ROSIGLITAZON (Rosiglitazone)

     Chemical name : 5-[4-[2 - (Methyl piridinilamino) etoksi] phenyl] methyl] -2,4 - tiazolidindion (and as maleate)

     Description : Peroralnoe hypoglycemic means tiazolidindionov class.

Rosiglitazona maleate-white, or almost white solid, easily soluble in ethanol and water in buffer solutions with pH 2.3; Solubility decreases with the increase in the physiological pH range.

     Pharmacology : The drugs-hypoglycemic effect.

It is a selective agonist of nuclear receptors PPAR? (peroxisome proliferator-activated receptor-gamma). In humans, these receptors are essential for the actions of insulin tkanyah- "target" : the adipose tissue in the liver and skeletal muscles. Nuclear receptors PPAR? insulinotvetstvennyh regulate transcription of genes involved in the control of the production, transport and disposal of glucose. In addition, PPAR? - Sensitive genes involved in metabolism of fatty acids.

Rosiglitazon lowers blood glucose by increasing the sensitivity of insulin receptors in adipose tissue, skeletal muscle and liver. Reduces levels of circulating insulin, suppressing glyukoneogenez in the liver.

A feature that characterizes the pathogenesis of type 2 diabetes is insulinrezistentnost. Hypoglycemic Effects rosiglitazona studied in the laboratory animal model with type 2 diabetes whose hyperglycemia and / or breach of tolerance to glucose is a consequence of insulin resistance "tkaney- targets." Revealed that rosiglitazon reduces the concentration of glucose in the blood and level giperinsulinemii in mice with genotype ob / ob (obesity), in mice with genotype db / db (diabetes), and in rats with genotype from Zucker fa / fa (obesity). A laboratory animals antidiabeticheskoe of rosiglitazona reflected increased sensitivity to insulin liver cells, poperechnopolosatyh muscle and adipose tissue. In adipose tissue increased allocation insulinozavisimogo specific membrane vector glucose GLUT? 4. Rosiglitazon causing hypoglycemia and lower tolerance to glucose in laboratory animals with type 2 diabetes.

Pharmacokinetics

Cmax and AUC plasma increase in proportion to dose in the range of therapeutic doses. In rosiglitazona dose of 1 mg-AUC = 358 ng / mL / h, Cmax = 76 ng / ml; The dose of 2 mg-AUC = 733 ng / mL / h, Cmax = 156 ng / ml; The dose of 8 mg-AUC = 2971 ng / mL / h, Cmax = 598 ng / ml. T1 / 2 at 3-4 h and is not dependent on dose.

Suction. Absolute bioavailability rosiglitazona-99%. Cmax plasma is approximately within 1 h after administration. Reception with food has no effect on AUC, Cmax but reduces by about 28% and lengthens Tmax to 1.75 h. These changes are clinically insignificant, so rosiglitazona maleate can be taken regardless of the meal.

Distribution. The average amount of rosiglitazona in equilibrium with the ingestion (Vss / F) is 17.6 litres. Proteins associated with the plasma of about 99.8%, mainly with albumin.

Metabolism. Rosiglitazon extensively metabolized, unchanged kidneys appears. The main road metabolism-N-demethylation and gidroksilirovanie followed by conjugation with glyukuronovoy acid and sulfate. All circulating metabolites much less active than the original substance, it did not participate in insulinosensibiliziruyuschem rosiglitazona action. According to studies in vitro, rosiglitazon mainly metabolised with izofermenta CYP2 S8 tsitohroma P450, and to a lesser extent, CYP2C9.

Excretion. After oral or / in use rosiglitazona maleate, mechennogo carbon 14 C in urine and feces displayed about 64 doses and 23% respectively. T1 / 2 of plasma mechennogo 14 C substances range from 103 to 158 hours

Population pharmacokinetics in patients with type 2 diabetes. In population pharmacokinetic studies in three advanced clinical trials was attended by 642 men and 405 women with type 2 diabetes aged 35 to 80 years. Studies have shown that age, race, smoking or alcohol consumption did not affect the pharmacokinetics rosiglitazona. Clearance oral introduction (Cl / F) and volume of distribution of the equilibrium state (Vss / F) increased with increasing body mass.

Dependence pharmacokinetic parameters of certain factors

Age. Results population analysis (<65 years, n = 716; ? 65, n = 331) showed that age does not significantly affect the pharmacokinetics rosiglitazona.

Paul. Results population pharmacokinetic analysis showed that the average clearance rosiglitazona oral women (n = 405) was about 6% lower than that for men (n = 642) with the same body mass index study. Rosiglitazona maleate in monotherapies and in combination with metformin improved control of glycemia, and in both men and women. In combination with metformin studies impact on the effectiveness of glycemia not dependent on gender. Revealed that in the case of monotherapies best therapeutic effects in women, probably because of the fact that for a given body mass index in women is usually more fat than men, a "molecular target" - PPAR? - expressed in adipose tissue. However, in patients with large body mass, the difference is losing visibility.

Violation of liver function. Clearance free rosiglitazona oral application significantly reduced in patients with medium and heavy liver pathology (classification Child-Pugh Class B / C) as compared with healthy people, so Cmax and AUC0-? free rosiglitazona increase in two and three times, respectively. T1 / 2 in patients with abnormal liver grew to 2 hours There should be appointed rosiglitazona maleate patients, and whose clinical examination before treatment identified active process in the liver or raising transaminaz plasma (ALT level in more than 2.5 times upper limit rules) (see "Precautions").

Violation of kidney function. Not identified clinically significant differences in the pharmacokinetics rosiglitazona in patients with kidney function violations of varying severity, or in hemodialysis and people with normal kidney function, so these patients do not need to change the dose rosiglitazona maleate. Because metformin contraindications to patients with kidney disease, the appointment rosiglitazona with metformin also contraindicated.

Race. In farmakokineticheskom population analysis, which included whites, blacks and other ethnic groups, found that race has no effect on the pharmacokinetics rosiglitazona.

Carcinogenicity, mutagenicity, the impact on fertility

Carcinogenicity. Two-year carcinogenicity studies were conducted on mice autbrednyh CD-I Charles River from receiving food intake 0.4; 1,5, and 6 mg / kg / day (maximum dose AUC about 12 times * AUC rights), and rats Line Sprague-Dawley receiving through gastric probe dose 0.05; 0.3 and 2.0 mg / kg / day (maximum dose AUC approximately 10 * and 20 * times AUC rights for male and female rats, respectively).

[Here, and designated by *. concentrations exceeding human AUC admission maximum recommended daily intake.

Mice have no cancer-causing rosiglitazona. The growth of hyperplasia of adipose tissue in mice dose? 1.5 mg / kg / day (AUC approximately 2 * times the human AUC). In rats, there was a significant increase in the frequency of occurrence of benign tumours adipose tissue (lime) with the dose? 0.3 mg / kg / day (AUC approximately 2 * times the human AUC). Proliferativnye changes in both cases due to excessive stimulation of pharmacological adipose tissue.

Mutagenicity. It found mutagennogo or klastogennogo of tests on mutations in bacteria in vitro, in a test for chromosomal aberration in the peripheral blood lymphocytes in vitro rights, in a microkernel test in mice in vivo, in a test nereparativnogo DNA synthesis in rats in vivo / in vitro.

The impact on fertility. There have rosiglitazona impact on the ability to mating and fertility in male rats receiving 40 mg / kg / day (approximately 116 AUC * times rights AUC). There are cyclical changes in male (dose of 2 mg / kg / day) and reduced fertility (40 mg / kg / day) of the female rats, associated with lower levels of progesterone and warm plasma (AUC about 20 and 200 * * times AUC Rights). Such effects are not observed when using doses of 0.2 mg / kg / day (AUC about 3-times the human AUC). U monkeys receiving rosiglitazon doses of 0.6 and 4.6 mg / kg / day (AUC about 3 * 15 * times the human AUC), revealed fewer gains of whey seconds in Acne phase legitimate subsequently reduced emissions LG, lower progesterone levels in lyuteinovuyu phase, and amenorrhea. The mechanism of these effects are linked to the direct inhibition of ovarian steroidogeneza.

Toxicology in animals

Before rosiglitazona increased heart weight in mice (3 mg / kg / day), rats (5 mg / kg / day) and dogs (2 mg / kg / day) (AUC about 5 * 22 * and * 2 times over AUC rights). In morphometric measurements revealed Poly tissue hypertrophy, which can be attributed to the increase in the heart of the increase in plasma.

Pregnancy. In rats, there has been no impact on rosiglitazona implantation of the embryo and during early pregnancy, but his reception at the middle and late gestations time delays associated with the growth and death of the foetus in rats and rabbits. Teratogennogo effects were observed at doses 3 mg / kg in rats and 100 mg / kg in rabbits (AUC about 20 and * 75 * times AUC members respectively). It appears that rosiglitazon pathology is the placenta in rats (dose of 3 mg / kg / day). Applications in rats during pregnancy and lactation reduces the size of offspring, the viability of neonatal and postnatal growth (stunting nivelirovalas after puberty). Dose, not having effect on the placenta, the embryo / fetus and the offspring was 0.2 mg / kg / day for rats and 15 mg / kg / day for rabbits (AUC approximately 4 * times the human AUC).

Clinical studies

In clinical studies better control of glycemia assignment rosiglitazona maleate confirmed measuring glucose in plasma shock, glikozilirovannogo hemoglobin (Hb with A1) and the attendant decrease in insulin and C-peptide. Also decreased glucose and insulin after meals. These data are consistent with the mechanism of action rosiglitazona maleate as a means to raise sensitivity to insulin. Improved controls glycemia was long, saving effect for 52 weeks. The maximum recommended dose of 8 mg per day. Study dosage showed that additional positive effects of the dose of 12 mg / day has not been observed.

The joint appointment with rosiglitazona maleatom metformin or derivatives sulfonamidov (the sulfonamid) led to a significant reduction giperglikemii than using any of these products individually. Patients with fat violation of the exchange would not be excluded from clinical trials rosiglitazona maleate. In all the 26-week controlled trials of the range of recommended doses rosiglitazona maleate as monotherapies rising concentrations of total cholesterol, and LPVP LPNP and reducing free fatty acids. These changes were statistically significant compared to placebo and gliburid- control. It has been noted that the dose of 4 mg rosiglitazona maleate level of free fatty acids decreased by an average of 7.8%, the level of certainty and LPVP grew by 14.1 and 11.4% respectively. In rosiglitazona maleate dose of 8 mg of free fatty acids decreased by an average of 14.7%, the level of certainty and LPVP grew by 18.6 and 14.2% respectively. When taken placebo level of free fatty acids increased by 0.2%, the level of certainty and LPVP rose by 4.8% and 8% respectively. In patients receiving gliburid, the level of free fatty acids decreased to 2.4%, the level of certainty and LPVP increased by 0.9 and 4.3% respectively. LPNP growth was concentrated in the first two months of receiving rosiglitazona maleate, the LPNP remained high throughout the test. In contrast, the LPVP continued to grow over time. As a result, the ratio LPNP / LPVP reached a peak after 2 months, and then declined. The picture changes in the level of certainty and LPVP assignment rosiglitazona maleate in combination with other gipoglikemicheskimi means similar to the one in monotherapies rosiglitazona maleatom.

Changing the level of triglycerides in the face rosiglitazona maleate diverse and, in general, not statistically different from placebo and gliburid- control.

Monotherapy

Total 2315 patients with type 2 diabetes lechivshiesya only diet or hypoglycemic drugs (drugs), were rosiglitazona maleate as monotherapies in 6 double blind study. A two 26-week platsebo- controlled study, a 52-week controlled study gliburid- and three platsebo- dozozavisimyh controlled study duration 8 and 12 weeks. Previously used gipoglikemicheskie drugs were removed, and patients receiving placebo for 2-4 months prior to randomization.

A two 26-week double blind platsebo- controlled tests in patients with type 2 diabetes with poor control of glycemia (median baseline plasma glucose concentrations approximately 12.65 mmol / l, the average baseline HbA1c 8.9%). Application rosiglitazona maleate had statistically significant changes in plasma glucose concentration and HbA1c compared to the reference level and placebo.

It has been observed that the appointment of the same daily dose rosiglitazona maleate as a whole more effectively reduce the concentration of plasma glucose and HbA1c levels in the division doses at two installments over the entire receiving daily doses at once (for the difference between the level of HbA1c receiving 4 mg rosiglitazona maleate 1 times a day and receive 2 mg twice a day was not statistically significant). Maintaining effects for a long time was in the 52-week double-blind controlled gliburid- test in patients with type 2 diabetes. Patients were divided into three groups : receiving rosiglitazona maleate dose of 2 mg twice daily (n = 195) or 4 mg twice daily (n = 189) or gliburid (n = 202) for 52 weeks. Patients who received gliburid, doses selected from the initial 2.5, or 5 mg / d for growing over the next 12 weeks to 15 mg / day; On average, 7.5 mg / day. All therapeutic results of the level of glycemia statistically reliable increased compared to baseline levels. By the end of 52 th week of decline in plasma glucose concentration and HbA1c compared with the baseline was : 2.26 mmol / L and 0.53% in the application rosiglitazona maleate 4 mg twice a day; 1.41 mmol / l 0 27% of in the dose of 2 mg twice a day; 1.67 mmol / L and 0.72% for gliburida. Changing concentrations of HbA1c 52-week study in the application rosiglitazona maleate and gliburida was statistically misdeclared. Primary decline in plasma glucose concentration in the application gliburida was greater than in the application rosiglitazona maleate, but this difference disappeared with the passage of time. Better control of glycemia in the application rosiglitazona maleate 4 mg twice a day for 26 weeks and persisted throughout the 52 weeks.

Hypoglycemia was 12.1% for patients receiving gliburid, compared with 0.5% (2 mg twice a day) and 1.6% (4 mg twice daily) in patients receiving rosiglitazona maleate. Revealed that the improved control glycemia was associated with an average weight gain of 1.75 kg and 2.95 kg for patients receiving 2 and 4 mg twice a day rosiglitazona maleate respectively, and 1.9 kg for patients receiving gliburid. It has been observed that in patients receiving rosiglitazona maleate, the levels of C-peptide, insulin, and proinsulina products proinsulina significantly decreased, depending on dose, compared with growth of the indicators in patients receiving gliburid.

A combination with metformin

Total 670 patients with type 2 diabetes participated in the two 26-week randomized double blind placebo controlled study and preparat- intended to evaluate the effectiveness rosiglitazona maleate in combination with metformin. Rosiglitazona maleate designated in any of the modes of reception (once a day or twice a day) was added to the treatment of patients for whom metfomina maximum dose (2.5 g / day) was insufficient.

In the first study, patients with insufficient metformin dose of 2.5 g / day (mean baseline plasma glucose concentration 11.99 mmol / l, the average baseline HbA1c 8.8%) were more randomizirovanno rosiglitazona maleate 4 mg once daily, 8 mg once a day or placebo. In patients receiving a combination of metformin and rosiglitazona maleate 4 mg once a day or 8 mg once a day, there was a statistically significant improvement in the concentration of glucose in plasma and HbA1c compared with patients who received only metformin. Thus, the appointment of 4 mg / day or 8 mg / day rosiglitazona maleate in addition to metformin, the average reduced plasma glucose levels at 1.83 and 2.66 mmol / L, respectively, and HbA1c decreased to 0.6 and 0.8% respectively on average baseline data. In patients who received only metformin, the concentration of glucose in plasma increased to 0.33 mmol / l and HbA1c at 0.5%.

In the second 26-week study, patients with type 2 diabetes with poor 2.5 mg daily metformin randomizirovanno received combination metformin and rosiglitazona maleate 4 mg twice daily (n = 105). Studies have shown a statistically significant improvement of glycemia control middle therapeutic effect -3.1 mmol / L glucose concentration in plasma and -0.8% for HbA1c compared with metformin. The combination of metformin and rosiglitazona maleate efficiently reduced concentrations of plasma glucose and HbA1c than each product separately. In patients with insufficient maximum doses of metformin transferred to monotherapies rosiglitazona maleatom noted the apparent decline in the level of glycemia control shown increasing concentrations of plasma glucose and HbA1c. Also in this group increased LPNP and LPONP.

Combined with sulfonamidom (see previous)

Total 1216 patients with type 2 diabetes participated in three 16-week double blind randomized placebo-controlled study and preparat- that will evaluate the effectiveness and safety rosiglitazona maleate in combination with sulfonamidom. Patients with insufficient sulfonamida appointed rosiglitazona maleate 2, or 4 mg / day or a time or in two installments.

Two platsebo- controlled studies of patients with poor performance sulfonamida randomizirovanno received more rosiglitazona maleate 4 mg once a day or in two installments. It has been a statistically significant decrease in plasma glucose concentration (at 2.1 mmol / L) and the concentration of HbA1c (at 0.9%) compared with placebo and combination sulfonamida. Using only sulfonamida plasma glucose concentrations increased by 0.33 mmol / l and HbA1c levels rose by 0.2% on the benchmarks.

The third study noted that in patients with insufficient gliburida maximum dose (20 mg / day) rosiglitazona maleate (2 mg twice daily) in combination with sulfonamidom significantly reduced plasma glucose level (n = 98, mean change in plasma glucose concentration The initial level of -1.72 mmol / L) and HbA1c (mean change from baseline -0.5%) compared with sulfonamidom with placebo (n = 99, mean change in plasma glucose concentration from baseline one, 33 mmol / l; HbA1c 0.9%). Revealed that the combination sulfonamida rosiglitazona maleate and effectively reduce the concentration of plasma glucose and HbA1c levels, as each product separately. In patients transferred from the maximum dose gliburida appointments rosiglitazona maleate (2 mg twice a day) as monotherapies, there was a deterioration in the level of glycemia control shown in the increase in plasma glucose concentration and the level of HbA1c.

A combination with insulin. Two 26-week randomized double blind study with a fixed dose to assess the efficacy and safety of rosiglitazona maleate in combination with insulin. Patients with poor control of glycemia insulin (from 65 to 76 ED / day on average) appointed 4 mg / day rosiglitazona maleate and insulin (n = 206) or insulin and placebo (n = 203). Mean duration of disease in these patients ravnyalas12-13 years.

In appointing rosiglitazona maleate 4 mg per day in one or two installments in combination with insulin significantly decreased level of plasma glucose shock (average decrease from 1.78 to 2.02 mmol / l) and HbA1c levels (average decrease from 0.6 to 0 7%) compared with the combination of insulin and placebo. Approximately 40% of all patients receiving more rosiglitazona maleate, has been able to reduce the dose of insulin.

     Application : According to the Physicians Desk Reference (2005), rosiglitazona maleate shown for improving glycemia control in patients with type 2 diabetes in addition to diet and physical stresses. Implemented as a singly or in combination with sulfonamidom, metformin or insulin when diet, exercise and monotherapies not adequate controls glycemia. In patients with poor control of glycemia using maximum doses of metformin or sulfonamida, rosiglitazona maleate can be added to the treatment, while not completely replace sulfonamid or metformin for rosiglitazona maleate.

     Contraindications : Giperchuvstvitelnost.

     Restrictions on the use of : Diabetes mellitus type 1 or ketoacidosis (in the absence of insulin ineffective), chronic heart failure, swelling, violation of liver function (see "Precautions"), age 18 (safety and efficacy of rosiglitazona maleate in patients under 18 years not identified).

     Application of pregnancy and breastfeeding : It should not be used during pregnancy, except in cases where the expected effect of therapy outweighs the potential risk to the fetus (adequate and well-controlled studies in pregnant women did not). Based on the available data is that changes in blood glucose during pregnancy is associated with increased frequency of congenital abnormalities and increased neonatal morbidity and mortality. To maintain glucose as close to normal, most experts recommend the use during pregnancy monotherapies insulin.

Rosiglitazona effect on the delivery and the birth has not been established.

Breast Feeding. Substances rosiglitazonu sister, identified in the milk of rats. There is no data on excretion rosiglitazona maleate with breast milk from women. As many LS infiltrating breast milk, rosiglitazona maleate should not appoint lactating women.

     Side Effects : In clinical studies of approximately 4,600 patients with type 2 diabetes treated rosiglitazona maleatom; 3300 patients were treated with 6 months or more, the 2000 patients, 12 months or more.

According to a double-blind clinical trial in patients who were on monotherapies rosiglitazona maleatom (n = 2526) compared to placebo (n = 601), the most common side effects were as follows (in parentheses% occurrence in the placebo group) : upper respiratory tract infection 9.9% (8.7) 7.6% trauma (4,3), headache 5.9% (5.0), back pain 4.0% (3.8), hyperglycemia 3.9 % (5.7), fatigability 3.6% (5.0), sinusitis 3.2% (4.5); diarrhea 2.3% (3.3), hypoglycemia 0.6% (0.2) .

A small number of patients receiving rosiglitazona maleate, developed anemia and swelling. In general, side effects were slight or moderate, and usually do not lead to the lifting of therapy. According to a double blind study, developed anemia from 1.9% of patients receiving rosiglitazona maleate, compared to 0.7% receiving placebo, 0.6% and 2.2 receiving sulfonamid% receiving metformin. Swelling evolved from 4.8% of patients receiving rosiglitazona maleate, compared to 1.3% receiving placebo, 1.0% and 2.2 receiving sulfonamid% metformin. All side effects reported in the appointment of a combination rosiglitazona maleate with sulfonamidom or metformin, were similar to the observed monotherapies. The largest percentage (7.1%) reported anemia is a combination rosiglitazona maleate and metformin as compared to rosiglitazonom monotherapies or combined with sulfonamidom. Perhaps the high frequency of reports of anaemia in combination with metformin study has a low baseline hemoglobin / gematokrita in patients included in this group (see Laboratory deviation from the norm. Hematology).

In the 26-week double blind study with a fixed dose combination with insulin and rosiglitazona maleate with great frequency reported swells (at the receiving insulin - 5.4%, from receiving rosiglitazona maleate in combination with insulin - 14.7%). The emergence or exacerbation of congestive heart failure met with only 1% receiving insulin, a 2% (dose rosiglitazona maleate 4 mg / day) and 3% (dose rosiglitazona maleate 8 mg / d) receiving the combination with insulin rosiglitazona maleatom (see " Precautions. " Heart failure and other kardialnye effects). In postmarketingovom experience rosiglitazona maleate reported side effects potentially associated with the increasing volume of liquid (long heart failure, swelling of the lungs, blood vypot).

The studies combination with a fixed dose of insulin rosiglitazona maleatom most frequent side effect was hypoglycemia. Some patients because of hypoglycemia were withdrawn from the test (4 of 408 receiving rosiglitazona maleate with insulin and one of 203 who received only insulin). The frequency of hypoglycemia, confirmed analysis glucose in the blood capillaries? 2.78 mmol / L was 6% for receiving insulin only, 12 and 14% for receiving combination rosiglitazona maleate (4 and 8 mg, respectively) with insulin.

Laboratory deviations from the norm

Hematology. In patients receiving rosiglitazona maleate, there dozozavisimoe decrease in the average level of hemoglobin and gematokrita (average decline in each case was 10.0 g / l for hemoglobin and 3.3% for gematokrita). The duration of the course and a reduction of these indicators in patients receiving rosiglitazona maleate in combination with other tools and gipoglikemicheskimi rosiglitazona maleate as monotherapies, were identical. The level of hemoglobin and gematokrita before treatment was reduced in patients in the study combination with metformin, which may contribute to the high frequency of reports of anemia in this group. The number of white blood cells also declined slightly in patients receiving rosiglitazona maleate. Reducing haematological parameters can be associated with the observed increase in plasma.

Lipid. During treatment rosiglitazona maleatom changes in plasma lipids (see "Pharmacology" and "Precautions").

Level transaminaz plasma. In clinical studies with 4,598 patients receiving rosiglitazona maleate, including about 3,600 patients a year with an exhibition, there was no apparent drug hepatotoxicity or rising ALT.

In controlled tests in 0.2% of patients receiving rosiglitazona maleate, ALT levels increased more than 3 times the upper limit of the rules, as compared to 0.2% for placebo, and 0.5% for the comparison drug. Hyperbilirubinemia identified in 0.3% of patients receiving rosiglitazona maleate, compared with 0.9% for the placebo and 1% compared to a drug. In clinical program, which included a lengthy public kategoriziruyuschee study transaminaz increase in the level of more than three times the upper limit of the rules was 0.35% for patients receiving rosiglitazona maleate, 0.59% for receiving placebo and 0.78% for receiving the active combination .

     Networking : Medicines metaboliziruyuschiesya with tsitohroma R450. In in vitro studies showed that rosiglitazon in clinically relevant concentrations is not ingibiruet none of the major izofermentov tsitohroma R450. According to studies in vitro, rosiglitazon metabolised, mainly involving CYP2C8 and to a lesser extent, CYP2 S9. Inhibitor CYP2C8 (gemfibrozil) may reduce metabolic rosiglitazona, inducer (rifampicin) - raise. Therefore, if the inhibitors or inducers CYP2C8 appoint or cancel during therapy rosiglitazona maleatom may require dose adjustment rosiglitazona maleate, in accordance with clinical response.

Rosiglitazona maleate (4 mg 2 times a day) has no clinically significant impact on the pharmacokinetics of oral contraceptives and nifedipina (levonorgestrel and noretindron), which are metabolised mainly by CYP3A4.

Gliburid. Before rosiglitazona maleate (2 mg 2 times a day) with gliburidom (3,75-10 mg / day) for 7 days average daily equilibrium plasma glucose concentrations in patients with diabetes, stabilized on medication gliburidom not changed.

Metformin. The simultaneous appointment rosiglitazona maleate (2 mg 2 times a day) and metformin (500 mg, 2 times a day) healthy volunteers over four days does not have effect on the pharmacokinetics of equilibrium or rosiglitazona maleate or metformin.

Akarboza. Joint application akarbozy (100 mg three times daily) for 7 days in healthy volunteers does not have a clinically meaningful effect on the pharmacokinetics of a single dose rosiglitazona maleate.

Digoxin. Admission rosiglitazona maleate (8 1 mg once a day) for 14 days did not change the equilibrium pharmacokinetics of digoxin (0,375 1 mg once a day) from healthy volunteers.

Racumin. Repetitive reception rosiglitazona maleate not have clinically significant effects on the pharmacokinetics of enantiomers racumin equilibrium.

Ethanol. Single admission moderate amounts of alcohol does not increase the risk of sudden development of hypoglycemia in patients with type 2 diabetes receiving rosiglitazona maleate.

Ranitidine. Preliminary admission ranitidine (150 mg, 2 times daily for 4 days) did not change the pharmacokinetics of a single oral dose of either or single on / in a rosiglitazona maleate healthy volunteers. These results indicate that the absorption rosiglitazona when administered no change in the face with a raise pH in the digestive tract.

Gemfibrozil. The combined application gemfibrozila (600 mg, 2 times a day) and rosiglitazona maleate (1 mg 4 times a day) for 7 days resulted in higher AUC rosiglitazona maleate 2 times compared with monotherapies rosiglitazona maleatom (4 1 mg once a day); given the potential effects dozozavisimye rosiglitazona maleate, in addition gemfibrozilom therapy may require lower doses rosiglitazona.

     Overdosing : Existing data on overdose rosiglitazona maleate person is not enough. Rosiglitazona maleate well transferred in a single admission volunteers dose up to 20 mg. In cases of overdose should be appointed by a supportive therapy in view of the patient.

     Dosing and Administration : inside, regardless of the meal. Tactics hypoglycemic therapy strictly individual.

Monotherapy : normal initial dose of 4 mg / day for 1 or 2 admission. According to clinical studies, the maximum reduction in plasma glucose and HbA1c a shock dose of 4 mg twice a day.

In combination with sulfonamidom, metformin or insulin dose of the past does not change at the beginning of treatment rosiglitazona maleatom.

In combination with the recommended dosage sulfonamidom rosiglitazona maleate is 4 mg / day for 1 or 2 admission. In developing hypoglycaemia dose sulfonamida decline.

In combination with metformin rosiglitazona maleate initial dose of 4 mg / day for 1 or 2 admission. It is likely to correct doses of metformin for hypoglycemia low.

Insulin : For patients stabilized for insulin, insulin dose still in the early treatment rosiglitazona maleatom. Dose rosiglitazona maleate-4 mg / day. Exceeding this dose in combination with insulin is not shown. Recommended lower dose rosiglitazona maleate at 10-25%, if the patient responded hypoglycemia or lower blood glucose concentrations less shock 5.55 mmol / l. Follow correct dose should be based on an individual response, reducing blood glucose.

The maximum recommended dose rosiglitazona maleate, which should not exceed 8 mg / day in a trick or divided into two installments. This dose showed a safe and effective in large-scale studies as monotherapies and in combination with metformin. Dose rosiglitazona maleate more than 4 mg / day, in combination with sulfonamidom not studied in controlled clinical trials. Dose rosiglitazona maleate over 4 mg / day in combination with insulin showed no.

     Precautions : General. In accordance with the act rosiglitazona maleate is active only in the presence of endogenous insulin, so it should not be used in patients with type 1 diabetes or for the treatment of ketoacidosis.

Heart failure and other kardialnye effects. Application rosiglitazona maleate, and other tiazolidindionov alone or in combination with various gipoglikemicheskimi funds may be delayed fluid, which in turn can cause or aggravate heart disease. There is a need to examine the patient to identify the signs and symptoms of heart failure. In combination with insulin tiazolidindiony may also increase the risk of other side effects of the cardiovascular system. Rosiglitazona maleate should be abolished in all cases, the deterioration of the cardiovascular system.

Patients with chronic congestive heart failure III and IV class (NYHA functional classification) did not participate in clinical trials. In patients rosiglitazona maleate is not recommended.

In the United States, in three 26-week study of patients with type 2 diabetes, 216 people were rosiglitazona maleate 4 mg daily in combination with insulin, 322 patients received 8 mg per day rosiglitazona maleate plus insulin, and 338 received only insulin. In these studies included patients with prolonged period of diabetes and high frequency related disorders, including peripheral neuropathy, retinopathy, IBS, disease and sclerotic heart disease. In these clinical studies increase in infections, heart failure and other undesirable phenomena of the cardiovascular system met more frequently in patients receiving combination rosiglitazona maleate with insulin compared with insulin and placebo. Patients who have developed cardiac irregularities were, on average, older and had a longer period of diabetes. Cardiovascular violations observed in the group of patients receiving more rosiglitazona maleate dose of 4 mg / day or in a group, which received 8 mg per day. However, the stock is not possible to identify specific risk factors that could be used to identify all patients with heart failure risk development and other cardiovascular complications in combination therapy. Three of the 10 patients developed heart failure during part of a double blind studies not previously aware of the existence of signs of congestive heart failure or predisposing factors for heart disease.

In a double blind study in patients with type 2 diabetes and chronic renal failure (112 receiving 4 or 8 mg rosiglitazona maleate plus insulin, and 108 received insulin control), the difference in the frequency of side effects of the cardiovascular system between the group receiving the combination rosiglitazona maleate with insulin, and the group, which received only insulin, no.

Patients receiving combination rosiglitazona maleate and insulin must be observed in order to identify possible side effects on the cardiovascular system. This combination therapy is contraindicated for patients who are not responding apparent decrease HbA1c or doses of insulin through 4-5 months of treatment, and patients developed any significant adverse reactions (see "Side Effects").

Hypoglycemia. There is the risk of hypoglycemia in patients receiving rosiglitazona maleate in combination with other gipoglikemicheskimi means. It may be necessary to reduce the doses of drugs.

Swelling. Rosiglitazona maleate should be used with caution in patients with infections. In a clinical study of healthy volunteers who received 8 mg rosiglitazona maleate 1 times a day every day for eight weeks, there was a statistically significant increase in the average level of plasma compared to placebo.

According to the controlled clinical trials in patients with type 2 diabetes receiving rosiglitazona maleate, reported on the development of low or moderate swells probably dozozavisimyh. In patients with existing swells likely development side effects when using combination therapy rosiglitazonom maleatom and insulin (see "Side Effects").

The increase in body mass. Using rosiglitazona maleate as monotherapies and in combination with other gipoglikemicheskimi means there dozozavisimoe increased body mass. According to the 26-week test using rosiglitazona maleate in doses 4 and 8 mg / day as monotherapies average increase in body weight was 1.0 and 3.1 kg respectively. In combination with sulfonamidom, metformin or insulin-dependent increase in the average body mass rosiglitazona maleate dose of 4 mg / day was 1.8; 0.8 and 4.1 kg respectively. The mechanism of increasing body mass unclear, but possibly due to the delay of liquid and fat accumulation.

In postmarketingovyh study reported rare cases of unusually rapid increase in body mass index greater than observed in clinical trials. Such patients should be evaluated accumulation of fluids and related side effects (expressed swelling, long heart failure).

Lipid. Recommended determine LPVP and triglyceride levels before treatment and monitored their levels in the future.

Hematology. In appointing rosiglitazona maleate as monotherapies or in combination with other gipoglikemicheskimi of all controlled clinical studies has been a decline in hemoglobin and gematokrita (average reduction in individual studies? 10.0 g / l? 3.3% respectively). Changes in these rates occurred mainly during the first three months following the start of therapy rosiglitazonom maleatom or after increasing dose. The number of leukocyte also declined slightly. These changes may be associated with increased plasma observed in the treatment rosiglitazonom maleatom and may be dozozavisimymi (see "Side Effects". Laboratory deviations from the norm).

Ovulation. Application rosiglitazona maleate, and other tiazolidindionov can lead to ovulation in some women with anovulyatornym premenopauze cycle. These women are at risk of pregnancy in the face of treatment rosiglitazonom maleatom, so women premenopauze recommended adequate contraception. This potential effect is not specifically studied in clinical research, and the frequency of occurrence is unknown.

Although the changes observed in the hormone balance of preclinical studies (see "Pharmacology". Carcinogenicity, mutagenicity, the impact on fertility), the clinical significance is unknown. If menstrual irregularities, it should be possible to assess the risks and expected benefits from continued therapy rosiglitazona maleatom.

The impact on the liver. In preliminary clinical studies in 4598 patients receiving rosiglitazona maleate, comprising about 3600 patients with an annual exhibition, was not reported drug hepatotoxicity or ALT level rise. In preliminary tests have controlled 0.2% of patients receiving rosiglitazona maleate, rebounded ALT more than 3 times the upper limit of the rules compared to 0.2% for placebo, and 0.5% for the comparison drug. Raising ALT in patients receiving rosiglitazona maleate, was reversible and did not have a clear causal connection with the application of the LS.

In postmarketingovom experience destination rosiglitazona maleate were reported on the development of hepatitis B and liver enzymes increase to 3 or more times the upper limit of the rules. There is a clear causal connection between the rare cases of liver failure with favorable or lethal outcomes and the use rosiglitazona maleate. Pending the results of additional large-scale long-term controlled clinical studies and additional data on postmarketingovoy safety of all patients recommended to monitor the level of liver enzymes before treatment rosiglitazonom maleatom. Where the original enzymes increased more than 2.5 times the upper limit of the rules rosiglitazona maleate is not appointed. In patients with normal baseline levels of enzymes after the start of treatment to control the level transaminaz every 2 months for the first 12 months and then periodically. Patients with minor increases in liver enzymes (exceeding normal? 2.5) at the beginning or during treatment rosiglitazonom maleatom need to be surveyed to identify the causes. Caution should begin or continue therapy rosiglitazonom maleatom with little increased liver enzymes; Such patients require more frequent monitoring to assess their level of performance. In all cases, recovery ALT more than 3 times the upper limit rules in patients receiving rosiglitazona maleate, urgent repeat this analysis. If ALT really an upper limit rules more than three times, the rosiglitazona maleate should be repealed.

If the patient develops symptoms to suspect a violation of the functions of the liver (unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and / or the appearance of dark urine), it is necessary to analyse in liver enzymes. The decision to continue the therapy rosiglitazona maleatom from these patients should be based on clinical and laboratory evaluation of the changes. If there jaundice, the rosiglitazona maleate should be repealed.

Laboratory performance. Periodic measurements of blood glucose and HbA1c shock to assess the therapeutic effect of the treatment. In all patients before therapy rosiglitazonom maleatom and periodically during treatment to check the level of liver enzymes (see "Side Effects". Level transaminaz plasma).

Information for patients

Patients should be informed of the following. Therapy type 2 diabetes include diet compliance. Limiting caloric intake, lower body mass and physical exercises necessary for the correct treatment, as this helps improve the sensitivity of tissues to insulin. This is important not only in early diabetes, but in order to maintain the effectiveness of subsequent drug therapy. It is important to follow the recommended diet and regular monitoring of blood glucose and hemoglobin glikozilirovannogo. Patients should be informed that the marked decrease in blood glucose be about 2 weeks, as the full effect from 2 to 8 months. Patients should be informed that it is necessary to carry out blood tests to measure liver function before treatment and every two months during the first 12 months of treatment and then periodically. Patients who have unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, should immediately report these symptoms physician. Patients who have observed abnormally rapid increase in weight, swelling, difficulty breath, or other symptoms of heart failure in the face of admission rosiglitazona maleate, should immediately inform their physician.

Rosiglitazona maleate can be taken regardless of the meal. When it is used in combination with other gipoglikemicheskimi means, the patient and his family must be informed of the risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to the development.

Although hormonal imbalance has been identified in the pre-study (see "Pharmacology". Carcinogenicity, mutagenicity, the impact on fertility), the clinical significance of this phenomenon is unknown. If there are sudden violations menstrual function, it is necessary to revise the expected positive effects of continued treatment rosiglitazona maleatom.

In patients with a risk of heart failure rosiglitazona maleate should be used with caution as tiazolidindiony, including rosiglitazona maleate, may be delayed liquid and create or promote expression of congestive heart failure. Such patients should be assessed before therapy.

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