Avandia - instructions for use of the medicine, structure, Contraindications
Active material: Rosiglitazone
When ATH: A10BG02
CCF: Oral hypoglycemic agents
ICD-10 codes (testimony): E11
Manufacturer: GLAXO WELLCOME PRODUCTION (France)
Avandia: dosage form, composition and packaging
Pills, Film-coated orange, pentagonal, with an inscription “GSK” on one side and “4” – on the other side.
| 1 tab. | |
| rosiglitazone * (in the form of maleate) | 4 mg |
Excipients: sodium starch glycolate, hydroxypropyl, microcrystalline cellulose, lactose monohydrate, magnesium stearate.
The composition of the coating film: hydroxypropyl, Titanium dioxide, polyethylene glycol, Talcum cleared, lactose, triacetine, iron oxide red, iron oxide yellow.
7 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 red-brown, pentagonal, with an 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, hydroxypropyl, microcrystalline cellulose, lactose monohydrate, magnesium stearate.
The composition of the coating film: hydroxypropyl, Titanium dioxide, polyethylene glycol, lactose, triacetine, iron oxide red.
7 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.
Avandia: pharmachologic effect
Oral hypoglycemic drug from the group of thiazolidinediones. It is a selective PPARγ nuclear receptor agonist. (peroxisomal proliferator activated gamma). Rosiglitazone lowers blood glucose, increasing adipose tissue insulin sensitivity, skeletal muscle and liver tissue, improves the course of metabolic processes, lowers glucose levels, insulin and free fatty acids in the blood.
The drug preserves the function of β-cells, as evidenced by an increase in the mass of the islets of Langerhans of the pancreas and the content of insulin, and prevents the development of severe hyperglycemia. It was also established, that the drug significantly slows down the development of renal dysfunction and systolic arterial hypertension. Does not stimulate pancreatic insulin secretion and does not cause hypoglycemia.
In accordance with the mechanism of action of rosiglitazone, improvement in glycemic control is accompanied by a clinically significant decrease in serum insulin levels.. Decreased production of insulin precursors, which are considered risk factors for the development of diseases of the cardiovascular system.
A key feature of Avandia therapy is a significant decrease in the content of free fatty acids in the blood..
Due to the different, but complementary mechanisms of action, combination therapy with rosiglitazone, sulfonylurea derivatives and metformin result in a synergistic effect and improve blood glucose control in type 2 diabetes mellitus. 2.
Avandia: pharmacokinetics
Absorption
After oral administration of the drug in doses 4 mg or 8 mg The absolute bioavailability of rosiglitazone is about 99%. After taking the drug inside Cmax rosiglitazone in plasma is achieved within 1 no.
Over the therapeutic dose range, plasma concentrations are approximately dose proportional..
Taking the drug with food causes a slight decrease in Cmax (approximately 20-28%) and increase the time to reach it 1.75 h compared with fasting. These small changes are not clinically significant., therefore, there is no need for any coordination of rosiglitazone intake with meal times. Absorption of rosiglitazone is not impaired by an increase in the pH of gastric secretions..
Distribution
High blood protein binding (about 99.8%) and does not depend on the concentration of rosiglitazone in the blood plasma or the age of the patient.
Vd rosiglitazone in healthy volunteers is approximately 14 l.
After taking the drug 1-2 times/day rosiglitazone does not accumulate.
Cumulation of metabolites in serum is expected with repeated doses of the drug. The main metabolite accumulates to a greater extent (parahydroxysulfate), for which a 5-fold increase in concentration can be expected.
Metabolism
Rosiglitazone is extensively metabolized predominantly by N-demethylation and hydroxylation followed by conjugation with sulfate and glucuronic acid. Metabolites of rosiglitazone do not have clinically significant activity.
In in vitro studies show, that rosiglitazone is mainly metabolized with the participation of the CYP2C8 isoenzyme and to a small extent – with the participation of CYP2C9.
Since rosiglitazone does not significantly inhibit in vitro CYP1A2 isoenzymes, 2A6, 2C19, 2D6, 2E1, 3A or 4A, unlikely to interact with drugs, whose metabolism is carried out with the participation of these isoenzymes.
In vitro rosiglitazone moderately inhibited CYP2C8 isozyme (inhibitory concentration18 µmol) and to a lesser degree – CYP2C9 (inhibitory concentration 50 mmol). An in vivo study with warfarin has shown, that rosiglitazone does not interact with CYP2C9 substrates.
Deduction
T1/2 rosiglitazone is about 3-4 no. The total plasma clearance – about 3 l /.
Appears in the form of metabolites, mainly by the kidneys – about 2/3 the dose, with feces – about 25%.
The final T1/2 is about 130 no, It is indicating a very slow elimination of metabolites.
Pharmacokinetics in special clinical situations
There were no differences in the pharmacokinetics of the drug depending on gender., as well as in adult patients and elderly patients.
In patients with moderate to severe hepatic impairment Cmax drug in plasma and AUC increased in 2-3 times, which, respectively, was due to a decrease in the degree of binding to plasma proteins and a decrease in the clearance of rosiglitazone.
Clinically significant differences in the pharmacokinetics of the drug in patients with kidney disease or renal failure in the terminal stage, hemodialysis, no.
Avandia: testimony
Diabetes mellitus type 2:
- as monotherapy with insufficient effectiveness of diet therapy and physical activity;
- in combination with sulfonylurea derivatives, metformin to improve glycemic control;
- in combination with sulfonylurea derivatives and metformin (triple combination therapy) to improve glycemic control.
Avandia: dosing regimen
The drug is taken orally. The dose of the drug and the treatment regimen are set individually..
The daily dose is taken in 1-2 admission, regardless of the meal.
To Adult The recommended starting dose is 4 mg / day. With insufficient efficiency through 6-8 weeks of treatment, the dose can be increased to 8 mg / day.
To elderly patients correction dose is not required.
Avandia: side effects
The frequency of adverse reactions is represented by the following gradation: Often (≥1/10), often (≥1/100, <1/10), sometimes (≥1/1000, <1/100), rarely (≥1/10 000, <1/1000), rarely (<1/10 000).
frequency category determined in comparison with the frequency of occurrence of adverse reactions in treatment comparisons of placebo or preparation, rather than absolute values for those adverse reactions, which may be associated with rosiglitazone. For dose-related adverse reactions the frequency category reflects the maximum dose of rosiglitazone. Frequency categories do not account for other factors, including differences in study duration, previous state and baseline characteristics of patients. Categories of frequency of adverse reactions identified through clinical trials and may not reflect the frequency of adverse reactions in clinical practice.
Data, obtained in clinical trials
P – rosiglitazone, M – metformin, FROM – sulifonilmochyevina
| Side effect | P | P + M | P + C | P + FROM + M |
| From the hematopoietic system | ||||
| Anemia | often | often | often | often |
| Leukopenia | often | |||
| Thrombocytopenia | often | |||
| Granulocytopenia | often | |||
| Mild to moderate anemia, often dose dependent | ||||
| Metabolism | ||||
| Hypercholesterolemia | often | often | often | often |
| Hyperglyceridemia | often | often | ||
| Hyperlipidemia | often | often | often | often |
| Weight gain | often | often | often | often |
| Increased appetite | often | sometimes | ||
| Gipoglikemiâ | often | Often | Often | |
| In hypercholesterolemia, total cholesterol increased simultaneously with an increase in HDL and LDL, the ratio cholesterol / HDL cholesterol remained unchanged. Weight gain is dose-dependent and possibly related to fluid retention and fat accumulation. Mild or moderate hypoglycemia, mostly dose-dependent. | ||||
| CNS | ||||
| Dizziness | often | often | ||
| Headache | often | |||
| Cardio-vascular system | ||||
| Heart failure / pulmonary edema | often | often | ||
| myocardial ischemia | often | often | often | often |
| An increase in the incidence of heart failure was observed when rosiglitazone was added to therapy., based on sulfonylurea or insulin. The number of cases does not allow to make an unambiguous conclusion about the relationship to the dose of the drug, however, the incidence of the above daily dose for rosiglitazone 8 mg, compared with a daily dose 4 mg. The symptoms of myocardial ischemia were more frequently observed in the appointment of rosiglitazone patients, with insulin. Data on the ability of rosiglitazone to increase the risk of myocardial ischemia are insufficient. Retrospective analysis of mostly short clinical trials with placebo, but not with the comparator, suggests an association between rosiglitazone and the risk of myocardial ischemia. These data are not confirmed by long-term clinical studies with comparators. (metformin and/or sulfonylurea), and the relationship between rosiglitazone and the risk of ischemia has not been established. An increased risk of developing ischemic myocardial damage was observed in patients, were during clinical trials on basic therapy with nitrates. 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. | ||||
The following adverse reactions have been reported in the post-marketing period
Allergic reactions: rarely – anaphylactic reactions.
Cardio-vascular system: rarely – Chronic heart failure / pulmonary edema.
Reports on the development of undesirable reactions data obtained for rosiglitazone, used as monotherapy and in combination with other hypoglycemic agents. Known, that the risk of developing heart failure is significantly increased in patients with diabetes compared to patients, do not have diabetes.
From the digestive system: rarely noted reports of hepatic dysfunction, accompanied by an increase in the concentration of liver enzymes, however, a causal relationship between treatment with rosiglitazone and liver dysfunction has not been established.
Allergic reactions: rarely – angioedema, hives, rash, itching.
On the part of the organ of vision: rarely – macular edema.
Avandia: Contraindications
- Diabetes mellitus type 1 (in the absence of insulin, rosiglitazone is ineffective);
- Heart failure (I-IV functional classes according to NYHA classification);
- Moderate or severe liver dysfunction;
- Pregnancy;
- Lactation (breast-feeding);
- Childhood and adolescence up 18 years (the efficacy and safety of the drug is not installed);
- the combined use of insulin;
- hypersensitivity to rosiglitazone and other components of the drug.
FROM caution use in patients with severe renal insufficiency.
Avandia: Pregnancy and lactation
The use of the drug Avandia during pregnancy and lactation is contraindicated..
Data on the use of the drug Avandia during pregnancy and lactation is not enough.
Patients with diabetes type 2 during pregnancy, insulin therapy is recommended.
If it is necessary to use the drug Avandia during lactation, breastfeeding should be stopped..
Avandia: Special instructions
An increase in total cholesterol was associated with both an increase in LDL, as well as HDL, while the ratio of total cholesterol to HDL did not change. These effects are usually mild to moderate 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 moderately pronounced., usually did not require discontinuation of treatment.
Thiazolidinediones may cause or worsen chronic heart failure. After initiation of rosiglitazone therapy and during dose titration, careful medical monitoring of the patient's condition is necessary in relation to the following symptoms and signs of heart failure: rapid and excessive weight gain, shortness of breath and/or swelling. With the development of symptoms of heart failure, treatment with rosiglitazone should be discontinued and therapy should be initiated in accordance with current standards for the treatment of heart failure..
The drug is contraindicated in patients with heart failure, incl. history, I-IV NYHA functional class classification.
Patients with acute coronary syndrome (OKS) They were not included in clinical studies. appointment of rosiglitazone, as well as other oral hypoglycemic drugs are not recommended in acute coronary syndrome, especially considering the increased risk of heart failure in ACS. During the acute phase to cancel receiving rosiglitazone. 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 plus active drugs). 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, not confirmed in further long-term randomized controlled clinical trials, comparing rosiglitazone with metformin and a sulfonylurea. The relationship between taking rosiglitazone and the risk of ischemia has not been established.. Increased risk of ischemic myocardial injury observed in patients, treated with nitrates at baseline or during a clinical trial for established coronary heart disease. Rosiglitazone is not recommended in patients, receiving concomitant therapy with nitrates.
In patients with mild hepatic impairment (class A /6 points or less / Child-Pugh) correction dose is not required. Due to the scarcity of data on the use of the drug in patients with moderate or severe hepatic impairment and identified changes in the pharmacokinetic profile, the drug is contraindicated in this category of patients (class B or C / more 6 points/Child-Pugh).
In case of mild to moderate renal failure, correction of the dosing regimen is not required.. Insufficient data regarding the use of the drug in patients with severe renal insufficiency., therefore, the drug should be administered with caution.
In a longitudinal study of monotherapy of diabetes mellitus type 2 patients, previously untreated oral hypoglycemic drugs, was an increase in the incidence of fractures in women in the rosiglitazone group (9.3%; 2.7 accidents 100 patients-years) compared with metformin groups (5.1%; 1.5 case of 100 patients-years) and glyburide / glibenclamide (3.5%; 1.3 case of 100 patients-years). Most of the reported reports in the rosiglitazone group were forearm fractures., hand and foot. A possible increase in the risk of fractures should be taken into account when prescribing rosiglitazone., especially women. It is necessary to monitor the condition of the bone tissue and maintain bone health in accordance with accepted standards of therapy.
When using rosiglitazone in premenopausal women, hormonal instability is noted, however serious side effects, associated with menstrual irregularities, not observed. In the case of such violations, it is necessary to evaluate the potential risk and expected benefit with continued therapy..
Due to increased insulin sensitivity in premenopausal patients with insulin resistance and anovulatory cycle (eg, the polycystic ovary syndrome) rosiglitazone may lead to resumption of ovulation and pregnancy.
Effects on ability to drive vehicles and management mechanisms
Avandia does not cause drowsiness and does not have a sedative effect.. The drug does not affect the ability to drive vehicles or other mechanisms.
Avandia: overdose
Data on drug overdose are limited.. In clinical studies on volunteers, the drug was well tolerated in a single dose up to 20 mg.
Treatment: in case of overdose, symptomatic therapy is carried out. Rosiglitazone is highly protein bound and therefore not eliminated by hemodialysis..
Avandia: drug interaction
There was no clinically significant interaction of the drug Avandia with other medicinal products..
Avandia at therapeutic doses does not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of other oral hypoglycemic drugs., including metformin, glibenclamide and acarbose.
With the simultaneous use of rosiglitazone with sulfonylurea derivatives or metformin, due to various complementary mechanisms of action, a synergistic hypoglycemic effect is observed in patients with type 2 diabetes mellitus. 2.
Rosiglitazone does not affect the pharmacokinetics of digoxin, and also does not affect the anticoagulant activity of warfarin.
Clinically significant pharmacokinetic interaction of Avandia with S(-)-varfarinom (substrate for CYP2C9) not observed.
Rosiglitazone does not affect the pharmacokinetics of nifedipine and oral contraceptives, containing ethinylestradiol and norethindrone, which indicates a low probability of interaction of the drug Avandia with drugs, metabolized with the participation of the CYP3A4 isoenzyme.
Gemfiʙrozil (CYP2C8 inhibitor) dose 600 mg 2 times/day increased Css rosiglitazone in 2 times. This increase in the concentration of rosiglitazone is associated with the risk of dose-dependent side effects., therefore, when Avandia is co-administered with CYP2C8 inhibitors, a dose reduction of rosiglitazone may be required..
Other inhibitors of CYP2C8 caused a slight increase in the systemic concentration of rosiglitazone.
Rifampicin (inductor CYP2C8) dose 600 mg/day reduced the concentration of rosiglitazone by 65%. Therefore patients, who receive both rosiglitazone and CYP2C8 enzyme inducers, it is necessary to carefully monitor blood glucose and change the dose of rosiglitazone if necessary.
Moderate alcohol consumption during treatment with Avandia does not affect glycemic control.
Avandia: terms of dispensing from pharmacies
The drug is released under the prescription.
Avandia: 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 year.
