinical condition of the patient. Hemodialysis should be used to remove lactate and metformin from the body., however, rosiglitazone is not removed by hemodialysis (due to high protein binding).
Avandamet: drug interaction
Special studies, concerning the interaction of Avandamet, not performed. The data below reflect the available information on the interactions of the individual active components of Avandamet (rosiglitazone and metformin).
Rosiglitazone
Gemfiʙrozil (CYP2C8 inhibitor) dose 600 mg 2 times/day increased Css rosiglitazone in 2 times. This increase in the concentration of rosiglitazone is associated with the risk of dose-dependent side effects., therefore, the combined use of Avandamet with CYP2C8 inhibitors may require a dose reduction of rosiglitazone.
Other inhibitors of CYP2C8 caused a slight increase in the systemic concentration of rosiglitazone.
Rifampicin (inductor CYP2C8) dose 600 mg/day reduced the concentration of rosiglitazone by 65%. Therefore patients, who receive both rosiglitazone and CYP2C8 enzyme inducers, it is necessary to carefully monitor blood glucose and change the dose of rosiglitazone if necessary.
Repeated administration of rosiglitazone increases Cmax and AUC of methotrexate 18% (90% CI: 11% – 26%) and 15% (90% CI: 8% – 23%), respectively, compared with the same dose of methotrexate in the absence of rosiglitazone.
Rosiglitazone at therapeutic doses had no clinically significant effect on the pharmacokinetics and pharmacodynamics simultaneously applied to other oral hypoglycemic agents, including metformin, glibenclamide, glimepiride and akarbozu.
It has been shown, that rosiglitazone has no clinically significant effect on the pharmacokinetics of S(-)-varfarina (CYP2C9 enzyme substrate).
Rosiglitazone does not affect the pharmacokinetics and pharmacodynamics of digoxin or warfarin and does not change the anticoagulant activity of the latter..
There were no clinically significant interaction as rosiglitazone and nifedipine or oral contraceptives (ethinyl estradiol and norethisterone) while applying, which confirms the low probability of interaction with drugs rosiglitazone, which are metabolized with the participation of CYP3A4.
Metformin
In acute alcohol intoxication during treatment with a combination of rosiglitazone + metformin, the risk of developing lactic acidosis increases., metformin-mediated.
Cationic drugs, which are excreted by renal glomerular secretion (in t. no. cimetidine) may interact with metformin, competing for a common excretion system (it is necessary to carefully monitor blood glucose levels and change, if necessary, treatment while using cationic drugs, excreted by renal glomerular secretion).
In / in the introduction of radiopaque preparations containing iodine, can lead to kidney failure, which may result in the accumulation of metformin and the development of lactic acidosis (Metformin should be discontinued before x-rays are started., it is possible to resume taking metformin after at least 48 h after X-ray and positive reassessment of renal function).
Preparations, the application of which requires special care
GCS (systemic and for local use), β agonists2-adrenoreceptorov, diuretics can cause hyperglycemia, therefore, if necessary, simultaneous use with Avandamet requires more frequent monitoring of blood glucose concentration, especially at the beginning of treatment; Avandamet dose adjustment may be required, incl. when drugs are discontinued.
ACE inhibitors can lower blood glucose levels. If necessary, the simultaneous use or withdrawal of drugs should be adequately adjusted the dose of Avandamet.
Avandamet: terms of dispensing from pharmacies
The drug is released under the prescription.
Avandamet: terms and conditions of storage
The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 2 year.
