Ezetrol® [Ezetimibe]

Brand Schering-Plough

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Available since: 2019-09-19

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Clinical Pharmacology

Ezetrol has a lipid-lowering effect.

Pharmacodynamics

Ezetrol is active and effective when taken orally.

The mechanism of action of ezetimibe is different from the mechanism of action of other classes of lipid-lowering compounds (for example, statins, sequestrants of bile acids, fibrates and plant styrenes).

Ezetimibe is localized in the brush border of the small intestine and prevents the absorption of cholesterol, which leads to a decrease in cholesterol cholesterol from the intestine to the liver, thereby reducing cholesterol stores in the liver and increasing the excretion of cholesterol from the blood. Ezetimibe does not enhance the excretion of bile acids (unlike drugs that bind bile acids) and does not inhibit cholesterol synthesis in the liver (unlike statins). In a 2-week clinical study that included 18 patients with hypercholesterolemia, Ezetrol reduced cholesterol absorption in the intestine by 54% compared with placebo.

By reducing the absorption of cholesterol in the intestine, ezetimibe reduces the flow of cholesterol to the liver. Statins reduce cholesterol synthesis in the liver. Due to two different mechanisms of action, the drugs of these two classes, when administered together, provide an additional reduction in cholesterol level. Ezetrol, administered in combination with statins, reduces the level of OX, low-density lipoprotein cholesterol (LDL cholesterol), apolipoprotein B (apo-B) and triglycerides (TG) and increases the high-density lipoprotein cholesterol (HDL cholesterol) in patients with hypercholesterolemia in more degree than ezetimibe or simvastatin, administered separately.

Clinical studies have shown that elevated levels of total cholesterol (OH), LDL cholesterol and apo-B (the main protein component of LDL) contributes to the development of atherosclerosis. In addition, a low level of HDL cholesterol is associated with the development of atherosclerosis. Epidemiological studies have found that diseases of the cardiovascular system and mortality from them are directly dependent on the level of OH and LDL cholesterol and inversely related to the level of HDL cholesterol. Like LDL, cholesterol and triglyceride-rich lipoproteins, including very low density lipoproteins (VLDL), intermediate density lipoproteins (LDLP) and remnant, can also contribute to the development of atherosclerosis.

To determine the selectivity of ezetimibe in relation to inhibition of cholesterol absorption, a series of preclinical studies have been conducted. Ezetimibe inhibited absorption (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.

Pharmacokinetics

Suction

After oral administration, ezetimibe is rapidly absorbed and intensively conjugates in the small intestine and liver to a pharmacologically active phenolic glucuronide (ezetimib glucuronide). WITH_max ezetimib glucuronide occurs after 1–2 hours, ezetimibe after 4–12 hours. The absolute bioavailability of ezetimibe cannot be determined, since this compound is practically insoluble in water.

Simultaneous ingestion of food (both high in fat and nonfat) does not affect the bioavailability of ezetimib when administered orally at a dose of 10 mg. Ezetrol can be taken both during and between meals.

Distribution

Ezetimibe and ezetimib glucuronide bind to human plasma proteins at 99.7 and 88–92%, respectively.

Metabolism

Ezetimibe is metabolized mainly in the small intestine and liver by conjugation with glucuronide (phase II reaction), followed by excretion with bile. Minimal oxidative metabolism (phase I reaction) was observed in all species studied. Ezetimibe and ezetimibe-glucuronide are the main substances detected in blood plasma. They constitute approximately 10–20 and 80–90% of the total content of the drug in the blood plasma, respectively.Ezetimibe and ezetimib glucuronide are slowly excreted from the blood plasma under conditions of intensive enterohepatic recirculation. T_1/2 ezetimiba and ezetimib glucuronide is about 22 hours.

Removal

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

After 48 hours, no radioactive traces of the drug were detected in the blood plasma.

Approximately 78 and 11% of the total dose received were excreted within 10 days with feces and urine, respectively.

Pharmacokinetics in Special Patient Groups

Children

Absorption and metabolism of ezetimibe in children, adolescents (10-18 years) and adults are the same. According to the measured concentration of total ezetimibe pharmacokinetic parameters in adolescents and adults do not differ. Pharmacokinetic data for children under 10 years of age are not available.

Clinical experience with ezetimibe in children and adolescents (9–17 years old) is limited to patients with homozygous familial hypercholesterolemia and sitosterolemia.

Elderly patients

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

The degree of reduction in LDL cholesterol levels and the safety profile are comparable in elderly and young patients who received the drug Ezetrol.

Patients with liver failure

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

In a 14-day study with 10 mg of ezetimibe per day in patients with moderate hepatic insufficiency (7–9 points on the Child-Pugh scale), the AUC for total ezetimibe was about 4 times greater than in healthy volunteers on 1 day, so and on day 14 of the study. Dose selection for patients with mild liver failure is not required.

Due to the lack of data on the use of doses of ezetimibe in excess of 10 mg, patients with moderate and severe liver failure (more than 9 points on the Child-Pugh scale) are not recommended to give ezetimibe (see "Contraindications").

Patients with renal failure

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

Floor

Plasma ezetimibe concentrations are slightly higher (less than 20%) in women than in men. Lower cholesterol levels of low-density lipoprotein LDL cholesterol and safety profile are comparable in men and women receiving ezetimibe treatment. Therefore, the dose adjustment of the drug in connection with belonging to the male or female sex is not required.

Indications

primary hypercholesterolemia - is prescribed in combination with HMG-CoA reductase inhibitors (statins) or as monotherapy in addition to a diet to reduce elevated levels of TC, LDL cholesterol, apo-B and TG, and also to increase the level of HDL cholesterol in patients with (heterozygous familial and non-familial) hypercholesterolemia;
homozygous familial hypercholesterolemia - in combination with a statin, it is recommended to reduce elevated levels of TC and LDL cholesterol in patients with homozygous familial hypercholesterolemia. Patients may also receive supportive treatment (for example, LDL-apheresis);
homozygous sitosterolemia (or phytosterolemia - elevated plasma plant styrene levels with elevated or normal cholesterol levels and normal TG levels); Ezetrol is recommended for reducing elevated levels of sitosterol and campesterol in patients with homozygous familial sitosterolemia.

Composition

1 tablet contains:

Active substance: ezetimibe 10 mg;

Excipients: sodium croscarmellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; Povidone; sodium lauryl sulfate.

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Dosage and Administration

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

Before treatment, patients should switch to an appropriate lipid-lowering diet and continue to follow this diet during the entire period of Ezethrol therapy.^®.

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

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

When liver failure

Selection of doses for patients with mild liver failure (5-6 points on the Child-Pugh scale) is not required. Ezetimibe treatment is not recommended for patients with moderate (7–9 points on the Child-Pugh scale) and severe (more than 9 points on the Child-Pugh scale) liver dysfunction (see “Pharmacokinetics” and “Contraindications”).

With renal failure

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

With concomitant treatment with fatty acid sequestrants

Ezetrol should be taken in a dose of 10 mg 1 time per day no later than 2 hours before or no earlier than 4 hours after taking fatty acid sequestrants.

Adverse reactions

In clinical studies with a duration of 8 to 14 weeks, in which 3366 patients were included, Ezetrol, administered at a dose of 10 mg per day in monotherapy or in combination with a statin, showed good tolerability.

Unwanted effects were usually mild and transient; The overall frequency of side effects and the frequency of cancellation of treatment due to undesirable effects when taking the drug Ezetrolne differed from these indicators when taking placebo.

In patients taking Ezetrol in monotherapy (n = 5691) or in combination with a statin (n = 1675), the most common (≥1 / 100,

Mototherapy Ezetimibe: headache, abdominal pain, diarrhea.

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

Laboratory indicators: the frequency of a clinically significant increase in serum ALT and / or ACT enzymes 3 or more times the upper limit of normal (VGN) was similar when prescribing Ezetrol in monotherapy (0.5%) and taking placebo (0.3%). When studying the safety of combination therapy, the frequency of a clinically significant increase in serum enzymes was 1.3% in patients taking Ezetrol in combination with a statin and 0.4% in patients taking a statin in monotherapy. Enhancement of serum enzymes was usually asymptomatic, was not accompanied by the occurrence of cholestasis, and took place with continued treatment and after discontinuation of the drug.

The incidence of a clinically significant increase in creatine phosphokinase (CPK - ≥10 × VGN) in patients receiving Ezetrol in monotherapy was similar to this indicator in patients receiving placebo or statin in monotherapy.

Clinical experience

When using the drug Ezetrol in clinical practice, the following undesirable reactions were reported: hypersensitivity reactions, including angioedema and skin rash; myalgia; increased CK, hepatic enzymes, hepatitis, thrombocytopenia, pancreatitis, nausea. Very rarely - myopathy / rhabdomyolysis.

Contraindications

Carefully: Patients receiving cyclosporine.

Drug interactions

In preclinical studies, it was shown that ezetimibe does not induce cytochrome P450 enzymes involved in the metabolism of drugs. There were no clinically significant pharmacokinetic interactions between ezetimibe and drugs metabolized by cytochrome P450 1A2, 2D6, 2C8, 2C9 and 3A4 or N-acetyltransferase.

Ezetimibe does not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, midazolam and warfarin.Simultaneous use of cimetidine with ezetimibe does not affect the bioavailability of ezetimibe.

Antacids: simultaneous administration reduces the rate of absorption of ezetimibe, but does not affect its bioavailability. This decrease in the rate of absorption is not considered clinically significant.

Cholestyramine: simultaneous administration reduces the average AUC of total ezetimibe (ezetimibe + glucuronide ezetimibe) by approximately 55%. An additional reduction in LDL cholesterol levels by adding ezetimibe to cholestyramine can be reduced by this interaction.

Cyclosporine: in patients undergoing kidney transplantation, with Cl creatinine> 50 ml / min, treated with cyclosporine in a constant dose, a single dose of Ezetrol at a dose of 10 mg resulted in an increase in AUC of Ezetrol drug by an average of 3.4 times (from 2.3 up to 7.9 times). In one patient after kidney transplantation and with severe renal insufficiency (Cl creatinine 13.2 ml / min / 1.73 m²), receiving complex therapy, including cyclosporine, there was a 12-fold increase in the level of the drug Ezetrol in comparison with the control group. In 12 healthy volunteers who received for 8 days ezetimibe at a dose of 20 mg per day simultaneously with cyclosporine at a dose of 100 mg per day on day 7, an increase in AUC of cyclosporine was detected on average by 15% (from a decrease of 10% to an increase of 51% ) in comparison with patients in whom cyclosporine was used in monotherapy at a dose of 100 mg / day.

Fibrates: simultaneous administration of fenofibrate or gemfibrozil increases the total concentration of ezetimibe by approximately 1.5 and 1.7 times, respectively. However, these enhancements are not considered clinically significant.

The safety and efficacy of ezetimibe in combination with fibrates has not been established. Fibrates can increase cholesterol secretion with bile, which can lead to cholelithiasis. In preclinical studies on dogs, ezetimibe increased cholesterol levels in the gallbladder. Although the significance of this data for humans is unknown, the simultaneous administration of ezetimibe with fibrates prior to clinical studies is not recommended.

Statins: while taking ezetimibe with atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin and rosuvastatin, there were no clinically significant pharmacokinetic interactions.

Pregnancy and Lactation

Studies on animals with the introduction of ezetimiba did not reveal direct and indirect adverse effects on pregnancy, embryo / fetus development, childbirth, and postnatal development. When ezetimibe was administered to pregnant rats in combination with lovastatin, simvastatin, pravastatin or atorvastatin, no teratogenic effects were observed. With the introduction of pregnant rabbits with a small frequency was observed defects in the skeleton of the fetus.

Clinical data on the use of the drug Ezetrol during pregnancy is not. Therefore, the use of the drug Ezetrol during pregnancy is not recommended. In the event of pregnancy, the drug Ezetrol should be discontinued.

Studies on rats have revealed that ezetimibe is excreted in breast milk. There is no data on the release of ezetimiba with breast milk in women. In this regard, Ezetrol is not recommended for use in nursing mothers. If use of the drug is necessary, the patient should stop breastfeeding.

Special instructions

Before treatment, patients should switch to an appropriate lipid-lowering diet and continue to follow this diet during the entire period of therapy with Ezethrol.

If Ezetrol is prescribed in combination with a statin, you should carefully read the instructions for medical use of a particular statin.

Liver enzymes

In controlled clinical trials with simultaneous administration of the drug Ezetrol and a statin, an increase in liver enzymes was observed in patients (3 times higher than the upper limit of normal).If Ezetrol is prescribed in combination with a statin, liver function monitoring should be carried out at the beginning of treatment and further in accordance with the recommendations for this statin.

Skeletal muscle

In clinical studies, the incidence of myopathy or rhabdomyolysis associated with the use of the drug Ezetrol did not exceed that in comparison with the corresponding control group (placebo or statin). However, myopathy and rhabdomyolysis are known undesirable reactions of statins and other lipid-lowering drugs. In clinical studies, the frequency of increase in CPK activity, more than 10 times higher than VGN, was 0.2% in the group of the drug Ezetrol compared with 0.1% in the placebo group, and 0.1% in the combined group of the drug Ezetrol with a statin in compared with 0.4% in the statin monotherapy group.

Liver failure

Since the effect of doses of ezetimibe exceeding 10 mg has not been studied in patients with moderate and severe liver failure, Ezetrol is not recommended for such patients.

Fibrates

The safety and efficacy of prescribing ezetimibe in combination with fibrates has not been established. Therefore, concomitant use of the drug Ezetrol and fibrates is not recommended.

Cyclosporine

When prescribing ezetimiba to patients receiving cyclosporine, precautions should be observed. The concentration of cyclosporine should be controlled while taking the drug Ezetrol and cyclosporine.

Overdosage

Symptoms: several cases of overdose were reported, most of which were not accompanied by the occurrence of adverse events, and if they occurred, the adverse events were not serious.

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

Treatment: symptomatic and supportive therapy.

Studies and clinical trials of Ezetimibe (Click to expand)