Expiration date: 11/2025

The composition and form of issue: 

Tablets. 1 tablet contains:

ezetimibe 10 mg

excipients: croscarmellose sodium lactose monohydrate magnesium stearate microcrystalline povidone sodium lauryl sulfate 

in packing contour cell 10 or 14 PCs. in cardboard pack 1, 2, 3 or 4 packs.

Description pharmaceutical form:

Capsulorraphy tablets from white to almost white number coded "414" on one side.

Feature:

Ezetrol is representative of a new class of lipid-lowering drugs that selectively inhibit the absorption of cholesterol (CH) and some plant of styrenes in the gut.

Pharmacokinetics:

Suction

After oral administration ezetimibe rapidly absorbed and rapidly conjugates in the small intestine and the liver to pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Cmax ezetimibe-glucuronide was observed after 1-2 h, ezetimiba — 4-12 h. the Absolute bioavailability ezetimibe cannot be determined, because this compound is practically insoluble in water.

Simultaneous administration of food (high fat and low fat) has no effect on the bioavailability ezetimibe in oral administration at a dose of 10 mg. Ezetrol can be taken with and between meals.

Distribution

Ezetimib and ezetimibe-glucuronide bind to proteins of human blood plasma 99.7 and 88-92%, respectively.

Metabolism

Ezetimibe metabolized mainly in the small intestine and the liver by conjugation with glucuronide (phase II reaction) with subsequent excretion in the bile. Minimal oxidative metabolism (a phase I reaction) has been observed in all investigated species. Ezetimib and ezetimibe-glucuronide are the major substances found in blood plasma. They are approximately 10-20 and 80-90% of the total drug in plasma, respectively. Ezetimib and ezetimibe-glucuronide are slowly eliminated from plasma in conditions of intense enterohepatic recirculation. T1/2 ezetimibe and ezetimibe-glucuronide is about 22 hours

Excretion

After intake of 20 mg of labeled 14C-ezetimibe the level of total ezetimibe in plasma was 93% of the total radioactivity of blood plasma.

After 48 h, the radioactive traces of the drug in plasma was not detected.

Approximately 78 and 11% of the total number of the dose were withdrawn within 10 days from the feces and urine, respectively.

Pharmacokinetics in special patient groups

Children

The absorption and metabolism of ezetimibe in children, adolescents (10-18 years) and adults alike. According to the measurement of concentration of total ezetimibe the pharmacokinetic parameters in adolescents and adults are no different. Pharmacokinetic data for children under 10 years do not exist.

Clinical experiences ezetimibe in children and adolescents (9-17 years) was limited to patients with homozygous familial hypercholesterolemia and sitosterolemia.

Elderly patients

In elderly patients (over 65 years) the concentration of total ezetimibe in plasma is approximately 2 times higher than in young (18 to 45 years).

The degree of reduction in LDL cholesterol and a safety profile comparable in older and younger patients treated with the drug Ezetrol.

Patients with hepatic insufficiency

After a single dose ezetimibe at a dose of 10 mg, the average area under the AUC for total ezetimibe in patients with mild hepatic insufficiency (5-6 points on a scale child-Pugh) increased by approximately 1.7 times compared with the healthy subjects are volunteers.

14-day study when taking 10 mg ezetimibe per day in patients with moderate hepatic impairment (7-9 points on a scale child-Pugh) the AUC for total ezetimibe was approximately 4 times higher compared to healthy volunteers both in 1 day and on day 14 of the study. Dose adjustment for patients with mild hepatic impairment is not required.

In the absence of data on the use of ezetimibe doses greater than 10 mg, patients with moderate to severe hepatic insufficiency (more 9 points on a scale child-Pugh) the appointment ezetimibe is not recommended (see "Contraindications").

Patients with renal insufficiency

After a single dose ezetimibe at a dose of 10 mg in patients with severe renal disease (n=8 Cl creatinine not more than 30 ml/min/1.73 m2), AUC for total ezetimibe increased approximately 1.5 times in comparison with healthy volunteers (n=9). This result is not clinically significant. Dose adjustment for patients with impaired renal function is not required.

Floor

Ezetimibe concentration in plasma is slightly higher (less than 20%) in women than in men. The reduction of cholesterol low-density lipoprotein LDL cholesterol and a safety profile comparable in men and women receiving treatment with ezetimibe. Therefore, dose adjustments of the drug in connection with belonging to the male or the female sex is not required.

Description pharmacological action:

Ezetrol active and effective in oral administration.

The mechanism of action ezetimibe different from the mechanism of action of other classes of lipid-lowering compounds (e.g. statins, bile acid resins, fibrates and plant of styrenes).

Ezetimibe is localized in the brush border of the small intestine and prevents the absorption of cholesterol, leading to reduced revenues of CH from the intestine into the liver, thereby decreasing the reserves of cholesterol in the liver and increases the excretion of cholesterol from the blood. Ezetimibe does not increase the excretion of bile acids (in contrast to drugs that bind bile acids) and does not inhibit cholesterol synthesis in the liver (unlike statins). In a 2-week clinical trial that included 18 patients with hypercholesterolemia, Ezetrol reduced the absorption of cholesterol in the intestine by 54% compared to placebo.

By reducing cholesterol absorption in the intestine ezetimibe reduces the intake of cholesterol in the liver. Statins reduce cholesterol synthesis in the liver. Due to two different mechanisms of action of drugs of these two classes with a joint appointment provide additional cholesterol-lowering. Ezetrol prescribed in combination with statins, reduces the level OH, of cholesterol low-density lipoprotein (LDL cholesterol), apolipoprotein b (apob) and triglycerides (TG) and increases the level of cholesterol of high density lipoproteins (HDL cholesterol) in patients with hypercholesterolemia to a greater extent than simvastatin ezetimib or assigned separately.

Clinical studies have shown that elevated levels of total cholesterol (OH), LDL cholesterol and apob (the main protein component of LDL) promotes atherosclerosis. In addition, a reduced level of HDL cholesterol is associated with atherosclerosis. Epidemiological studies have established that cardiovascular disease and mortality are directly depending on the level of OH and LDL cholesterol and in inverse proportion to the level of HDL cholesterol. Like LDL, lipoproteins, rich in cholesterol and triglycerides, including very low density lipoproteins (VLDL), intermediate density lipoproteins (LPPP) and remnant, can also promote atherosclerosis.

To determine the selectivity ezetimiba in relation to inhibiting cholesterol absorption, a series of preclinical studies. Ezetimibe inhibited the absorption of (14C)- cholesterol and had no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol and fat-soluble vitamins A and D.

Indications:

• primary hypercholesterolemia is administered in combination with inhibitors of HMG-COA reductase (statins) or as monotherapy in addition to diet to reduce elevated levels OH, LDL cholesterol, APO-b and TG, and to increase the level of HDL cholesterol in patients with primary (heterozygous familial and non-family) hypercholesterolemia
  
• homozygous familial hypercholesterolemia — in combination with a statin is recommended to reduce the increased level of OH, and LDL cholesterol in patients with homozygous familial hypercholesterolemia. Patients may also receive adjuvant treatment (e.g. LDL-apheresis)
  
• homozygous sitosterolemia (or phytosterolemia — enhanced vegetable of styrenes in the blood plasma at elevated or normal cholesterol, and normal triglycerides) Ezetrol recommended for the reduction of elevated sitosterol and campesterol in patients with homozygous familial sitosterolemia.
  

Contraindications:

• hypersensitivity to any component of the drug
  
• when you assign Ezetrol in combination with statin to control contraindications should follow the instructions on the application of the appointed statin
  
• patients with moderate to severe hepatic insufficiency (7-9 points on a scale child-Pugh — see "Pharmacokinetics")
  
• the administered in conjunction with fibrates (safety and efficacy have not been established — see "Interaction" and "Special instructions").
  

With caution:

Patients receiving cyclosporine.

Application of pregnancy and breast-feeding:

Animal studies with the introduction of ezetimibe have not identified direct and indirect adverse effects on the pregnancy, the embryo/fetus, childbirth and postnatal development. With the introduction into pregnant rats ezetimibe in combination with lovastatin, simvastatin, pravastatin or atorvastatin teratogenic effects were not observed. With the introduction of pregnant rabbits with very low frequency were observed defects in skeletal development in the fetus.

Clinical data on the use of the drug Ezetrol during pregnancy no. Therefore, the use of the drug Ezetrol during pregnancy is not recommended. In the case of pregnancy the drug Ezetrol should be terminated.

In studies on rats revealed that ezetimibe is excreted in breast milk. Allocation data ezetimibe with breast milk in women not. In this regard, Ezetrol is not recommended in nursing mothers. If drug use is necessary, the patient should stop breast-feeding.

Side effects:

In clinical studies lasting from 8 to 14 weeks, which was included 3366 patients, Ezetrol appointed in a dose of 10 mg per day in monotherapy or in combination with statin, showed good tolerability.

Adverse effects usually have been mild and transient, the overall incidence of side effects and the incidence of treatment discontinuation due to adverse effects while taking the drug Ezetrol® did not differ from these indicators when taking a placebo.

Patients who took Ezetrol in monotherapy (n=5691) or in combination with statin (n=1675), the most common (&GE. 1/100, <1/10) were as follows related to the drug adverse effects

Monoterapia ezetimibe: headache, abdominal pain, diarrhea.

Combination therapy with statin: headache, fatigue, abdominal pain, constipation, diarrhea, bloating, nausea, increased ALT and ACT, myalgia.

Laboratory findings: the frequency of clinically significant increase of the enzymes in serum ALT and/or ACT 3 or more times the upper limit of normal (ULN) was similar in the appointment of Ezetrol in monotherapy (0.5%) and receiving placebo (0.3 percent). In studying the safety of combination therapy, the frequency of clinically significant increase of the enzymes in serum was 1.3% in patients who took Ezetrol in combination with a statin and 0.4% in patients taking a statin in monotherapy. Increasing enzymes in the blood serum was usually asymptomatic, was not accompanied by the appearance of cholestasis and passed with continued treatment or after discontinuation of the drug.

The incidence of clinically significant increases of creatine phosphokinase (CPK — &ge10×ULN) in patients receiving the drug Ezetrol as monotherapy was similar to the rate in patients receiving placebo or a statin in monotherapy.

Clinical experiences

In applying the drug Ezetrol in clinical practice was reported the following adverse reactions: hypersensitivity reactions, including angioedema and skin rash myalgia increase in CPK, liver enzymes, hepatitis, thrombocytopenia, pancreatitis, nausea. Very rarely myopathy/rhabdomyolysis (see "Special instructions").

Drug interactions:

In preclinical studies it has been shown that ezetimibe not induce enzymes of the cytochrome P450 involved in the metabolism of drugs. Between ezetimibe and tools that are metabolized by the action of cytochromes P450 1A2, 2D6, 2?8, 2C9 and ZA4, or N-acetyltransferase, clinically significant pharmacokinetic interactions were observed.

Ezetimib while admission has no effect on the pharmacokinetics of Dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizida, tolbutamide, midazolam and warfarin. Concomitant use of cimetidine with ezetimibe has no effect on the bioavailability ezetimibe.

Antacids: concurrent administration reduces the rate of absorption ezetimibe, but has no effect on its bioavailability. This decrease in the rate of suction is not considered as clinically meaningful.

Cholestyramine: concomitant use decreases the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. Further reduction in the level of LDL cholesterol by joining ezetimibe to cholestyramine can be reduced by this interaction.

Cyclosporin: in patients undergoing kidney transplant with creatinine Cl >50 ml/min who received cyclosporine in continuous dose, a single dose of the drug Ezetrol at a dose of 10 mg resulted in an increase in AUC of the drug Ezetrol on average 3.4 times (from 2.3 to 7.9 times). One patient after renal transplantation with severe renal insufficiency (Cl creatinine of 13.2 ml/min/1.73 m2) treated with combined therapy, including cyclosporine, noted a 12-fold increase in the level of the drug Ezetrol in comparison with the control group. In 12 healthy volunteers, treated for 8 days ezetimib at a dose of 20 mg / day simultaneously with cyclosporine at a dose of 100 mg / day on day 7 revealed an increase in AUC of cyclosporine by 15% (from a decline of 10% to an increase of 51%) in comparison with patients in whom cyclosporine was used as monotherapy in a dose of 100 mg/day (see "Contraindications").

Fibrates: concomitant use of phenofibrate or gemfibrozil increases the total concentration ezetimibe approximately 1.5 and 1.7 times, respectively. However, these increases are not considered as clinically relevant.

The safety and efficacy of ezetimibe in combination with fibrates is not installed. Fibrates can increase the excretion of cholesterol in the bile, which can lead to cholelithiasis. In a preclinical study on dogs ezetimibe increased cholesterol in the gallbladder. Although the significance of these findings to humans is unknown, coadministration with fibrates ezetimibe to clinical trials is not recommended.

Statins: while admission ezetimibe with atorvastatin, lovastatin, pravastatin, simvastatin, and rosuvastatin fluvastatinom clinically significant pharmacokinetic interactions were observed.

Method of application and dose:

Inside, at any time of the day, regardless of meals.

Before treatment patients must go to the appropriate lepidotrigla diet and continue to observe this diet during the whole period of therapy Ezetrol.

The recommended dose of Ezetrol monotherapy or in combination with a statin is 10 mg 1 time per day.

Selection of doses for elderly patients is not required (see "Pharmacokinetics").

When liver failure

Selection of doses for patients with mild hepatic insufficiency (5-6 points on a scale child-Pugh) is not required. Treatment ezetimibe is not recommended in patients with moderate (7-9 points on a scale child-Pugh) and severe (more than 9 points on a scale child-Pugh) liver dysfunction (see "Pharmacokinetics" and "Contraindications").

In renal failure

Selection of doses for patients with impaired renal function is not required (see "Pharmacokinetics").

If concomitant therapy with sekwestrantami fatty acids

Ezetrol should be taken in the dose of 10 mg 1 time per day at least 2 hours before or at least 4 hours after taking sekwestrantov fatty acids.

Overdose:

Symptoms: there have been several reported cases of overdose, the majority of which was not accompanied by the occurrence of undesirable phenomena, as in the case of occurrence of adverse events were not serious.

In clinical studies, one of which ezetimibe was administered to 15 healthy volunteers at a dose of 50 mg per day for 14 days, and in the other 18 patients with primary hypercholesterolemia at a dose of 40 mg per day for 56 days, was demonstrated good tolerability.

Treatment: symptomatic and supportive therapy.

Special instructions:

Before treatment patients must go to the appropriate lepidotrigla diet and continue to observe this diet during the entire period of drug therapy Ezetrol.

If Ezetrol administered in combination with a statin, you should carefully read the instructions for medical use of specific statin.

Liver enzymes

In controlled clinical trials with simultaneous appointment of the drug Ezetrol and a statin in patients was an increase in liver enzymes (3 times upper limit of normal). If Ezetrol administered in combination with a statin, monitoring of liver function should be carried out at the beginning of treatment and then in accordance with the recommendations of the statin (see "Side effects").

Skeletal muscles

In clinical studies, the incidence of myopathy or rhabdomyolysis associated with the use of the drug Ezetrol did not exceed one in comparison with the corresponding control group (placebo or statin). However, myopathy and rhabdomyolysis are known adverse reactions of statins and other lipidemias funds. In clinical trials, the frequency of increasing the activity of the KLF more than 10 times the ULN was 0.2% in the group of drug Ezetrol in comparison with 0.1% for placebo, and 0.1% in the group of co-administration of the drug Ezetrol with statin in comparison with 0.4% in the group of monotherapy with a statin (see "Side effects").

Liver failure

Since the influence of ezetimibe doses exceeding 10 mg in patients with moderate and severe hepatic insufficiency have not been studied, Ezetrol such patients is not recommended (see "Pharmacokinetics" and "Contraindications").

Fibrates

The safety and effectiveness of destination ezetimibe in combination with fibrates is not installed. Therefore, simultaneous reception of the drug Ezetrol and fibrates is not recommended (see "Interactions" and "Contraindications").

Cyclosporine

When assigning ezetimibe patients receiving cyclosporine should follow precautions. The concentration of cyclosporine should be monitored while receiving the drug and cyclosporine Ezetrol (see "Interactions" and "Contraindications").