Cholesterol is supplied in blood plasma as a result of intestinal absorption and endogenous synthesis ezetimibe and simvastatin, two lipid-lowering component is complementary to its mechanism testosterone suspension side effects of action.The mechanism of action of ezetimibe is different from other classes of lipid-lowering drugs (for example, statins, bile acid sequestrants, fibrates).Ezetimibe when entering the small intestine, slow down the absorption of cholesterol, leading to umensheniyupostupleniya cholesterol from the intestine to the liver.After 2 weeks of treatment Ezetimibe reduces absorption of cholesterol in the intestine by 54% compared to placebo.Several preclinical studies confirms the selectivity of ezetimibe in reducing absorption holesterina.Ezetimib slows absorption of [14C] -cholesterol, and has no effect on the absorption of triglycerides, zhirnyhkislot, bile acids, progesterone, ethynyl – estradiol, or fat-soluble vitamins A and D.
Simvastatin after oral administration in testosterone suspension side effects the form neaktivnogolaktona undergoes hydrolysis to form the corresponding b-hydroxy acid derivative having a high inhibitory activity against HMG-CoA reductase (3 hydroxy – 3 metilglyutarilKoA reductase). The enzyme triggers inaibolee initial significant step conversion of cholesterol biosynthesis of HMG-CoA to mevalonate. Simvastatin snizhaetkak elevated and normal levels kontsentratsiyLPNP. LDL are derived from proteins of very low density lipoproteins (VLDL) and subjected to cleavage using predominantly high affinity LDL receptor LPNP.Snizhenie after administration of simvastatin leads kumensheniyu content of VLDL and LDL-receptor activation, which reduces the formation and increase LDL catabolism. When Apo B simvastatinomuroven therapy also reduced. Furthermore, simvastatinumerenno raises HDL levels and reducing triglyceride plazmykrovi. As a result of these changes testosterone suspension side effects in total cholesterol and LDL cholesterol are reduced.
INEDZHI bioequivalent to a combination of ezetimibe and simvastatin. At the same time taking ezetimibe and simvastatin did not reveal clinically significant pharmacokinetic interaction.
After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
The maximum concentration (Cmax) of ezetimibe in plazmekrovi after oral administration is achieved cherez4-12 hours. The absolute bioavailability of ezetimibe can not be determined testosterone suspension side effects because it is insoluble in any solvents derivatives used for injections.
Food intake (low or high-fat) does not affect ezetimibe oral bioavailability, particularly in the form of tablets of 10 mg.
Bioavailability b-hydroxy simvastatin after receiving inside is less than 5% of the dose. Besides? Hydroxyacids are found in the blood plasma are 4 active metabolite.
Food intake has no effect on plasma concentrations of total and active metabolites of simvastatin.
Ezetimibe and ezetimibe-glucuronide are bound testosterone suspension side effects to plasma proteins at 99.7% and 88-92%, respectively.
Simvastatin and b-hydroxy acid are bound to plasma proteins by 95%. Pharmacokinetic studies showed that simvastatin does not accumulate in the tissues after administration of repeated doses. The maximum level of metabolites in the blood plasma observed after 1,3-2,4 hours after ingestion.
Ezetimibe primary metabolism occurs in the liver and small intestine by conjugation to glucuronide (reaction phase II), followed by isolation of the bile. Minimal oxidative metabolism (a phase I reaction) has been observed at all stages of the transformation of ezetimibe. Ezetimibe and ezetimibe-glucuronide derivatives of the basic preparation is 10-20%, and 80-90% of the total drug in plasma, respectively.
Ezetimibe and ezetimibe-glucuronide are displayed slowly from plasma in the process of enterohepatic recirculation. The half-life for ezetimibe and ezetimibglyukuronida is approximately 22 hours.
Simvastatin – inactive lactone, which is rapidly hydrolyzed in vivo to the corresponding b-hydroxy acid, a potent inhibitor of HMG-CoA reductase. Hydrolysis occurs mainly in the liver; rate of hydrolysis in plasma is very low. Simvastatin is well absorbed and almost completely metabolised already in the “first pass” through the liver. Capture simvastatin liver determined by the rate of hepatic blood flow. The main metabolism occurs in the liver, metabolites u1087 drug excreted in the bile. Therefore, the amount of active drug in the systemic circulation testosterone suspension side effects is very slight.
After ingestion of 20 mg of ezetimibe labeled 14C, 93% of the total cumulative ezetimibe level radioactive products were found in blood plasma. Approximately 73% and 11% respectively taken radioactive products were withdrawn through the intestines and kidneys for 10 days. After 48 hours, the radioactive products in plasma were observed.
Within 96 hours after ingestion of radioactive simvastatin, kidneys 13% of the radioactive products were withdrawn, and 60% – in the intestine. After intravenous administration of b-hydroxy acid metabolite is only 0.3% of the administered dose was derived by the kidneys as metabolites.
Pharmacokinetics in special groups of patients
Pharmacokinetic data, absorption and metabolizmezetimiba same in children / adolescents (10-18 years) ivzroslyh. Data on the pharmacokinetics of the drug in 10 years deteymladshe not. Clinical application vpediatricheskoy practice preparation (in children and adolescents 9-17 years) is limited data on patients with homozygous familial hypercholesterolemia (Gosgen) or homozygous sitosterinemiey (hyper-beta-apo lipoproteinemia).
In elderly patients (65 years) concentration of total plasma ezetimibe approximately 2-fold higher than in younger patients (18-45 years). The level of LDL reduction and safety profile in elderly and younger patients taking ezetimibe, are about the same.
Patients with hepatic insufficiency
After a single dose of 10 mg ezetimibe average value of area under the curve (AUC) for total ezetimibabylo 1.7 higher in patients with mild hepatic insufficiency (5-6 points on a scale Child-Pyuga) than upatsientov with preserved liver function. The 14-dnevnomissledovanii ezetimibe 10 mg daily with uchastiempatsientov with moderate hepatic insufficiency (Child 7-9ballov scale-Pyuga) the average AUC dlyaobschego ezetimibe was increased by 4 times on the 1st and 14th denpo compared with patients with preserved liver function. For patients with mild hepatic nedostatochnostyukorrektsii dose is not required. Since the effects of elevated concentrations of total ezetimibe are unknown, ezetimibe is not recommended in patients with moderate or severe (more than 9 points on a scale Child-Pyuga) pechenochnoynedostatochnostyu (see. Section WITH CARE).
Patients with renal impairment
After a single oral administration of 10 mg ezetimibe mean AUC in patients with severe renal insufficiency (mean creatinine clearance <30 mL / min. / 1.73 m 2 ) was increased 1.5-fold compared to healthy patients.
In a study of patients with severe renal failure testosterone suspension side effects (creatinine clearance (CC) of less than 30 ml / min) after administration of HMG-CoA reductase inhibitor simvastatin metabolites total concentration was 2-fold higher than in healthy volunteers.
The total concentration of ezetimibe slightly higher (20%) in women than in men. The level of LDL reduction and safety profile are about the same in men and women taking ezetimibe.
INEDZHI indicated in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia as an adjunct to diet to reduce total cholesterol, LDL, apolipoprotein B, triglycerides, low density lipoprotein, and for increasing high density lipoprotein levels.
Homozygous Familial Hypercholesterolemia (Gosgen)
INEDZHI shown to reduce elevated total and LDL cholesterol in patients with Gosgen both as complementary treatment to other lipid-lowering therapy (eg, LDL apheresis) or in its absence.
- Hypersensitivity to any component of the drug;
- liver disease in the active phase or persistent elevation of liver transaminases of unknown etiology;
- moderate to severe hepatic insufficiency (7 or more points on a scale Child-Pyuga);
- pregnancy or lactation;
- age 18 years.Carefully
Severe renal impairment (creatinine clearance less than 30 ml / min.), Alcohol abuse, liver disease, a history testosterone suspension side effects of pain in the muscles or changes in skeletal muscle tone of unknown etiology, gallbladder disease, while the appointment INEDZHI with fibrates.
Dosing and Administration
Before starting therapy with INEDZHI patsientydolzhny go on a diet hypocholesterolemic isoblyudat it throughout the course lecheniya.INEDZhI take 1 time a day, in the evening, nezavisimoot meal.
The dosage depends on the initial levels of LDL, the goals of treatment and therapeutic effect, and may vary from 10.10 mg (10 mg of ezetimibe + simvastatin 10mg) to 10/80 mg (10 mg of ezetimibe + simvastatin 80mg) in den.Obychno recommended starting dose of 10 / 20 mg (10 mgezetimiba + simvastatin 20 mg) per day.
In order to gradually reduce the level of LDL cholesterol can bytrekomendovana dose is 10/10 mg (10 mg of ezetimibe + simvastatin 10 mg).
To significantly reduce LDL cholesterol (greater than 55%) patients with therapy dozy10 / 40 mg (10 mg to 40 mg of ezetimibe + simvastatin) may be recommended in den.Cherez 2 weeks after the start of treatment and during the entire course of treatment, kontrolirovaturoven be lipids, and optionally – skorrektirovatdozu drug.
Patients with primary hypercholesterolemia
INEDZHI recommended to take daily doze10 / 40 mg (10 mg ezetimibe + 40mg simvastatin) or 10/80 mg (10 mg ezetimibe + 80mg simvastatin) in the evening to reduce the high level obschegoholesterina, LDL cholesterol, apolipoprotein B, triglycerides yin-HDL, and to increase HDL-C levels in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed dislipidemiey.Terapiyu always carried out against the background of cholesterol-lowering diet. To further reduce the levels of TG and HDL-yin raising HDL in patients with treatment smeshannoydislipidemiey INEDZHI can be dopolnenofenofibratom.
Patients with homozygous familial hypercholesterolemia
Patients with homozygous familial hypercholesterolemia is recommended to take INEDZHI once sutki10 / 40 mg or 10/80 mg in the evening. INEDZHI dolzhenprimenyatsya these testosterone suspension side effects patients in combination with other lipid-lowering therapy (eg, LDL apheresis). Prinevozmozhnosti of additional lecheniyaINEDZhI can be administered as a monotherapy.
USE IN ELDERLY PATIENTS
For elderly patients No dose adjustment is required (see. Pharmacokinetics in special patient groups).
Use in patients with hepatic insufficiency
For patients with mild hepatic insufficiency (5-6 points on a scale Child-Pyuga) korrektsiidozy not required. INEDZHI recommended patsientams moderate (7-9 points on a scale Child-Pyuga) or severe (more than 9 points on a scale Child-Pyuga) hepatic insufficiency (see. CONTRAINDICATIONS sections and Pharmacokinetics in special patient groups).
Use in patients with renal insufficiency
For patients with moderate renal failure dose not require correction. If necessary, therapy in patients with severe renal insufficiency (creatinine clearance <30 mL / min.) The drug in a dose of 10 / 10mg per day should be used with caution (see. Sections with caution and pharmacokinetics in patients osobyhgrupp).
APPLICATION OF DRUG
INEDZHI should be at least 2 or through chasado 4 hours after administration sequestrants zhelchnyhkislot.Dlya patients taking niacin vdoze> 1 g per day, or tacrolimus danazol INEDZHI dose should not exceed 10.10 mg per day (see. RazdelVZAIMODEYSTVIE RELATED LEKARSTVENNYMISREDSTVAMI) .For patients taking amiodarone or verapamil, INEDZHI dose should not exceed 10/20 mg daily (see. section INTERACTION WITH OTHER DRUGS).