AVANDAGLIM
Active material: Glimepiride, Rosiglitazone
When ATH: A10BD04
CCF: Oral hypoglycemic agents
ICD-10 codes (testimony): E11
Manufacturer: GlaxoSmithKline (Britain)
DOSAGE FORM, COMPOSITION AND PACKAGING
Pills, Film-coated Pink colour, triangular with rounded edges, with print “GSK” on one side and “4/4” on the other side; of presentations – white.
| 1 tab. | |
| rosiglitazone * (in the form of maleate) | 4 mg |
| glimepiride | 4 mg |
Excipients: lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch, gipromelloza (HPMC) 3cP, magnesium stearate.
The composition of the shell: Opadry® brown 03B267184 (gipromelloza (HPMC) 6cP (E464), Titanium dioxide (E171, CI77891), iron oxide red dye (E172, Cl77491), dye iron oxide black (E172, Cl77499), macrogol 400).
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
14 PC. – blisters (8) – packs cardboard.
Pills, Film-coated of red color, lenticular, triangular with rounded edges, with print “GSK” on one side and “8/4” on the other side; of presentations – white.
| 1 tab. | |
| rosiglitazone * (in the form of maleate) | 8 mg |
| glimepiride | 4 mg |
Excipients: lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch, gipromelloza (HPMC) 3cP, magnesium stearate.
The composition of the shell: Opadry® red 03B253474 (gipromelloza (HPMC) 6cP (E464), Titanium dioxide (E171, Cl77891), iron oxide red dye (E172, Cl77491), macrogol 400).
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
14 PC. – blisters (8) – packs cardboard.
* international non-proprietary name, recommended by the WHO – Rosiglitazone.
Pharmacological action
Oral hypoglycemic agents. The structure Avandaglima contains two active substances with complementary mechanisms of action, improve glycemic control in patients with diabetes mellitus type 2: rosiglitazone maleate, belonging to the class of thiazolidinediones, and glimepiride, sulfonylureas class representative. thiazolidinediones, the mechanism of action is, mainly, in enhancing the sensitivity of target tissues to insulin, whereas sulfonylureas act, primarily, enhancing insulin release functioning pancreatic β-cells. Due to the different, but complementary mechanisms of action, Combination therapy rosiglitazone and sulfonylureas leads to a synergistic improvement in glycemic control in patients with diabetes mellitus type 2.
Rosiglitazone
Selective and potent agonist core PPAR-γ-receptors (Peroxisome proliferator-activated receptors – gamma), belonging to the thiazolidinedione class of hypoglycemic drugs. 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. Hence, rosiglitazone improves metabolic control of blood glucose by reducing, circulating insulin and free fatty acids.
The hypoglycemic activity of rosiglitazone demonstrated in animal models of diabetes mellitus type 2 in animals. It has been shown, rosiglitazone that 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 the progression of renal dysfunction and systolic hypertension. Rosiglitazone not stimulate the secretion of pancreatic insulin and does not cause hypoglycemia in rats and mice.
In accordance with the mechanism of action of rosiglitazone, improve glycemic control followed 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.
Glimepiride
The main mechanism of glimepiride hypoglycemic action is to stimulate insulin release functioning pancreatic β-cells. Besides, extrapancreatic effects also play a role in the action of sulfonylureas, such as glimepiride, which was confirmed as the preclinical, and clinical research, who showed, that the appointment of glimepiride can increase the sensitivity of peripheral tissues to insulin. These findings are consistent with long-term, randomized, placebo-controlled study, wherein glimepiride therapy improved postprandial insulin / C-peptide response, and glycemic control in general without developing clinically significant increase in the level of insulin / C-peptide fasting. But, As in the case of other sulfonylureas, hypoglycemic action mechanism of glimepiride term use is not entirely clear.
In healthy volunteers, the minimum effective dose when administered approximately 600 g. The effect of glimepiride is dose-dependent and is reproducible. The physiological response to acute physical exercise, ie. decrease insulin secretion, stored under glimepiride.
No significant differences were found in the glimepiride action while taking the drug for 30 minutes before meals or immediately before meal. A single dose of glimepiride provides good metabolic control in diabetic patients for more 24 no. Besides, in clinical studies of good metabolic control was achieved in 12 from 16 patients with impaired renal function (QC less 80 ml / min). Although the hydroxylated metabolite of glimepiride causes a slight, but significant decrease in serum glucose in healthy people, it is only a small component of the overall effect of the drug.
Pharmacokinetics
Avandaglim
Repeated reception rosiglitazone (8 mg / day) no significant effect on the pharmacokinetics of glimepiride when single dose (4 mg). Odnokratnaya dose (4 mg) glimepiride has no clinically meaningful effect on the pharmacokinetics of rosiglitazone equilibrium (8 mg / day).
The bioequivalence study Avandaglima (4 mg / 4 mg) by such parameters as AUC and Cmax rosiglitazone has been shown, that the single dose of the combination preparation Avandaglima he was bioequivalent to a dose of rosiglitazone 4 mg while receiving a dose glimepiride 4 mg on an empty stomach.
Glimepiride AUC with single dose on an empty stomach in the dose Avandaglima 4 mg / 4 mg was bioequivalent to that in the same time taking rosiglitazone glimepiride. The degree of suction glimepiride and rosiglitazone when receiving Avandaglima after meal was equivalent to that while applying them in the form of separate preparations.
Further information reflects the pharmacokinetic properties of the individual components Avandaglima.
Absorption
Rosiglitazone
The absolute bioavailability after oral administration of rosiglitazone 4 mg or 8 mg is about 99%. FROMmakh 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, and therefore rosiglitazone may be taken without regard to meals. An increase in gastric pH does not affect the absorption of rosiglitazone.
Glimepiride
After ingestion fully glimepiride (100%) absorbed in the digestive tract. Studies in healthy people, taking glimepiride inwardly singly or in patients with diabetes mellitus type 2, taking glimepiride in regularly, shown, that a significant part of it is absorbed within 1 h after administration, Tmax 2-3 no.
Distribution
Rosiglitazone
Vd rosiglitazone is approximately 14 l, and the total plasma clearance is about 3 l / h in healthy volunteers. The high degree of binding to plasma proteins (about 99.8%), It does not depend on the concentration of the drug and the patient's age. Currently no data about accumulation of rosiglitazone at its reception 1 or 2 times / day.
Glimepiride
The on / in healthy volunteers administered Vd is equal to 8.8 l (113 ml / kg), total clearance was 47.8 ml / min. Protein binding – more 99.5%.
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, and so it is unlikely, that in vivo it will engage in significant metabolic interactions with drugs, these are metabolized by cytochrome P450 isozymes system. In vitro rosiglitazone moderately inhibited CYP2C8 isozyme (inhibitory concentration of 18 mmol) and weakly inhibits CYP2C9 isozyme (inhibitory concentration of 50 mmol). Investigation of the interaction with warfarin rosiglitazone showed in vivo, that rosiglitazone does not interact with CYP2C9 substrates isoenzyme.
Glimepiride
Glimepiride completely metabolized by oxidation as in on / in, and after ingestion. Its main metabolite is tsiklogeksilgidroksimetil-derivative (M1) and a carboxylic acid derivative (M2). Biotransformation derivative glimepiride to M1 takes place with the participation of CYP2C9 isozyme. M1 further metabolized to M2 with one or more cytosolic enzymes. M1, Unlike M2, has 1/3 farmakologicheskoy activities glimepiride. The clinical significance of hypoglycemic action of M1 is unclear.
Deduction
Rosiglitazone
Total plasma clearance of rosiglitazone is about 3 l /, and the final T1/2 is about 3-4 no. Currently no data about accumulation of rosiglitazone at its reception 1 or 2 times / day. About 2/3 an oral dose of rosiglitazone excreted by the kidneys, about 25% displayed intestine. The unmodified audio is not detected in the urine, our fortress. The final T1/2 is about 130 no, It is indicating a very slow elimination of metabolites. Repeated ingestion of rosiglitazone has not ruled out the cumulation of metabolites in the plasma, in particular, osnovnogo metabolite (paragidroksisulyfata), a concentration, presumably, may increase 5 time.
Glimepiride
T1/2 glimepiride is approximately 5-8 no. After oral administration of glimepiride, -labeled 14FROM, about 60% of the administered dose excreted in the urine on the 7th day, 80-90% – as M1 and M2. About 40% of the administered dose excreted in the feces, to 70% – as M1 and M2. The unmodified audio is not detected in the urine, our fortress. The on / in the route of administration no signs of removal of glimepiride or its metabolite M1 in bile.
Pharmacokinetics in special clinical situations
There were no significant differences in the pharmacokinetics of rosiglitazone and glimepiride in men and women.
There were no significant differences in the pharmacokinetics of rosiglitazone and glimepiride in elderly and adult patients without renal dysfunction.
There were no significant differences in the pharmacokinetics of rosiglitazone in patients with impaired kidney function or endstage renal disease in chronic hemodialysis.
There are no data on the use of glimepiride in patients, It is undergoing hemodialysis. In patients with renal insufficiency (CC less than 22 ml / min) managed to maintain adequate control of glucose levels at a dose of only 1 mg / day.
In patients with moderate and severe hepatic impairment (Classes B and C on the Child-Pugh) Cmax and were AUC 2-3 times higher, as a result of increased plasma protein binding and a reduction in clearance rosiglitazone.
Since adequate data on the use of glimepiride in patients with impaired liver function no, Avandaglim is not recommended in these patients.
Testimony
- Diabetes mellitus type 2 (for glycemic control monotherapy after failure of sulfonylurea or a thiazolidinedione, and patients, which have already received the combined therapy with sulfonylurea and thiazolidinedione);
Avandaglim may be used in combination with metformin (triple combination) for glycemic control.
Dosage regimen
Dosage regimen Avandaglima selected and installed individually. It is necessary to take into account the current individulny glycemic control in the patient and the risk of hypoglycaemia.
Avandaglim be taken 1 times per day with meals.
Adults during the transition from rosiglitazone therapy + glimepiride as monotherapies to a combined preparation (Avandaglimu) initial combination dosage should be based on already received dosages rosiglitazone and glimepiride.
With insufficient glycemic control when receiving a dose monotherapies glimepiride 4 mg / day initial dose is Avandaglima 4 mg rosiglitazone / 4 mg glimepiride.
Patients with inadequate glycemic control, are on treatment with other sulfonylureas (except hlorpropramida) at a dosage of at least half of the maximum dose, treatment is added at a dosage of rosiglitazone 4 mg / day, for achieving adequate glycemic control can proceed to treatment at a dose of Avandaglimom 4 mg rosiglitazone / 4 mg glimepiride 1 time / day.
Avandaglima daily dose can be increased to maintain the individual glycemic control in patients. Therapeutic effect of dose after correction can not be shown for 6-8 weeks and for rosiglitazone 1-2 weeks to glimepiride. In case of need, increasing the dose of rosiglitazone is possible only after 8 weeks of use. Dose titration is carried out to a maximum daily dose 8 mg rosiglitazone / 4 mg glimepiride. Increasing the dose of rosiglitazone to 8 mg per day should be undertaken with caution after a risk assessment of adverse reactions, related to fluid retention.
Demand for glimepiride may decrease during therapy. In the case of hypoglycemia should reduce the dose of glimepiride or completely cancel it. Correction doses of one of the components Avandaglima, rosiglitazone or glimepiride, It may be required in concomitant use with other drugs.
There is currently no data on the use of at Avandaglima Children up to 18 years, so Avandaglima use is not recommended in this age group.
Initial and maintenance dose in Avandaglima elderly patients They should be adequately adjusted due to possible loss of kidney function in this patient group. Any dose adjustment should be based on data on renal function, which should be continuously monitored.
In patients with renal insufficiency mild and moderate (CC 30-80 ml / min) during the transition from other sulfonylurea therapy to therapy Avandaglimom have an increased risk of hypoglycaemia, Therefore, in such cases, appropriate monitoring is recommended.
Patients with severe renal insufficiency (CC less than 30 ml / min) Avandaglim contraindicated.
Data on the use of glimepiride in patients, It is undergoing hemodialysis, no.
Since adequate data on the use of glimepiride in patients with impaired liver function no, Avandaglim is not recommended in these patients.
Side effect
The frequency of adverse reactions is defined as follows: Often (≥ 1/10), often (≥ 1/100 and <1/10), sometimes (≥1 / 1000 <1/100), rarely (≥ 1/10 000 and <1/1000) and very rare (<1/10 000), including isolated reports.
Avandaglim
Limited data, obtained in the recently concluded clinical trials, show, that in general the safety profile of the drug combination of rosiglitazone and glimepiride fixed dose similar to that, observed in the combined use of rosiglitazone and other sulfonylureas.
Underwritten data reflect information on the safety profile of, obtained when applying glimepiride and rosiglitazone as individual components.
Rosiglitazone
Data, obtained in clinical trials
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 can be connected 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.
P – rosiglitazone, M – metformin, FROM – sulifonilmochyevina
| Side effects | P | P + M | P + FROM | P + FROM + M |
| From the hematopoietic system | ||||
| Anemia | Often | Often | Often | Often |
| Leukopenia | Often | |||
| Thrombocytopenia | Often | |||
| Granulocytopenia | Often | |||
| Anemia is often dose-dependent, mild-to-moderate | ||||
| On the part of metabolism | ||||
| Hypercholesterolemia | Often | Often | Often | Often |
| Hypertriglyceridemia | Often | Often | ||
| Hyperlipidemia | Often | Often | Often | Often |
| Weight gain | Often | Often | Often | Often |
| Increased appetite | Often | Sometimes | ||
| Gipoglikemiâ | Often | Often | Often | |
| Total cholesterol was increased while increasing the concentration of HDL and LDL, the ratio cholesterol / HDL cholesterol remained unchanged. Weight gain is mainly dose-dependent manner, possibly related to fluid retention and accumulation of body fat. Gipoglikemiâ, usually, moderate or mild degree, dozozavisima, primarily, the combined use with sulfonylureas and insulin. | ||||
| From the nervous system | ||||
| Dizziness | Often | Often | ||
| Headache | Often | |||
| Cardio-vascular system | ||||
| Heart failure / pulmonary edema | Often | Often | ||
| myocardial ischemia | Often | Often | Often | Often |
| Increased incidence of heart failure was observed when connecting rosiglitazone therapy regimens, based on sulfonylureas 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 possibility of rosiglitazone increase the risk of myocardial ischemia are insufficient. Retrospective analysis of short-term clinical studies showed an increased risk of ischemic events with rosiglitazone in the treatment compared to the control group as a whole (placebo + active preparations) In the same analysis by comparing rosiglitazone to other oral hypoglycemic drugs differences in the incidence of ischemic events were observed. An increased risk of myocardial ischemia, associated with rosiglitazone, was not confirmed in the subsequent long-term randomized controlled clinical trials, comparing rosiglitazone with metformin and a sulfonylurea. Association between rosiglitazone and the risk of myocardial ischemia has not been established. Increased risk of ischemic myocardial injury observed in patients, receiving nitrate therapy at baseline or during clinical studies about the established CHD. Rosiglitazone is not recommended in patients, receiving concomitant 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, more often observed in the combined therapy with sulfonylureas or insulin | ||||
Data, obtained post-marketing period
Categories unwanted frequency responses are defined based on the frequency of adverse reactions in the application messages rosiglitazone in post-marketing period, regardless of the dose or concomitant therapy hypoglycemic drugs. Occurrence of rare and very few side effects were determined based on post-marketing data, and it concerns more the frequency of such effects Messaging, than the true frequency effects themselves.
Allergic reactions: rarely – anaphylactic reactions, angioedema, hives, rash, itching
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 liver enzyme levels, however, a causal relationship between treatment with rosiglitazone and liver dysfunction has not been established. Patients with diabetes often have disorders of the liver.
On the part of the organ of vision: rarely – macular edema.
Glimepiride
Data from clinical studies and post-marketing period
Adverse reactions are shown below by organ systems and frequency. Very frequent occurrence, frequent adverse reactions, sometimes occur, usually, It was determined based on pooled data controlled clinical studies, and represents the difference between the frequency of occurrence of adverse events when taking the reference preparation and glimepiride. Occurrence of rare and very few side effects were determined based on post-marketing data, and it concerns more the frequency of such effects Messaging, than the true frequency effects themselves.
From the hematopoietic system: rarely – thrombocytopenia, leukopenia, gemoliticheskaya anemia, erythropenia, granulocytopenia, agranulocytosis, pancytopenia.
Metabolism: often – gipoglikemiâ; rarely – giponatriemiya.
On the part of the organ of vision: rarely – visual impairment.
There may be temporary visual impairment, especially at the beginning of treatment, related to changes in blood glucose levels. The cause is a temporary change in tissue turgor, which leads to a change in the refractive index of the lens, This phenomenon depends on the level of glucose in the blood.
From the digestive system: often – nausea; rarely – elevated liver enzymes; rarely – gastrointestinal disorders (vomiting, a feeling of pressure and overcrowding epigastric, abdominal pain and diarrhea), abnormal liver function, manifested cholestasis, jaundice, hepatitis or liver failure. There are some reports, describing liver function abnormalities, including cholestasis, jaundice, hepatitis and liver failure in patients, receiving sulfonylurea, incl. glimepiride.
Skin and subcutaneous tissue disorders: sometimes – or pseudo-allergic reactions (itch, hives or rash); rarely – sensitization vasculitis, photosensitivity reactions. Mild reactions may develop into serious, including anaphylactic shock. In the case of hives must be put immediately to the doctor's reputation.
Contraindications
- Heart failure (I-IV functional class NYHA classification);
- acute coronary syndrome (unstable angina, myocardial infarction without ST-segment elevation, myocardial infarction with ST segment elevation);
- Severe renal insufficiency (CC less than 30 ml / min), including patients on hemodialysis;
- Abnormal liver function;
- Diabetes mellitus type 1;
- diabeticheskiy ketoacidosis or coma diabeticheskaya;
- Galactose intolerance, lactase deficiency or malabsorption of glucose-galactose;
- Up to 18 years (there is currently no data on the use in children under Avandaglima 18 years, so Avandaglima use is not recommended in this age group);
- the combined use of insulin;
- hypersensitivity to rosiglitazone, glimepiridu, other drugs sulfonamides or sulfonylureas or any other component of the preparation.
Pregnancy and lactation
It reported on the ability of rosiglitazone to cross the placenta in humans and is found in fetal tissues. Currently, there is insufficient data for use in pregnant women Avandaglima. During pregnancy women, diabetes, usually it recommended to prescribe insulin. appointment of pregnant women Avandaglima not shown.
At present, there is insufficient data on the use Avandaglima in lactating women, Avandaglim therefore should not be used while breastfeeding. Unknown, Do Avandaglim passes into breast milk. Nursing women with diabetes usually recommended to assign insulin. Appointment Avandaglima lactating women have not shown.
Cautions
Diabetes mellitus type 1
Avandaglim effective only in the presence of insulin and therefore should not be used for the treatment of diabetes mellitus type 1.
Premenopausal women age with anovulation
Due to the ability of rosiglitazone to increase insulin sensitivity, Avandaglimom treatment of women in pre-menopausal women with anovulation and insulin resistance (eg, patients with polycystic ovary syndrome) may lead to the resumption of ovulation. Such patients may become pregnant.
Cardiovascular diseases
Rosiglitazone, like other thiazolidinediones, in some cases, may cause or aggravate the development of chronic heart failure. After initiation of therapy Avandaglimom and selection of the desired dosage should be closely monitored for the patient's condition in relation to the development of heart failure symptoms (rapid and excessive weight gain, breathlessness, swelling).
Application Avandaglima contraindicated in heart failure (I-IV NYHA functional class classification). With the development of heart failure symptoms should consider removing the Avandaglima and assign therapy in accordance with the current standards of treatment of heart failure.
Patients with acute coronary syndrome (OKS) They were not included in clinical studies. appointment of rosiglitazone, as well as other oral hypoglycemic drugs are contraindicated in ACS, especially considering the increased risk of heart failure in ACS. During the acute phase to cancel receiving rosiglitazone.
Currently there is no reliable data on reducing the risk of macrovascular complications of diabetes 2 type with oral hypoglycemic agents, including thiazolidinediones. Unnecessarily. patients with diabetes 2 such as an increased risk of CHD, regardless of the choice of oral hypoglycemic drug, you must take appropriate measures to reduce the risk of cardiovascular complications.
Patients with ocular disorders
The post-marketing period rarely reported cases of primary or worsening cases of diabetic macular edema with decreased visual acuity when using rosiglitazone. Many of these patients had peripheral edema. In some cases, visual disturbances were completely or improved after drug withdrawal. It is necessary to pay special attention to the possibility of macular edema in patients, were impaired visual acuity.
The regulation of blood glucose levels
In a stressful situation (eg, trauma, surgical intervention, infection) regulation of blood glucose levels can be violated, in such a case to maintain a good metabolic control necessary time correction doses of hypoglycemic agents or administration of insulin.
When the risk factors for hypoglycemia, including kidney failure, underweight, malnutrition or simultaneous use of certain medications may require correction or glimepiride dose therapy in general. This also applies to periods of any diseases during therapy, or change the style of life of the patient.
Effect on bone
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 patient-years) compared with metformin groups (5.1%; 1.5 case of 100 patient-years) and glyburide / glibenclamide (3.5%; 1.3 case of 100 patient-years). The majority of registered messages in the rosiglitazone group concerned shoulder fracture, hand and foot. Possible increased risk of fractures should be considered in the appointment of rosiglitazone, especially, women. Requires monitoring of bone health and maintain her health in accordance with accepted standards of care.
Gemoliticheskaya anemia
Treatment of patients with deficiency of glucose-6-phosphate dehydrogenase preparations of sulfonylurea derivatives can lead to hemolytic anemia. Because, that glimepiride belongs to the class of sulfonylureas, active drug should be administered with cautious patients with deficiency of glucose-6-phosphate dehydrogenase. As an alternative treatment should be considered preparations, It does not contain a sulphonylurea.
The simultaneous appointment of other drugs
Careful control of blood glucose and correction dose of rosiglitazone or glimepiride may be required while appointing Avandaglima with CYP2C8 or CYP2C9 inhibitors or inducers.
Lactose intolerance
Avandaglima tablets contain lactose and should not be administered to patients with the following rare hereditary diseases: galactose intolerance, lactase deficiency, malabsorption of glucose-galactose.
Effects on ability to drive vehicles and management mechanisms
Special studies Avandaglima influence on the ability to drive and / or other mechanisms not been. Nonetheless, assessing the patient's ability to perform tasks, It requires clear thinking, motor and cognitive skills, should consider the possibility of hypoglycemia.
Overdose
There is currently no data on overdose Avandaglima. In clinical trials, volunteers tolerated single oral dose of rosiglitazone to 20 mg.
Symptoms: sulfonylurea overdose, including glimepiride, can cause severe life-threatening hypoglycaemia.
Treatment: in case of overdose recommended appropriate supportive therapy, guided by the clinical condition of the patient. Glimepiride and rosiglitazone highly bound to proteins, so we would expect, they are not displayed by hemodialysis.
Drug Interactions
individual studies, concerning interactions Avandaglima, not performed.
When concomitant administration of rosiglitazone and glimepiride clinically significant pharmacokinetic interaction was observed between them.
The following data reflect the available information about the interactions of the individual active components Avandaglima (rosiglitazone and glimepiride).
Rosiglitazone
In in vitro studies have shown, that rosiglitazone predominantly metabolized isoenzyme CYP2C8, with the participation of isoenzyme CYP2C9 as only a minor way.
Simultaneous administration of rosiglitazone with inhibitors of CYP2C8 isozyme (eg, gemfibrozilom) rosiglitazone leads to an increase in the plasma concentration. Since there is a potential risk of dose-related side effects, the combined use with Avandaglima CYP2C8 isozyme inhibitors may require a reduction in the dose of rosiglitazone.
The simultaneous appointment of rosiglitazone with inducers of CYP2C8 isoenzyme (eg, rifampicin) It leads to a reduction in the plasma concentration of rosiglitazone. Therefore patients, are obtained simultaneously rosiglitazone and inductors CYP2C8 isozyme, necessary to carry out careful monitoring of blood glucose and modify, if necessary, hypoglycemic therapy.
Rosiglitazone has no effect on the pharmacokinetics and pharmacodynamics of warfarin or digoxin (isoenzyme CYP2C9 substrate) and does not alter the anticoagulant activity of the latter.
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.
Gemfiʙrozil (isoenzyme inhibitor of CYP2C8) dose 600 mg 2 times / day twice rosiglitazone increased the concentration at equilibrium.
Other inhibitors of CYP2C8 isozyme caused a slight increase in the systemic concentration of rosiglitazone.
Rifampicin (inductor izofermenta CYP2C8) dose 600 mg / day reduced to 65% systemic concentration of rosiglitazone.
Repeated receiving rosiglitazone increases the Cmakh and AUC of methotrexate 18% (confidence interval 90%: 11-26%) and 15% (confidence interval 90%: 8-23%), respectively, compared with the same dose of methotrexate in the absence of rosiglitazone.
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, that are metabolized by CYP3A4 isoenzyme.
Studies have shown no effect on glycemic control at the same time a moderate intake of alcohol and rosiglitazone.
Glimepiride
Glimepiride metaboliziruetsya izofermentom CYP2C9. This should be taken into account with concomitant administration of glimepiride with inducers or inhibitors of this enzyme.
Simultaneous administration of glimepiride CYP2C9 isozyme inhibitors (eg, fluconazole) It leads to increased plasma concentrations of glimepiride. The study showed, that fluconazole (isoenzyme inhibitor of CYP2C9) dose 200 mg 1 times / day increases the concentration of approximately glimepiride 2.5 times. Since there is a potential risk of dose-related side effects (eg, gipoglikemii), the combined use with Avandaglima CYP2C9 isozyme inhibitors may require dose reduction glimepiride.
The study showed, rifampicin (inductor izofermenta CYP2C9) dose 600 mg 1 times / day reduces the concentration of glimepiride per 65%.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children at or above 30 ° C. Shelf life – 2 year.
