Pharmacological action Actos 45 mg
Oral hypoglycemic drug, thiazolidinedione derivative of the series. Is a potent and highly selective agonist at gamma-receptors, peroxisome proliferator-activated (PPARγ). PPARγ-receptors are found in adipose and muscle tissues and liver. Activation of PPARγ nuclear receptors modulates the transcription of several genes that are sensitive to insulin, involved in controlling glucose and lipid metabolism. Actos reduces insulin resistance in peripheral tissues and liver, as a result of this is increased flow of glucose and reduced insulin release of glucose from the liver. Unlike sulfonylureas, pioglitazone does not stimulate insulin secretion by β-cells of the pancreas.
In diabetes type 2 reduce insulin resistance under the action of the drug causes a decrease in Actos blood glucose levels, lower plasma insulin and hemoglobin A1c (glycosylated hemoglobin, HbA1c). As monotherapy and in combination with sulfonylureas, metformin or insulin drug improves control of blood sugar levels.
In diabetes mellitus type 2 with lipid disorders in patients receiving the drug there is a decrease in triglycerides and increase HDL. The level of LDL and total cholesterol in these patients does not change.
Using the drug Actos patients with diabetes mellitus type 2, conducted by echocardiographic examination showed no appreciable increase in the average left ventricular mass index or a noticeable decrease in the average cardiac index.
Pharmacokinetics Actos 45 mg
Absorption
After oral administration, pioglitazone is found in fasting plasma after 30 minutes. Cmax in plasma is reached after 2 h. The meal there was a slight increase in time to reach Cmax of 3-4 hours, but the extent of absorption was not changed.
Distribution
After a single dose of pioglitazone apparent Vd averaged 0.63 ± 0.41 (mean ± SD-standard deviation) L / kg. Pioglitazone is largely bound to serum proteins in human blood (> 99%), primarily to albumin and to a lesser extent – with other serum proteins. The metabolites of pioglitazone M-III and M-IV also significantly associated with serum albumin (> 98%).
In both healthy volunteers and patients with insulin-dependent diabetes (type II) equilibrium concentration of pioglitazone is about 30-50% of peak concentrations of total pioglitazone serum and 20% -25% of the AUC.
Metabolism
Pioglitazone is extensively metabolized in the liver as a result of reactions of hydroxylation and oxidation with the formation of metabolites. Metabolites M-II, M-IV (hydroxide derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) exhibit pharmacological activity in models of type 2 diabetes in animals.
The metabolism of pioglitazone in the liver occurs with the participation of the major cytochrome P450 isoenzymes (CYP2C8 and CYP3A4).
In the in vitro study with pioglitazone did not inhibit the activity of P450. In vivo studies have been conducted.
Breeding
T1 / 2 of unchanged pioglitazone is 3-7 hours, total pioglitazone (pioglitazone and active metabolites) – 16-24 hours clearance of pioglitazone is 5-7 L / h.
After oral administration about 15-30% of the dose of pioglitazone is found in urine. Kidneys displayed a negligible amount of pioglitazone, mainly in the form of metabolites and their conjugates. It is believed that the ingestion of a large dose is excreted in the bile in unchanged form, and in the form of metabolites and excreted in the feces.
The concentrations of pioglitazone and active metabolites in serum remained at a high level 24 h after a single daily dose.
Statement Actos 45 mg
Diabetes mellitus type 2:
- As an adjunct to diet and exercise;
- For a single agent or in combination therapy with sulfonylureas, metformin, or insulin in case of failure of diet, exercise and assignment alone one of the above drugs.
Dosage regimen Actos 45 mg
The dose is determined individually.
Actos appointed interior 1 time / day regardless of meals.
For the treatment of type 2 diabetes as monotherapy Actos prescribe a dose of 15 mg or 30 mg 1 time / day. If necessary, the dose may be gradually increased to a maximum of 45 mg / day. With the ineffectiveness of monotherapy should be considered for combination therapy.
In the combination therapy of sulfonylurea derivatives c Actos prescribe a dose of 15 mg or 30 mg 1 time / day. At the beginning of treatment with sulfonylureas Actos dose can be left unchanged, with the development of hypoglycemia last dose should be reduced.
In combination with metformin Actos prescribe a dose of 15 mg or 30 mg 1 time / day. At the beginning of treatment with metformin dose Actos can be left unchanged. The risk of hypoglycemia in this combination is negligible, so the need for dose adjustment of metformin is unlikely.
In combination with insulin Actos prescribe a dose of 15 mg or 30 mg 1 time / day. At the beginning of treatment with insulin Actos can be left unchanged. With the development of hypoglycemia and lower plasma glucose concentrations to less than 100 mg / dL can reduce insulin dose by 10-25%. Further adjustment of insulin dose should be individually based on the level of glycemia.
In the combination therapy maximum dose Actos 30 mg / day.
In patients with renal impairment dose adjustment Actos not required.
Side effect Actos 45 mg
From a metabolism: possible hypoglycemia (mild to severe) – 1% of cases in patients receiving placebo, 2% of the application Actos in combination with sulfonylureas, 5% with placebo in combination with insulin, 8 % of cases when using Actos 15 mg in combination with insulin, 15% of cases with a combination of Actos a a dose of 30 mg of insulin, edema – 4.8% in monotherapy, 15.3% – in combination with insulin.
From the hemopoietic system: 1-1.6% – anemia, 2-4% – decrease in hemoglobin and hematocrit. These changes mainly occurred 4-12 weeks after initiation of treatment, remained relatively constant and were not associated with any clinically significant hematological effects.
From the laboratory parameters: increasing reported cases of ALT ≥ 3 times (0.25%), which were reversible and not associated with the use of the drug Actos , there were rare cases of a temporary increase in CK levels, which had no clinical consequences and the relationship that drug-Actos not installed, the average values of bilirubin, AST, ALT, ALP and GGT decreased at the end of treatment compared with those of before treatment.
Contraindications Actos 45 mg
- Diabetes mellitus type 1;
- Diabetic ketoacidosis;
- Pregnancy
- Lactation (breastfeeding);
- Established hypersensitivity to pioglitazone or to any of the ingredients of the drug.
Pregnancy and breastfeeding Actos 45 mg
Adequate and well controlled studies of the safety of Actos a during pregnancy was conducted. Since the currently available information strongly suggests that elevated blood glucose levels during pregnancy are associated with increased incidence of congenital anomalies, as well as increased incidence of disease in the neonatal period and an increase in mortality during pregnancy is recommended to use insulin.
It is not known whether pioglitazone is allocated to breast milk, so if you must use Actos a lactation breastfeeding should be discontinued.
Use in hepatic dysfunction Actos 45 mg
It should not be prescribed the drug in the presence of clinical manifestations of liver disease in the active phase or an increase in ALT of 2.5 times the upper limit of normal. At moderately elevated liver enzymes (ALT less than 2.5 times the upper limit of normal) before treatment or during treatment with Actos patients should be examined to determine the cause of improving the performance. With a moderate increase in liver enzymes should be cautious to initiate or continue treatment with Actos . In this case, we recommend more frequent monitoring of clinical study and the level of liver enzymes.
Use in renal impairment Actos 45 mg
In patients with renal impairment dose adjustment Actos not required.
Cautions Actos 45 mg
The complex of measures for the treatment of type 2 diabetes in addition to the drug Actos to include the recommended diet and exercise. It is important not only in the early treatment of type 2 diabetes, but also to maintain the effectiveness of drug therapy.
The effectiveness of drug treatment is preferable to assess the level of HbA1c, which is the most appropriate indicator of glycemic control over time, compared with the definition of fasting glucose levels only. HbA1c reflects blood glucose levels over the past 2-3 months. Treatment with Actos recommended for a sufficient time to assess changes in levels of HbA1c (three months), if no observed deterioration in glycemic control.
It should not be prescribed the drug in the presence of clinical manifestations of liver disease in the active phase or an increase in ALT of 2.5 times the upper limit of normal. At moderately elevated liver enzymes (ALT less than 2.5 times the upper limit of normal) before treatment or during treatment with Actos patients should be examined to determine the cause of improving the performance. With a moderate increase in liver enzymes should be cautious to initiate or continue treatment with Actos . In this case, we recommend more frequent monitoring of clinical study and the level of liver enzymes.
In case of increase of transaminases in serum (ALT> 2.5 times the upper limit of normal) during treatment with the drug Actos monitoring of liver function should be performed more often and for as long as the level returns to normal or to the indicators that were observed prior to treatment . If ALT 3 times the upper limit of normal, then re-test to determine the activity of ALT should be held as soon as possible. If ALT remained at 3 times the upper limit of normal, treatment with Actos should be discontinued.
During treatment for suspected development of liver dysfunction (nausea, vomiting, abdominal pain, fatigue, lack of appetite, dark urine) should define indicators of liver function tests. The issue of continuation therapy with Actos should be taken on the basis of clinical data with respect to laboratory parameters. In the case of jaundice treatment for drug should be discontinued.
In the study of liver function in patients taking Actos , there was no evidence that the drug has hepatotoxic effects or increased ALT.
Precautions should be prescribed to patients with Actos edema.
Anemia, decreased hemoglobin and hematocrit decrease may be associated with increased plasma volume and not associated with any clinically significant hematological effects.
In patients with insulin resistance and anovulatory cycles in the period of treatment premenopauznom thiazolidinediones, including drug Actos may cause ovulation. The consequence of greater sensitivity to insulin in these patients is the risk of pregnancy, unless you use adequate contraception.
Clinical trials using the drug at a dose of Actos more than 30 mg / day in combination with other hypoglycemic agents were not conducted.
Data on the use of the drug Actos in combination with other drugs thiazolidinedione is not available.
Monitoring of laboratory parameters
Before starting treatment with Actos , during the first year of treatment (every 2 months) and then periodically monitor the activity of ALT should be.
Use in Pediatrics
Data on the safety and efficacy of the drug Actos in children and adolescents in the age of 18 are missing, so the drug Actos in these patients is not recommended.
Overdose Actos 45 mg
Was registered one case of drug overdose Actos (receiving 120 mg / day). It is not mentioned any specific clinical symptoms.
Treatment: symptomatic therapy, depending on the clinical manifestations.
Drug Interactions Actos 45 mg
The influence of the drug on the effectiveness of contraceptives Actos oral not known. However, when applying another thiazolidinedione derivative, together with oral contraceptives observed decrease in the concentration of ethinyl estradiol and norethindrone in plasma by approximately 30%. Therefore, patients taking oral contraceptives Actos and may decrease the effectiveness of contraception.
While taking the drug Actos (45 mg / day) and glipizide (5 mg / day) for 7 days was not observed changes in the equilibrium state pharmacokinetics of glipizide.
A single dose of metformin (1000 mg) on the background of the 7-day admission Actos a 45 mg / day did not cause changes in the pharmacokinetics of metformin.
While taking the drug Actos (45 mg / day) and digoxin (0.25 mg / day) for 7 days was not observed changes in the equilibrium state pharmacokinetics of digoxin.
With the simultaneous use of the drug Actos (45 mg / day) and warfarin for 7 days was not observed changes in the equilibrium state pharmacokinetics of warfarin. In addition, Actos had no marked influence on the prothrombin time in patients who underwent long-term treatment with warfarin.
Ketoconazole inhibits the metabolism of up to 85% of pioglitazone in the liver in vitro. Patients receiving ketoconazole together with the drug Actos should be more regular blood glucose control.
