Form of production, composition and packaging
Tablets, film-coated orange, pentagonal, with the inscription “GSK” on one side and “4″ – on the other side.
1 tab.
* rosiglitazone (as maleate) 4 mg
Excipients: sodium starch glycolate, hydroxypropyl methylcellulose, microcrystalline cellulose, lactose monohydrate, magnesium stearate.
Composition of membrane shell: hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, purified talc, lactose, triatsetin, iron oxide red, iron oxide yellow.
7 – blisters (1) – packs cardboard.
14 – blisters (2) – packs cardboard.
14 – Valium (4) – packs cardboard.
14 – Crohn’s & Colitis (8) – packs cardboard.
Tablets, film-coated red-brown, pentagonal, with the inscription “GSK” on one side and “8″ – on the other side.
1 tab.
* rosiglitazone (as maleate) 8 mg
Excipients: sodium starch glycolate, hydroxypropyl methylcellulose, microcrystalline cellulose, lactose monohydrate, magnesium stearate.
Composition of membrane shell: hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, lactose, triatsetin, iron oxide red.
7 – blisters (1) – packs cardboard.
14 – blisters (2) – packs cardboard.
14 – Valium (4) – packs cardboard.
14 – Crohn’s & Colitis (8) – packs cardboard.
* International nonproprietary name, as recommended by WHO – rosiglitazone.
Clinico-pharmacological group: Oral hypoglycemic drug. Pharmacological action
Oral hypoglycemic agent from the group of thiazolidinediones. Is a selective agonist of nuclear receptor PPARγ (peroxisomal proliferator activated gamma). Rosiglitazone lowers blood glucose by increasing insulin sensitivity in adipose tissue, skeletal muscle and liver tissue, improves the course of metabolic processes, reduces the levels of glucose, insulin and free fatty acids in the blood.
The product retains the function of β-cells, as evidenced by the mass of islets of Langerhans of the pancreas and insulin, and prevents the development of severe hyperglycemia. It was also established that the drug significantly slows the development of renal dysfunction and systolic hypertension. Not stimulates the secretion of insulin in the pancreas and does not cause hypoglycemia.
In accordance with the mechanism of action of rosiglitazone improved glycemic control accompanied by a clinically significant reduction in insulin levels in the serum. Also reduced production of precursors of insulin, which are considered risk factors for developing cardiovascular system.
A key feature of drug therapy Avandia is a significant reduction in free fatty acids in the blood.
Due to different but complementary mechanisms of action, combined therapy of rosiglitazone, metformin and sulfonylurea derivatives provided by the synergistic effect and improves control of blood glucose in diabetes mellitus type 2.
Pharmacokinetics
Suction
After taking the drug orally at a dose of 4 mg or 8 mg of rosiglitazone absolute bioavailability is about 99%. After taking the drug inside rosiglitazone Cmax plasma levels achieved within 1 h.
In the range of therapeutic doses plasma concentrations are approximately proportional to dose.
Receiving medication with food causes a small reduction in Cmax (approximately 20-28%) and increase the time to achieve it to 1.75 h compared with fasted. These small changes are not clinically significant, so there is no need for any coordination with the receiving rosiglitazone meal times. Absorption of rosiglitazone is 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 of rosiglitazone in plasma or age of the patient.
Vd rosiglitazone in healthy volunteers is approximately 14 liters.
After taking the drug rosiglitazone 1.2 not cumulative.
Cumulation of metabolites in the blood serum is expected after repeated dosing. To a greater degree of accumulated major metabolite (paragidroksisulfat), for which we can expect 5-fold increase in concentration.
Metabolism
Rosiglitazone subjected to intensive metabolism mainly through N-demethylation and hydroxylation with subsequent conjugation with sulphate and glucuronic acid. Metabolites of rosiglitazone did not have clinically significant activity.
In in vitro studies showed that rosiglitazone is metabolized primarily with the participation of isoenzyme CYP2C8 and to a small extent – with the involvement of CYP2C9.
Since the use of rosiglitazone is no significant inhibition of in vitro isozymes CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A, it is unlikely interaction with drugs whose metabolism is carried out with the participation of these isoenzymes.
In vitro rosiglitazone moderately inhibits the isoenzyme CYP2C8 (inhibiting kontsentratsiya18 mmol), and to a lesser degree – CYP2C9 (inhibitory concentration 50 mmol). In in vivo studies with warfarin has been shown that rosiglitazone does not interact with substrates of CYP2C9.
Withdrawal
T1 / 2 rosiglitazone is approximately 3-4 h. The total plasma clearance – about 3 liters / h.
Excreted as metabolites, mostly kidneys – approximately 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 cases
No differences were observed in the pharmacokinetics of the drug depending on sex, as well as in adult patients and patients of advanced age.
In patients with moderate to severe hepatic impairment Smax drug in plasma and AUC were raised by 2-3 times, respectively, which was due to lower degree of binding to plasma proteins and reduced clearance rosiglitazone.
Clinically significant differences pharmacokinetics in patients with kidney disease or kidney failure in the terminal stage, in hemodialysis, are absent.
Indications for use drugs Avandia
Diabetes mellitus type 2:
- As monotherapy in case of insufficient effectiveness of diet therapy 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 is taken orally. Dose and treatment regimen set individually.
The daily dose taken every 1-2 hours, regardless of the meal.
For adults the recommended starting dose is 4 mg / For lack of efficacy after 6-8 weeks of treatment the dose can be increased to 8 mg /
For older patients, correction of the dose is not required.
Side effects
The frequency of adverse reactions is presented in accordance with the following gradation: very common (≥ 1 / 10), common (≥ 1 / 100, <1 / 10), sometimes (≥ 1 / 1000, <1 / 100), rare (≥ 1 /10 000, <1 / 1000), very rare (<1 / 10 000).
Categories frequency determined in comparison with the frequency of unwanted reactions in the treatment of placebo or drug comparison, and not the absolute values for those side effects that may be associated with rosiglitazone. For dose-dependent adverse reactions the frequency category reflects the maximum dose of rosiglitazone. Categories frequency does not account for other factors, including differences in the duration of studies, pre-existing conditions and baseline characteristics of patients. Categories of frequency of adverse reactions are defined on the basis of clinical studies and may not reflect the frequency of adverse reactions in routine clinical practice.
Data from clinical trials
R – rosiglitazone, M – metformin, N – sulfonylurea
Side effects R R + M P + P + C + M
The part of the hemopoietic system
Anemia often often often often
Leukopenia often
Thrombocytopenia often
Granulocytopenia often
Anemia is mild to moderate severity, is often dose-dependently
From metabolism
Cholesterol often often often often
Giperglitseridemiya often often
Hyperlipidemia often often often often
Weight gain often often often often
Increased appetite is often occasionally
Hypoglycemia is often very often very often
When hypercholesterolemia total cholesterol increased simultaneously with an increase in HDL and LDL, the ratio of cholesterol / HDL remained unchanged.
Increased body weight is dose-dependent and possibly related to fluid retention and accumulation of fatty deposits.
Hypoglycemia weak or moderate degree, is largely a dose-dependently.
From CNS
Dizziness often often
Headache often
Since the cardiovascular system
Heart failure / pulmonary edema often often
Myocardial ischemia often often often often
Increased number of cases of heart failure was observed in accession to rosiglitazone therapy, based on sulfonylureas or insulin. The number of observations does not allow an unambiguous conclusion about the connection with the dose, but the incidence is higher for daily dose of rosiglitazone 8 mg, compared with a daily dose of 4 mg. Symptoms of myocardial ischemia more frequently observed in the appointment of rosiglitazone in patients who are on insulin therapy. Data on the ability of rosiglitazone to increase the risk of myocardial ischemia insufficient. Retrospective analysis of mostly short-clinical studies with placebo, but not with the comparator, said the relationship between taking rosiglitazone and the risk of myocardial ischemia. These data are not confirmed by long-term clinical studies with drugs of comparison (metformin and / or sulfonylurea), and the relationship between rosiglitazone and the risk of ischemia is not installed. Increased risk of ischemic myocardial lesions observed in patients who were in clinical research on basic therapy with nitrates. Rosiglitazone is not recommended in patients receiving concomitant therapy with nitrates.
From the digestive system
Constipation (mild or moderate) often often often often
On the part of the musculoskeletal system
Fractures often
Myalgia often
Most reports related to fractures of the forearm, hand and foot women
On the part of the organism as a whole
Edema often often often often
Edema from mild to moderate severity, often dose-dependent manner.
In post-marketing 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 rosiglitazone, used as monotherapy and in combination with other hypoglycaemic agents. It is known that the risk of heart failure significantly increased in patients with diabetes compared with patients without diabetes.
From the digestive system: rarely seen reports of liver damage, accompanied by increasing concentrations of liver enzymes, but the causal link between treatment of rosiglitazone and liver dysfunction is not established.
Allergic reactions: seldom – angioedema, hives, rashes, itchy skin.
The part of the organ of vision: a very rare – macular edema.
Contraindications to the drug Avandia
- Diabetes mellitus type 1 (in the absence of insulin rociglitazon ineffective);
- Heart failure (I-IV functional classes in the classification NYHA);
- Moderate or severe hepatic impairment;
- Pregnancy;
- Lactation (breastfeeding);
- Childhood and adolescence to 18 years (effectiveness and safety of the drug not established);
- Combined use with insulin;
- Hypersensitivity to rosiglitazone and other components of the drug.
Precautions should be used drug in renal failure and severe.
Avandia use of the drug during pregnancy and breastfeeding
Contraindicated drug use 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 therapy.
If necessary, the drug Avandiya during lactation should stop breastfeeding.
Application for violations of liver function
The drug is contraindicated in moderate or severe hepatic impairment.
Use in Renal Impairment
Sostorozhnostyu should use the drug for renal insufficiency.
Cautions
Increased total cholesterol was associated with an increase in both LDL and HDL, while the ratio of total cholesterol to HDL cholesterol did not change. These effects are usually mild or moderate expressed and do not require discontinuation of treatment.
The frequency of anemia was higher with the combined use of the drug with metformin. In general, this effect was weak or moderate, generally did not require discontinuation of treatment.
Thiazolidinediones can cause or worsen during chronic heart failure. After the start of rosiglitazone therapy 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. In the development of symptoms of heart failure should discontinue treatment and to designate rosiglitazone therapy in accordance with current standards of treatment of heart failure.
The drug is contraindicated in patients with heart failure, including history, I-IV functional class classification NYHA.
Patients with acute coronary syndrome (ACS) is not included in clinical studies. Appointment of rosiglitazone, as well as other oral hypoglycemic drugs are not recommended for acute coronary syndrome, especially taking into account the increased risk of heart failure in acute coronary syndrome. During acute phase to cancel the reception rosiglitazone. Data on the possibility of rosiglitazone increase the risk of myocardial ischemia insufficient. A retrospective analysis of short-term clinical studies showed an increased risk of ischemic events with rosiglitazone treatment compared with control groups as a whole (placebo plus active drugs). In the same analysis comparing rosiglitazone with other oral hypoglycemic drugs differences in the incidence of ischemic events were observed. Elevated risk of myocardial ischemia associated with rosiglitazone, was not confirmed in further long-term randomized controlled clinical trials comparing rosiglitazone with metformin and sulfonylureas. Relationship between taking rosiglitazone and the risk of ischemia is not installed. Increased risk of ischemic myocardial lesions observed in patients receiving treatment with nitrates initially or during the clinical study concerning the introduction of coronary heart disease. Rosiglitazone is not recommended in patients receiving concomitant therapy with nitrates.
Patients with mild hepatic impairment (Class A / 6 points or less / by Child-Pugh) correction of the dose is not required. In connection with the few data on the use of the drug in patients with moderate or severe hepatic impairment and identified changes pharmacokinetic profile, the drug is contraindicated in this category of patients (class B or C / more than 6 points / by Child-Pugh).
In renal insufficiency mild to moderate correction dosing regime is not required. In the application of the drug in patients with severe renal insufficiency insufficient data, so the drug should be prescribed with caution.
In the long term study of monotherapy of diabetes mellitus type 2 patients previously treated with oral hypoglycemic agents, there was an increase incidence of fractures among women in the rosiglitazone group (9.3%, 2.7 cases per 100 patient-years) compared with metformin group (5.1%, 1.5 cases per 100 patient-years) and glyburide / glibenclamide (3.5%, 1.3 cases per 100 patient-years). Most of the cases registered in the rosiglitazone group concerned the fracture of the forearm, hand and foot. Possible increased risk of fractures should take into account in the appointment of rosiglitazone, especially women. Requires monitoring of bone tissue and the maintenance of bone health in accordance with accepted standards of therapy.
When using rosiglitazone in premenopausal women observed hormonal instability but serious side effects associated with the violation of the menstrual cycle were observed. In the case of such violations is necessary to evaluate the potential risks and potential benefits with continued therapy.
Because sensitivity to insulin in patients with insulin resistance and anovulatory cycles in premenopausal (eg, polycystic ovary syndrome), rosiglitazone may lead to the resumption of ovulation and pregnancy.
Effects on ability to drive vehicles and management mechanisms
Avandia 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 overdose is limited. In clinical trials with human volunteers observed well tolerated in a single dose to 20 mg.
Treatment: In case of overdose spend symptomatic therapy. Rosiglitazone is highly bound to blood proteins and therefore does not appear in hemodialysis.
Drug Interactions
Neither was there a clinically significant drug interactions Avandiya with other drugs.
Avandia 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 use of rosiglitazone with metformin or sulfonylurea derivatives as a result of various complementary mechanisms of action observed synergy hypoglycemic action in patients with diabetes mellitus type 2.
Rosiglitazone does 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) is not observed.
Rosiglitazone does not affect the pharmacokinetics of nifedipine and oral contraceptives containing ethinyl estradiol and norethindrone, which indicates 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 Css rosiglitazone increased in 2 times. This increase in concentration of rosiglitazone is associated with the risk of dose-dependent side effects, so when the combined use of Avandia with inhibitors of CYP2C8 may require lower doses of rosiglitazone.
Other CYP2C8 inhibitor caused a slight increase in systemic concentrations of rosiglitazone.
Rifampin (inductor CYP2C8) in a dose of 600 mg reduced the concentration of rosiglitazone by 65%. Therefore, patients who receive both rosiglitazone and inducers of enzyme CYP2C8, should conduct a careful control of blood glucose and change if necessary dose of rosiglitazone.
Moderate alcohol consumption in the treatment Avandia no effect on blood glucose control.
Conditions of supply of pharmacies
The drug is released with a prescription.
Conditions and terms of storage
List B. The drug should be stored in a place inaccessible to children at or above 25 ° C. Shelf life – 2 years.
