2010/06/24

Avandia

Composition, structure and packing

Tablets, film-coated orange, pentagonal, with the inscription "GSK" on one side and "4" - on the other party.

1 tab. rosiglitazone - (through maleate) 4 mg.

Excipients: sodium starch glycolate, hydroxypropylmethylcellulose, microcrystalline cellulose, lactose monohydrate, magnesium stearate.

Composition of tablet film coating: hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, talc purified, lactose, triacetin, iron oxide red, iron oxide yellow. Tablets, film-coated red-brown, pentagonal, with the inscription "GSK" on one side and "8" - on the other side.

1 tab. rosiglitazone - (in the form of maleate) 8 mg.

Excipients: sodium starch glycolate, hydroxypropylmethylcellulose, microcrystalline cellulose, lactose monohydrate, magnesium stearate.

Composition of tablet film coating: hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, lactose, triacetin, iron oxide red.

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

Clinico-pharmacological group: oral hypoglycemic drug.

Pharmacological action

Oral hypoglycemic drug from the thiazolidinedione group. Is a selective agonist of nuclear receptor PPAR╬│ (peroxisomal proliferator activated gamma). Rosiglitazon reduces blood glucose by increasing insulin sensitivity of adipose tissue, skeletal muscle and liver tissue, improves during metabolic processes, reduces the level of glucose, insulin and free fatty acids in the blood. The product retains the function of ╬▓-cells, as evidenced by the increase in mass islets of Langerhans of the pancreas and insulin, and prevents the development of marked hyperglycemia. It was also found that the drug significantly slows the development of renal dysfunction and systolic arterial hypertension treatment. Not stimulates the secretion of insulin the pancreas and does not cause hypoglycemia. In accordance with the mechanism of action rosiglitazona improve glycemic control accompanied by a clinically significant reduction in insulin levels in blood serum. Also decreases production of precursors of insulin, which are considered risk factors for diseases of the cardiovascular system. A key feature of therapy with Avandiya a significant reduction in free fatty acids in the blood.

Due to different but complementary mechanisms of action, combination therapy rosiglitazonom, derivatives and sulfonylureas, metformin has as a result of a synergistic effect and improves control of blood glucose in diabetes mellitus type 2.

Pharmacokinetics

Absorption

After taking the drug by mouth in doses of 4 mg or 8 mg absolute bioavailability rosiglitazona is about 99%. After taking the drug inside rosiglitazona Cmax in blood plasma is reached within 1 h. In the range of therapeutic doses plasma concentrations are approximately proportional to dose. Acceptance of the drug with food is a small reduction in Cmax (approximately 20-28%) and increased time to achieve it to 1.75 h compared with the reception on an empty stomach. These small changes are not clinically significant, so there is no need for any coordination with the reception rosiglitazona mealtime. Absorption rosiglitazona not violated with increasing pH of gastric secretion.

Distribution

Cvyazyvanie with blood proteins is high (about 99.8%) and does not depend on the concentration rosiglitazona in blood plasma or age of the patient.

Vd rosiglitazona in healthy volunteers is approximately 14 liters.

After taking the drug 1-2 times / day rosiglitazon not cumulative.

Cumulation of metabolites in blood serum is expected after repeated drug administration. To a greater degree of accumulated principal metabolite (paragidroksisulfat), for which we can expect 5-fold increase in concentration.

Metabolism

Rosiglitazon subjected to intensive metabolism predominantly via N-demethylation and hydroxylation followed by conjugation with sulfate and glucuronic acid. Metabolites rosiglitazona not have clinically significant active.

In in vitro studies showed that rosiglitazon mainly metabolized with the participation of isoenzyme CYP2C8 and to a lesser extent - with the involvement of CYP2C9. Since the application is not rosiglitazona significant inhibition of in vitro isozymes CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A, it is unlikely interaction with drugs, the metabolism of which involve the participation of these isoenzymes.

In vitro rosiglitazon moderately inhibits the isoenzyme CYP2C8 (IC50 18 uM) and to a lesser degree - CYP2C9 (IC50 50 uM). In a study in vivo with warfarin has been shown that rosiglitazon not interact with substrates of CYP2C9.

Withdrawal

T1 / 2 rosiglitazona is about 3-4 hours total plasma clearance - about 3 l / h. Outputs in the form of metabolites, mainly by the kidneys - about 2 / 3 of the dose in feces - about 25%. Final T1 / 2 is about 130 h, indicating a very slow breeding metabolites.

Pharmacokinetics in special clinical situations

There were no differences in the pharmacokinetics of sex, as well as in adult patients and elderly patients.

In patients with moderate to severe hepatic impairment C max of the drug in plasma and AUC increased in 2-3 times, respectively, owing to lower the degree of binding to plasma proteins and decreased clearance rosiglitazona.

Clinically significant differences in pharmacokinetics in patients with kidney disease or renal failure in the terminal stage, located on dialysis, no.

Statement

Diabetes mellitus type 2:
as monotherapy in case of insufficient effectiveness of diet and exercise;
in combination with derivatives of sulfonylurea, metformin to improve glycemic control,
in combination with derivatives of sulfonylurea and metformin (triple combination therapy) to improve glycemic control.

Dosage regimen

The drug taken by mouth. Dose and treatment regimen set individually. The daily dosage take a 1-2 admission, regardless of the meal. For adults the recommended initial dose is 4 mg / day. For lack of effectiveness after 6-8 weeks of treatment dose can be increased to 8 mg / day. For elderly patients dose adjustment is required.

Side effect

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

Frequency categories are defined in comparison with the frequency of unwanted reactions in the treatment of placebo or drug comparison, and not absolute values for those adverse reactions that may be associated with rosiglitazonom. For dose-dependent adverse reactions the frequency category reflects the maximum dose rosiglitazona.

Categories of frequency do not account for other factors, including differences in study duration, antecedent conditions and the initial characteristics of patients. Categories of frequency of undesirable reactions are based on clinical studies and may not reflect the frequency of adverse reactions in normal clinical practice.

In hypercholesterolemia total cholesterol increased while the increase of HDL and LDL, the ratio of cholesterol / HDL remained unchanged.

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

In the postmarketing period reported the following adverse reactions

Allergic reactions: very rare - anaphylactic reactions.

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

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

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

Contraindications
diabetes mellitus type 1 (in the absence of insulin rociglitazon ineffective);
Heart failure (I-IV functional classes classification NYHA);
moderately or severely impaired liver function;
Pregnancy
Lactation (breastfeeding);
childhood and adolescence to 18 years (efficacy and safety of the drug is not installed);
combined use with insulin;
Hypersensitivity to rosiglitazonu and other components of the drug.

With care use in patients with renal failure and severe.

Pregnancy and lactation

Do not use this medication Avandiya during pregnancy and lactation. Data on the use of the drug Avandiya during pregnancy and lactation is not enough. Patients with type 2 diabetes in pregnancy is recommended holding of insulin. If necessary, use of the drug Avandiya during lactation should stop breastfeeding.

The drug is contraindicated in moderate or severe liver function.

With care use in patients with marked renal insufficiency.

Cautions

Increased levels of total cholesterol was associated with an increase in both LDL and HDL, while the ratio of total cholesterol to HDL did not change. These effects are usually mild to moderate expressed and do not require cessation of treatment. The frequency of anemia was higher in the combined use of the drug with metformin. In general, this effect was weak or moderate, usually do not require termination of treatment.

Thiazolidinediones can cause or worsen chronic heart failure. After initiation of therapy rosiglitazonom and during dose titration, careful medical monitoring of the patient in respect of the following signs and symptoms of heart failure: a rapid and excessive weight gain, shortness of breath and / or swelling. With the development of symptoms of heart failure should discontinue treatment and to designate rosiglitazonom therapy, in accordance with current standards treatment of heart failure.

The drug is contraindicated in patients with heart failure, including history, I-IVfunktsionalnogo class classification NYHA.

Patients with acute coronary syndrome (ACS) are not included in clinical studies. Appointment rosiglitazona, as well as other oral hypoglycemic agents is not recommended for acute coronary syndrome, especially taking into account the increased risk of heart failure in ACS. During the acute phase should stop taking rosiglitazona. Data on the possibility rosiglitazona increase the risk of myocardial ischemia insufficient. Retrospective analysis of short-term clinical studies showed an increased risk of ischemic events in the treatment of rosiglitazonom compared with the control group as a whole (placebo plus active drug) in the same analysis when compared with other rosiglitazona oral antidiabetic drugs differences in the incidence of ischemic events were observed. An elevated risk of myocardial ischemia associated with rosiglitazonom, was not confirmed in further long-term randomized controlled clinical trials comparing rosiglitazon with metformin and sulfonylureas. Relationship between the intake rosiglitazona and the risk of ischemia is not installed. Increased risk of ischemic myocardial damage was observed in patients receiving nitrate therapy initially or during the clinical study on the setting of ischemic heart disease. Rosiglitazon not recommended in patients receiving concomitant therapy with nitrates. In patients with mild hepatic impairment (Class A / 6 points or less / scale Child-Pugh) correction dose is not required. In connection with the few data on the use of the drug in patients with moderately or severely impaired liver function and detect changes pharmacokinetic profile, the drug is contraindicated in this group of patients (class B or C / more than 6 points / on the scale of Child-Pugh). In renal insufficiency, mild to moderate severity of the correction dose regimen is not required. With respect to the use of the drug in patients with severe renal insufficiency insufficient data, and the drug should be prescribed with caution.

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

In applying rosiglitazona in premenopausal women observed hormone imbalance, but serious side effects associated with menstrual cycle were observed. In the case of such violations is necessary to evaluate the potential risks and potential benefits with continued therapy. Because of increasing sensitivity to insulin in patients with insulin resistance and anovulyatornym cycle in premenopausal (eg, polycystic ovary syndrome) rosiglitazon can lead to the resumption of ovulation and pregnancy.

Effects on ability to drive vehicles and management mechanisms

Avandiya does not cause drowsiness and has no sedative effect.

The drug has no effect on the ability to drive vehicles or other mechanisms.

Overdose

Data on drug overdose is limited. In clinical studies on volunteers observed good tolerability of a single dose to 20 mg.

Treatment: In case of overdose spend symptomatically. Rosiglitazon highly bound to proteins in the blood and therefore does not appear in hemodialysis.

Drug Interactions

There were no clinically significant drug interactions Avandiya with other drugs. Avandiya in therapeutic doses does not cause clinically significant changes in pharmacokinetics and pharmacodynamics of other oral hypoglycemic drugs, including metformin, glibenclamide and acarbose. With simultaneous application rosiglitazona with metformin or sulfonylurea derivatives for a variety of complementary mechanisms of action, there is synergy hypoglycemic action in patients with diabetes mellitus type 2.

Rosiglitazon not affect the pharmacokinetics of digoxin, and does not affect the anticoagulant activity of warfarin. Clinically significant pharmacokinetic drug interactions Avandiya with S (-)-warfarin (substrate for CYP2C9) was not observed.

Rosiglitazon not affect the pharmacokinetics of nifedipine and oral contraceptives containing ethinylestradiol and noretindron, indicating a low probability of drug interaction Avandiya with drugs, is metabolized with the participation of isoenzyme CYP3A4.

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

Moderate alcohol consumption in the treatment Avandiey no effect on glycemic control.

Terms and Conditions of storage

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