Ezetimibe 10 mg 30 tablets blister

Primary Hypercholesterolemia
Ezetimibe in combination with HMG-CoA reductase inhibitors (statins) or as monotherapy in addition to diet is indicated for the reduction of elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), as well as for increasing high-density lipoprotein cholesterol (HDL-C) levels in adults and adolescents (10-17 years) with primary (heterozygous familial and non-familial) hypercholesterolemia.
Ezetimibe in combination with fenofibrate in addition to diet is indicated for the reduction of elevated levels of TC, LDL-C, Apo B, and non-HDL-C in patients with mixed hypercholesterolemia (see "Dosage and Administration").

Prevention of Cardiovascular Diseases
Ezetimibe taken in combination with statins is indicated for reducing the risk of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, or the need for revascularization) in patients with ischemic heart disease (IHD).

Prevention of Major Cardiovascular Complications in Patients with Chronic Kidney Disease
Ezetimibe taken in combination with simvastatin is indicated for reducing the risk of serious cardiovascular events (non-fatal myocardial infarction or cardiac death, stroke, or any revascularization procedure) in patients with chronic kidney disease.

Homozygous Familial Hypercholesterolemia
Ezetimibe in combination with a statin is indicated for the reduction of elevated levels of TC and LDL-C in adults and adolescents (10-17 years) with homozygous familial hypercholesterolemia. Patients may also receive adjunctive therapy (e.g., LDL apheresis).

Before starting treatment, patients should switch to an appropriate lipid-lowering diet and continue to adhere to this diet throughout the entire therapy period with Ezetimibe.
Use in patients with primary hypercholesterolemia
The drug is taken orally, at any time of the day, regardless of meal times.
The recommended dose of the drug in monotherapy or in combination with a statin or fenofibrate is 10 mg once daily. The dose of fenofibrate should not exceed 160 mg once daily when used concurrently with Ezetimibe.
Use in patients with ischemic heart disease
Combination therapy with statins
To further reduce cardiovascular events in patients with IHD, Ezetimibe 10 mg may be used with statins that have proven efficacy in reducing the risk of cardiovascular complications.
Use in patients with renal impairment/chronic kidney disease
For patients with renal impairment, dose adjustment of the drug is not required (see "Pharmacological properties," "Pharmacokinetics in specific patient groups").
Combination therapy with simvastatin
For patients with mild renal impairment (glomerular filtration rate (GFR) of at least 60 ml/min/1.73 m²), dose adjustment of Ezetimibe or simvastatin is not required. For patients with renal impairment and GFR less than 60 ml/min/1.73 m², Ezetimibe is prescribed at a dose of 10 mg and simvastatin at a dose of 20 mg once daily in the evening.
In these patients, the use of simvastatin at a higher dose should be carefully monitored (see "Pharmacological properties," "Pharmacokinetics in specific patient groups").
Use in elderly patients
For elderly patients, dose adjustment of the drug is not required (see "Pharmacological properties," "Pharmacokinetics in specific patient groups").
Use of the drug in children and adolescents
For children and adolescents aged 6 years and older, dose adjustment of the drug is not required (see "Pharmacological properties," "Pharmacokinetics in specific patient groups"). The use of Ezetimibe in children under 6 years of age is not recommended due to a lack of safety and efficacy data in this age group.
Use in patients with liver insufficiency
For patients with mild liver insufficiency (5-6 points on the Child-Pugh scale), dose adjustment of the drug is not required. The use of the drug 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 "Pharmacological properties," "Pharmacokinetics in specific patient groups," "Special precautions").
When used in combination therapy with bile acid sequestrants
Ezetimibe should be taken at a dose of 10 mg once daily at least 2 hours before or 4 hours after taking bile acid sequestrants.

Composition per 1 tablet:
Active ingredient: ezetimibe - 10.0 mg
Excipients: lactose monohydrate (milk sugar) - 57.0 mg; microcrystalline cellulose (MCC-101) - 20.0 mg; croscarmellose sodium - 8.0 mg; hypromellose - 2.0 mg; sodium lauryl sulfate - 2.0 mg; magnesium stearate - 1.0 mg.

Round biconvex tablets of white or almost white color with a score line.

• Increased sensitivity to any of the components of the drug.
• When prescribing ezetimibe simultaneously with a statin or fenofibrate, it is necessary to follow the instructions for the additional medications.
• Ezetimibe is not recommended for patients with moderate to severe hepatic insufficiency (7-9 or more points on the Child-Pugh scale - see sections "Pharmacological Properties," "Pharmacokinetics in Specific Patient Groups," "Dosage and Administration").
• Pediatric age under 6 years.
• Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

With caution
Caution should be exercised when using ezetimibe simultaneously with fibrates, cyclosporine, and indirect anticoagulants (including warfarin and fluindione). Patients taking ezetimibe and fenofibrate together should be aware of the potential risk of developing gallbladder diseases.

Use during pregnancy and breastfeeding
Animal studies with ezetimibe administration did not reveal direct or indirect adverse effects regarding pregnancy, embryo/fetal development, labor, and postnatal development. No teratogenic effects were observed when ezetimibe was administered to pregnant rats in combination with lovastatin, simvastatin, pravastatin, or atorvastatin. In pregnant rabbits, developmental skeletal defects in the fetus were observed with low frequency. There are no clinical data on the use of ezetimibe during pregnancy, so caution should be exercised when prescribing the drug to pregnant women. If pregnancy occurs, the use of ezetimibe should be discontinued. When using ezetimibe and a statin together, it is necessary to follow the instructions for that statin.
Studies in rats have shown that ezetimibe is excreted in milk. There are no data on the excretion of ezetimibe in breast milk in women. Therefore, ezetimibe is not recommended during breastfeeding unless the potential benefit outweighs the potential risk to the child. If the use of the drug is necessary, the patient should discontinue breastfeeding.

Before starting treatment, patients should switch to an appropriate lipid-lowering diet and continue to adhere to this diet throughout the entire therapy period with Ezetimibe.
If Ezetimibe is prescribed in combination with a statin or fenofibrate, it is important to carefully review the instructions for the medical use of the additional medication.
Liver enzymes
In clinical studies involving the simultaneous use of Ezetimibe and a statin, patients experienced sequential increases in liver transaminase activity (3 times above the upper limit of normal). If Ezetimibe is prescribed in combination with a statin, liver function should be monitored at the beginning of treatment and thereafter according to the recommendations for that statin (see "Side Effects").
In a clinical study, patients with coronary artery disease received simvastatin + Ezetimibe at a dose of 40 mg + 10 mg daily or simvastatin at a dose of 40 mg daily (the median duration of observation was 6 years). The frequency of sequential increases in liver transaminase activity (at least 3 times above the upper limit of normal) was 2.5% in the group receiving simvastatin + Ezetimibe and 2.3% in the group receiving simvastatin (see "Side Effects").
In a clinical study involving patients with chronic kidney disease, the frequency of sequential increases in liver transaminase activity (3 times or more above the upper limit of normal) was 0.7% in the group receiving the combined lipid-lowering medication with fixed doses of Ezetimibe (10 mg) and simvastatin (20 mg) once daily, and 0.6% in the placebo group (see "Side Effects").
Skeletal muscle
In clinical studies, the frequency of myopathy or rhabdomyolysis associated with the use of Ezetimibe did not exceed that of the corresponding control group (placebo or statin monotherapy); however, myopathy and rhabdomyolysis are known adverse reactions of statins and other lipid-lowering agents. In clinical studies, the frequency of increases in CK activity exceeding 10 times the upper limit of normal was 0.2% in the Ezetimibe group compared to 0.1% in the placebo group, and 0.1% in the group receiving Ezetimibe with a statin compared to 0.4% in the statin monotherapy group (see "Side Effects").
Before starting treatment with Ezetimibe, the physician should inform the patient about the risk of developing myopathy and rhabdomyolysis and that the patient should report any unexplained muscle pain, tenderness, or weakness to the physician.
During the post-marketing period of Ezetimibe, reports of cases of myopathy and rhabdomyolysis were received regardless of the cause of their development. Most patients who developed rhabdomyolysis had been taking statins before starting Ezetimibe. However, very rarely, rhabdomyolysis has been reported with Ezetimibe monotherapy and in combination with medications known to be associated with an increased risk of rhabdomyolysis.
All patients prescribed Ezetimibe should be warned about the risk of developing myopathy and rhabdomyolysis and should report any unexplained muscle pain, tenderness, or weakness to their physician. If myopathy is diagnosed or suspected, the use of Ezetimibe and any statin taken concurrently with Ezetimibe should be immediately discontinued. The presence of these symptoms and an increase in CK activity (more than 10 times above the upper limit of normal) indicates the development of myopathy.
In a clinical study, patients with coronary artery disease received simvastatin + Ezetimibe at a dose of 40 mg + 10 mg daily or simvastatin at a dose of 40 mg daily (the median duration of observation was 6 years). The frequency of myopathy was 0.2% in the group receiving simvastatin + Ezetimibe and 0.1% in the group receiving simvastatin, where myopathy was defined as unexplained muscle weakness or muscle pain accompanied by an increase in CK activity of at least 10 times above the upper limit of normal or two sequential increases in CK activity from 5 to 10 times above the upper limit of normal.
The frequency of rhabdomyolysis was 0% in the group receiving simvastatin + Ezetimibe and 0.2% in the group receiving simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or muscle pain accompanied by an increase in CK activity of at least 10 times above the upper limit of normal with signs of impaired kidney function, two sequential increases in CK activity from 5 to 10 times above the upper limit of normal with signs of impaired kidney function, or CK activity of at least 10,000 IU/ml without signs of impaired kidney function (see "Side Effects").
In a clinical study involving patients with chronic kidney disease, the frequency of myopathy/rhabdomyolysis was 0.2% in the group receiving the combined lipid-lowering medication with fixed doses of Ezetimibe (10 mg) and simvastatin (20 mg) daily, and 0.1% in the placebo group (see "Side Effects").
Children aged 6 to 17 years
The safety and efficacy of Ezetimibe in children aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia were studied in a clinical trial lasting 12 weeks. The side effect profile in children receiving Ezetimibe was comparable to the side effect profile in adult patients receiving Ezetimibe. In this clinical study, no significant impact on growth or sexual maturation in boys or girls was observed. However, the effects of Ezetimibe on growth and sexual maturation have not been studied with treatment durations longer than 12 weeks (see "Dosage and Administration," "Side Effects").
The safety and efficacy of Ezetimibe taken concurrently with simvastatin in children aged 10 to 17 years with heterozygous familial hypercholesterolemia were studied in a clinical trial involving boys and girls who were at least one year post-menarche. The side effect profile in adolescents receiving Ezetimibe and up to 40 mg/day simvastatin was comparable to the side effect profile in adult patients receiving Ezetimibe and simvastatin. In this clinical study, no significant impact on growth or sexual maturation in boys or girls, or any effect on the duration of the menstrual cycle in girls was observed (see "Dosage and Administration," "Side Effects").
Liver failure
Since the consequences of increased AUC of total Ezetimibe are unknown, Ezetimibe is not recommended for patients with moderate to severe liver failure (see "Pharmacological Properties," "Pharmacokinetics in Special Patient Groups," "Contraindications").
Fibrates
The safety and efficacy of Ezetimibe when used concurrently with fibrates (excluding fenofibrate) have not been established. The concurrent use of Ezetimibe with fibrates (excluding fenofibrate) is not recommended (see "Interactions with Other Medications").
Fenofibrate
Patients taking fenofibrate concurrently with Ezetimibe should be warned about the possible risk of developing gallbladder disease and gallbladder disorders. If the physician suspects the possible development of the aforementioned diseases in the patient, gallbladder studies should be conducted, and alternative lipid-lowering therapy should be prescribed (see "Side Effects" and the instructions for the use of fenofibrate).
Cyclosporine
When prescribing Ezetimibe to patients taking cyclosporine, precautions should be taken. Regular monitoring of cyclosporine plasma concentration is necessary when Ezetimibe and cyclosporine are used concurrently (see "Precautions," "Interactions with Other Medications").
Indirect anticoagulants
When Ezetimibe is used concurrently with indirect anticoagulants, including warfarin or fluindione, monitoring of INR values is necessary (see "Interactions with Other Medications").
Effect on the ability to drive vehicles and operate machinery
No studies have been conducted to assess the effect on the ability to drive vehicles and operate machinery; however, some adverse effects observed with Ezetimibe may affect the ability of some patients to drive vehicles and operate machinery (see "Side Effects").

In clinical studies, ezetimibe at a dose of 10 mg per day, either as monotherapy or in combination with a statin or fenofibrate, demonstrated good tolerability. Adverse reactions were generally mild and transient. The overall frequency of adverse reactions and the rate of treatment discontinuation due to adverse effects while taking ezetimibe were comparable to those observed with placebo.

The following common (> 1/100 and 1/1000 and < 1/100) adverse reactions were observed with ezetimibe monotherapy at a frequency exceeding that of placebo, or with concurrent use of ezetimibe and a statin at a frequency exceeding that of the statin used alone.With ezetimibe monotherapy: Metabolism and nutrition disorders: Uncommon: decreased appetite. Vascular disorders: Uncommon: flushing of the skin, increased blood pressure. Respiratory system, thoracic organs, and mediastinal disorders: Uncommon: cough. Gastrointestinal disorders: Common: abdominal pain, diarrhea, flatulence. Uncommon: dyspepsia, gastroesophageal reflux, nausea. Musculoskeletal and connective tissue disorders: Uncommon: arthralgia, muscle cramps, neck pain. General disorders: Common: fatigue. Uncommon: chest pain, pain. Laboratory and instrumental data: Uncommon: increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) activity, increased creatine phosphokinase (CPK) activity in serum, increased gamma-glutamyltransferase activity, liver function test abnormalities.With concurrent use of ezetimibe and a statin: Nervous system disorders: Common: headache. Uncommon: paresthesia. Gastrointestinal disorders: Uncommon: dry mucous membranes, gastritis. Skin and subcutaneous tissue disorders: Uncommon: pruritus, rash, urticaria. Musculoskeletal and connective tissue disorders: Common: myalgia. Uncommon: back pain, muscle weakness, limb pain. General disorders: Uncommon: asthenia, peripheral edema. Laboratory and instrumental data: Common: increased ALT and/or AST activity.With concurrent use of ezetimibe and fenofibrate: Gastrointestinal disorders: Common: abdominal pain.In a clinical study involving patients with mixed hyperlipidemia, the frequency of sequential clinically significant increases (more than 3 times the upper limit of normal (ULN)) in serum "liver" transaminase activity was 4.5% in the group of patients taking fenofibrate alone and 2.7% in the group taking ezetimibe with fenofibrate. The frequency of cholecystectomy was 0.6% in the fenofibrate monotherapy group and 1.7% in the ezetimibe plus fenofibrate group (see "Special Instructions"). No increase in CPK activity (more than 10 times the ULN) was observed in either treatment group in this study.Patients with ischemic heart disease: In a clinical study, patients with ischemic heart disease received simvastatin + ezetimibe at a dose of 40 mg + 10 mg or simvastatin at a dose of 40 mg. The safety profile of the drugs in both groups was similar throughout the observation period (the median duration of observation was 6 years). The rate of discontinuation due to adverse events was 10.6% in the simvastatin + ezetimibe group and 10.1% in the simvastatin group. The incidence of myopathy was 0.2% in the simvastatin + ezetimibe group and 0.1% in the simvastatin group, where myopathy was defined as unexplained muscle weakness or muscle pain accompanied by an increase in CPK activity of at least 10 times the ULN or two consecutive increases in CPK activity from 5 to 10 times the ULN. The incidence of rhabdomyolysis was 0.1% in the simvastatin + ezetimibe group and 0.2% in the simvastatin group, where rhabdomyolysis was defined as unexplained muscle weakness or muscle pain accompanied by an increase in CPK activity of at least 10 times the ULN with signs of renal dysfunction, two consecutive increases in CPK activity from 5 to 10 times the ULN with signs of renal dysfunction, or CPK activity of at least 10,000 IU/ml without signs of renal dysfunction. The frequency of sequential increases in "liver" transaminase activity (at least 3 times the ULN) was 2.5% in the simvastatin + ezetimibe group and 2.3% in the simvastatin group (see "Special Instructions"). Adverse events related to the gallbladder were observed in 3.1% of patients taking simvastatin + ezetimibe and 3.5% of patients taking simvastatin. The hospitalization rate for cholecystectomy was 1.5% in both groups. Cancer (defined as any new malignant neoplasm) was diagnosed during the study in 9.4% of patients taking simvastatin + ezetimibe and 9.5% of patients taking simvastatin.Patients with chronic kidney disease: In a clinical study of the cardio- and nephroprotective effects involving patients taking a fixed-dose combination lipid-lowering drug with ezetimibe (10 mg) and simvastatin (20 mg) once daily, and patients taking placebo, the safety profiles were comparable throughout the observation period (the median duration of observation was 4.9 years). In this clinical study, only serious adverse events and discontinuation of treatment due to the development of adverse events were recorded. The rate of discontinuation was comparable in both groups (10.4% in the group taking the fixed-dose combination of ezetimibe and simvastatin and 9.8% in the placebo group). The incidence of myopathy/rhabdomyolysis was 0.2% in the group taking the fixed-dose combination of ezetimibe and simvastatin and 0.1% in the placebo group. Sequential increases in "liver" transaminase activity (more than 3 times the ULN) were observed in 0.7% of patients taking the fixed-dose combination of ezetimibe and simvastatin and in 0.6% of patients taking placebo. In this clinical study, no statistically significant increase in the frequency of adverse events such as malignant neoplasms (9.4% in the group taking the fixed-dose combination of ezetimibe and simvastatin and 9.5% in the placebo group), hepatitis, cholecystectomy, or complications of cholelithiasis or pancreatitis was observed.Children and adolescents aged 6 to 17 years: In a clinical study involving children aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia, the safety and tolerability profile of ezetimibe was comparable to that of adult patients receiving ezetimibe. In a clinical study involving children aged 10 to 17 years with heterozygous familial hypercholesterolemia receiving combination therapy with ezetimibe and simvastatin, the safety and tolerability profile was comparable to that of adult patients receiving combination therapy with ezetimibe and simvastatin.Laboratory indicators: In clinical studies, the frequency of sequential clinically significant increases in serum "liver" transaminase activity (ALT and/or AST activity exceeding the ULN by 3 or more times) was comparable with ezetimibe monotherapy (0.5%) and with placebo (0.3%). In the study of the safety of combination therapy, the frequency of clinically significant increases in serum "liver" transaminase activity was 1.3% in patients taking ezetimibe with a statin and 0.4% in patients taking a statin alone. Increases in transaminase activity in serum were generally asymptomatic, did not accompany the development of cholestasis, and returned to baseline levels both during continued treatment and after discontinuation of the drug.The frequency of clinically significant increases in CPK activity (10 or more times the ULN) in patients taking ezetimibe monotherapy was similar to that in patients taking placebo or a statin alone.Post-marketing surveillance: During the post-marketing period, the following adverse reactions were reported without establishing a causal relationship. Blood and lymphatic system disorders: thrombocytopenia. Immune system disorders: hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Psychiatric disorders: depression. Nervous system disorders: dizziness, paresthesia. Gastrointestinal disorders: pancreatitis, constipation. Liver and biliary tract disorders: hepatitis, cholelithiasis, cholecystitis. Skin and subcutaneous tissue disorders: erythema multiforme. Musculoskeletal and connective tissue disorders: myalgia, myopathy/rhabdomyolysis. General disorders: asthenia.Several cases of overdose have been reported, most of which did not result in the occurrence of adverse effects; when they did occur, the adverse effects were not serious. In clinical studies where ezetimibe was administered to 15 healthy volunteers at a dose of 50 mg/day for 14 days, to 18 patients with primary hypercholesterolemia at a dose of 40 mg/day for 56 days, or to 27 patients with homozygous sitosterolemia at a dose of 40 mg/day for 26 weeks, good tolerability of the drug was demonstrated. In the case of overdose, symptomatic and supportive therapy should be provided.In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 isoenzymes involved in drug metabolism. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs metabolized by the CYP1A2, CYP2D6, CYP2C8/9, and CYP3A4 cytochrome P450 isoenzymes or N-acetyltransferases.Ezetimibe does not affect the pharmacokinetics of dapson, dextromethorphan, digoxin, oral contraceptives (ethinylestradiol and levonorgestrel), glipizide, tolbutamide, and midazolam when taken simultaneously. The concomitant use of cimetidine with ezetimibe does not affect the bioavailability of ezetimibe.Antacids: The simultaneous use of antacids reduces the absorption rate of ezetimibe but does not affect its bioavailability. This reduction in absorption rate is not considered clinically significant.Cholestyramine: The simultaneous use of cholestyramine decreases the mean AUC of total ezetimibe (ezetimibe + ezetimibe-glucuronide) by approximately 55%. The effect of additional reduction in LDL cholesterol concentration due to the simultaneous use of ezetimibe and cholestyramine may be diminished by this interaction.Cyclosporine: In patients who have undergone kidney transplantation with a creatinine clearance (CC) greater than 50 mL/min receiving cyclosporine at a constant dose, a single dose of 10 mg ezetimibe resulted in an average increase in the AUC of total ezetimibe by 3.4 times (ranging from 2.3 to 7.9 times) compared to this parameter in healthy volunteers. In one patient after kidney transplantation with severe renal insufficiency (CC 13.2 mL/min/1.73 m²) receiving combination therapy including cyclosporine, a 12-fold increase in the concentration of total ezetimibe was observed compared to the control group. In a crossover study with two periods involving 12 healthy volunteers receiving ezetimibe at a dose of 20 mg/day simultaneously with cyclosporine at a dose of 100 mg/day, an increase in the AUC of cyclosporine by an average of 15% (ranging from a decrease of 10% to an increase of 51%) was observed on day 7 compared to this parameter in healthy volunteers who received cyclosporine alone at a dose of 100 mg (see "With Caution").Fibrates: The safety and efficacy of ezetimibe when used simultaneously with fenofibrate have been evaluated in clinical studies (see "Side Effects"). The safety and efficacy of ezetimibe when used simultaneously with other fibrates have not been studied. Fibrates may increase cholesterol excretion with bile, which may lead to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol concentration in bile. Although the significance of these data for humans is currently unknown, the simultaneous use of ezetimibe with fibrates (except fenofibrate) is not recommended until additional clinical study data are available. The simultaneous use of ezetimibe and fenofibrate or gemfibrozil increases the concentration of total ezetimibe by approximately 1.5 and 1.7 times, respectively; however, these increases are not considered clinically significant.Statins: No clinically significant pharmacokinetic interactions were observed when ezetimibe was taken simultaneously with atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, and rosuvastatin.Indirect anticoagulants: The simultaneous use of ezetimibe at a dose of 10 mg once daily and warfarin did not have a significant effect on the bioavailability of warfarin and prothrombin time in a study involving 12 healthy volunteers. During the post-registration period, reports were received of increased International Normalized Ratio (INR) in patients taking ezetimibe simultaneously with warfarin or fluindione. These patients were also taking other medications (see "Special Instructions").

Ezetimibe is a representative of a new class of hypolipidemic agents that selectively inhibit the absorption of cholesterol (Ch) and certain plant sterols in the intestine.

Mechanism of Action
The drug is effective when taken orally. The mechanism of action of ezetimibe differs from the mechanisms of other classes of hypolipidemic agents (for example, HMG-CoA reductase inhibitors (statins), bile acid sequestrants, fibrates, and plant stanols). The molecular target of ezetimibe is the transport protein (Niemann-Pick Cl-Like 1, NPC1L1), responsible for the absorption of cholesterol and phytosterols in the intestine.
Ezetimibe localizes in the brush border of the small intestine and prevents the absorption of Ch, leading to a reduction in the intake of Ch from the intestine to the liver, which decreases Ch stores in the liver and enhances the elimination of Ch from the blood. Ezetimibe does not increase the excretion of bile acids (unlike bile acid sequestrants) and does not inhibit the synthesis of Ch in the liver (unlike statins).
In a clinical study involving patients with hypercholesterolemia, ezetimibe reduced the absorption of Ch in the intestine by 54% compared to placebo. By inhibiting the absorption of Ch in the intestine, ezetimibe reduces the intake of Ch into the liver. Statins reduce the synthesis of Ch in the liver. When used together, these two groups of drugs provide additional reduction in Ch concentration. Ezetimibe taken simultaneously with statins reduces the concentration of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo-B), non-high-density lipoprotein cholesterol (non-HDL-C, calculated as the difference between TC and HDL-C concentration), and triglycerides (TG), while also increasing the concentration of high-density lipoprotein cholesterol (HDL-C) in the plasma of patients with hypercholesterolemia to a greater extent than ezetimibe or statin used in monotherapy. The simultaneous use of ezetimibe with fenofibrate reduces the concentration of TC, LDL-C, apo-B, TG, and non-HDL-C, while also increasing the concentration of HDL-C in the plasma of patients with mixed hypercholesterolemia.
Clinical studies have shown that elevated concentrations of TC, LDL-C, and apo-B (the main protein component of LDL) contribute to the development of atherosclerosis. Additionally, reduced concentrations of HDL-C are also associated with the development of atherosclerosis. Epidemiological studies have shown that cardiovascular morbidity and mortality are directly related to the concentrations of TC and LDL-C and inversely related to the concentration of HDL-C. Like LDL, lipoproteins rich in Ch and TG, including very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also contribute to the development of atherosclerosis.
To determine the selectivity of ezetimibe in inhibiting the absorption of Ch, a series of preclinical studies were conducted.
Ezetimibe inhibited the absorption of [14C]-cholesterol and did not affect the absorption of TG, fatty acids, bile acids, progesterone, ethinylestradiol, and fat-soluble vitamins A and D.

Absorption
After oral administration, ezetimibe is rapidly absorbed and extensively metabolized in the small intestine and liver through conjugation to the pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). The maximum plasma concentration (Cmax) of ezetimibe-glucuronide is observed within 1-2 hours, while that of ezetimibe is reached within 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined, as this substance is practically insoluble in any of the aqueous solvents used for preparing injection solutions. Food intake (whether low or high in fat) does not affect the bioavailability of ezetimibe when taken orally in the form of 10 mg tablets. The drug can be taken regardless of the timing of meals.
Distribution
Ezetimibe and ezetimibe-glucuronide bind to plasma proteins at 99.7% and 88-92%, respectively.
Metabolism
The metabolism of ezetimibe primarily occurs in the small intestine and liver through conjugation with glucuronide (phase II reaction), followed by excretion in bile. Ezetimibe undergoes minimal oxidative metabolism (phase I reaction). Ezetimibe and ezetimibe-glucuronide (the main metabolites of ezetimibe identified in plasma) account for 10-20% and 80-90%, respectively, of the total ezetimibe concentration in plasma. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma through enterohepatic recirculation. The half-life (T1/2) for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Excretion
After oral administration of 20 mg of 14C-labeled ezetimibe, 93% of the total ezetimibe (ezetimibe + ezetimibe-glucuronide) was detected in plasma as radioactive products. Approximately 78% and 11% of the administered radioactive products were excreted through the intestines and kidneys, respectively, within 10 days. No radioactive products were detected in plasma after 48 hours.
Pharmacokinetics in Special Patient Groups
Children and Adolescents
The pharmacokinetic parameters of ezetimibe were similar in children over 6 years of age and adults. Pharmacokinetic data for children under 6 years of age are not available.
Elderly Patients
In elderly patients (over 65 years), the total ezetimibe concentration in plasma is approximately twice as high as in younger patients (aged 18 to 45 years). The degree of reduction in LDL cholesterol and the safety profile are comparable in elderly and younger patients receiving ezetimibe. No dose adjustment is required for elderly patients.
Patients with Liver Impairment
After a single dose of 10 mg of ezetimibe, the mean area under the concentration-time curve (AUC) of total ezetimibe was 1.7 times greater in patients with mild liver impairment (5-6 points on the Child-Pugh scale) than in healthy volunteers. In a 14-day study of 10 mg of ezetimibe daily in patients with moderate liver impairment (7-9 points on the Child-Pugh scale), the mean AUC of total ezetimibe increased 4-fold on days 1 and 14 compared to healthy volunteers.
For patients with mild liver impairment, dose adjustment is not required. Due to the unknown consequences of increased AUC of total ezetimibe, ezetimibe is not recommended for patients with moderate to severe liver impairment (more than 9 points on the Child-Pugh scale).
Patients with Kidney Impairment
After a single dose of 10 mg of ezetimibe in patients with severe renal impairment (n=8; creatinine clearance (CrCl) no more than 30 ml/min/1.73 m²), the AUC of total ezetimibe increased approximately 1.5 times compared to healthy volunteers (n=9). This result is not clinically significant. For patients with renal impairment, dose adjustment is not required. In a patient after kidney transplantation receiving combination therapy including cyclosporine, the AUC of total ezetimibe increased 12-fold.
Gender
The concentration of total ezetimibe in plasma is slightly higher (less than 20%) in women than in men. The degree of reduction in LDL cholesterol and the safety profile are the same in men and women taking ezetimibe, therefore, no dose adjustment is required for male or female patients.