Ezetimib Canon (Tablets) Instructions for Use

Marketing Authorization Holder

Canonpharma Production, CJS (Russia)

ATC Code

C10AX09 (Ezetimibe)

Active Substance

Ezetimibe

Dosage Form

Ezetimibe Canon

Tablets 10 mg: 7, 10, 14, 20, 21, 28, 30, 40, 42, 50, 56, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, flat-cylindrical with a bevel, white or almost white in color.

Excipients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, sodium lauryl sulfate, povidone K30, microcrystalline cellulose PH101.

7 pcs. – blister packs (from 1 to 4) – cardboard packs with an insert.
14 pcs. – blister packs (from 1 to 4) – cardboard packs with an insert.
10 pcs. – blister packs (from 1 to 6) – cardboard packs with an insert.
30, 60 or 90 pcs. – jar (1) – cardboard packs with an insert.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agents; other hypolipidemic agents

Pharmacological Action

Hypolipidemic agent. It selectively inhibits the absorption of cholesterol and some plant sterols in the intestine.

When it enters the small intestine, Ezetimibe localizes in the brush border of the small intestine and prevents the absorption of cholesterol, which leads to a decrease in the delivery of cholesterol from the intestine to the liver, thereby reducing cholesterol stores in the liver and increasing the clearance of cholesterol from the blood. Ezetimibe does not increase the excretion of bile acids (unlike bile acid sequestrants) and does not inhibit cholesterol synthesis in the liver (unlike statins).

By reducing cholesterol absorption in the intestine, Ezetimibe reduces the delivery of cholesterol to the liver. Statins reduce cholesterol synthesis in the liver. Due to two different mechanisms of action, drugs from these two classes, when co-administered, provide an additional reduction in cholesterol levels.

Clinical studies have shown that elevated levels of total cholesterol, LDL-C, and apolipoprotein B – the main protein component of LDL – contribute to the development of atherosclerosis. Furthermore, a low level of HDL-C is associated with the development of atherosclerosis. Epidemiological studies have established that cardiovascular morbidity and mortality are directly dependent on the level of total cholesterol and LDL-C and inversely dependent on the level of HDL-C. Like LDL, cholesterol- and triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also promote atherosclerosis.

A series of preclinical studies have shown that Ezetimibe inhibits the absorption of ¹⁴C-cholesterol and does not affect the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.

Pharmacokinetics

After oral administration, Ezetimibe is rapidly absorbed and extensively conjugated in the small intestine and liver to form the pharmacologically active phenolic glucuronide (Ezetimibe-glucuronide). The C_max of Ezetimibe-glucuronide is reached within 1-2 hours, and that of ezetimibe within 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined as this compound is practically insoluble in water.

Concomitant food intake (both high-fat and non-fat) does not affect the bioavailability of ezetimibe when taken orally at a dose of 10 mg.

Plasma protein binding for ezetimibe and Ezetimibe-glucuronide is 99.7% and 88-92%, respectively.

Ezetimibe is metabolized primarily in the small intestine and liver by conjugation with glucuronide (phase II reaction) with subsequent excretion in the bile. Minimal oxidative metabolism (phase I reaction) is observed in all species studied. Ezetimibe and Ezetimibe-glucuronide are the main substances detected in plasma, accounting for approximately 10-20% and 80-90% of the total drug in plasma, respectively. Ezetimibe and Ezetimibe-glucuronide are slowly cleared from plasma due to extensive enterohepatic recirculation.

The T_1/2 of ezetimibe and Ezetimibe-glucuronide is about 22 hours. Within 10 days, about 78% of the total administered dose is excreted in the feces, and about 11% in the urine.

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.

Indications

Primary hypercholesterolemia (in combination with statins or as monotherapy in addition to diet to reduce elevated levels of total cholesterol, LDL-C, apolipoprotein B, and triglycerides, and to increase HDL-C levels in patients with primary hypercholesterolemia); homozygous familial hypercholesterolemia (in combination with statins, it is indicated to reduce elevated concentrations of total cholesterol and LDL-C in adults and adolescents 10-17 years of age with homozygous familial hypercholesterolemia; LDL apheresis may also be used); homozygous sitosterolemia (or phytosterolemia) – elevated levels of plant sterols in plasma with elevated or normal cholesterol levels and normal triglyceride levels.

Prevention of cardiovascular diseases (in combination with statins, it is indicated to reduce the risk of developing cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, or the need for revascularization in patients with coronary artery disease.

Prevention of major cardiovascular complications in patients with chronic kidney disease. Ezetimibe in combination with simvastatin is indicated to reduce the risk of serious cardiovascular events (non-fatal MI or cardiac death, stroke, or any revascularization procedure) in patients with chronic kidney disease.

ICD codes

Dosage Regimen

Before starting and during treatment, patients should follow a hypolipidemic diet. The recommended dose as monotherapy and in combination with statins is 10 mg once daily.

For concomitant therapy with bile acid sequestrants, Ezetimibe is used at a dose of 10 mg once daily no later than 2 hours before taking the bile acid sequestrants or no earlier than 4 hours after taking them.

Adverse Reactions

Metabolism and nutrition disorders uncommon – decreased appetite.

Cardiac disorders uncommon – flushing, increased blood pressure.

Respiratory, thoracic and mediastinal disorders uncommon – cough.

Gastrointestinal disorders common – abdominal pain, diarrhea, flatulence; uncommon – dyspepsia, gastroesophageal reflux, nausea, increased ALT, AST, GGT activity.

Musculoskeletal and connective tissue disorders uncommon – arthralgia, muscle spasms, neck pain, increased serum CPK activity.

General disorders and administration site conditions common – fatigue; uncommon – chest pain.

Contraindications

Hypersensitivity to ezetimibe; moderate (7-9 points on the Child-Pugh scale) and severe (>9 points on the Child-Pugh scale) hepatic impairment; children under 6 years of age; when using ezetimibe simultaneously with a statin or fenofibrate, it is necessary to follow the instructions for use of the additionally prescribed drugs.

With caution

Concomitant use of ezetimibe with fibrates, cyclosporine, and indirect anticoagulants (including warfarin and fluindione).

Use in Pregnancy and Lactation

The use of ezetimibe during pregnancy is possible only in case of extreme necessity. There are no available clinical data on the use of the drug ezetimibe during pregnancy. If pregnancy occurs, ezetimibe should be discontinued.

Animal studies with the administration of ezetimibe did not reveal direct or indirect adverse effects on pregnancy, embryo/fetal development, childbirth, or postnatal development. When ezetimibe was administered to pregnant rats in combination with lovastatin, simvastatin, pravastatin, or atorvastatin, no teratogenic effects were observed. When administered to pregnant rabbits, skeletal development defects in the fetus were observed with low frequency.

Ezetimibe should not be used during breastfeeding unless the potential benefit outweighs the potential risk to the infant. If the use of the drug is necessary, the patient should stop breastfeeding. Studies in rats have shown that Ezetimibe is excreted in breast milk. There are no data on the excretion of ezetimibe in human breast milk.

Use in Hepatic Impairment

For patients with mild hepatic impairment (5-6 points on the Child-Pugh scale), dose adjustment is not required. The use is contraindicated in moderate (7-9 points on the Child-Pugh scale) and severe (> 9 points on the Child-Pugh scale) hepatic impairment.

Use in Renal Impairment

For patients with impaired renal function, dose adjustment is not required.

Pediatric Use

For children and adolescents from 6 years of age, dose adjustment of the drug is not required.

The use of ezetimibe in children under 6 years of age is not recommended because there are no data on safety and efficacy in this age group.

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

Before starting treatment, patients should switch to an appropriate diet and continue to follow this diet throughout the entire period of ezetimibe therapy.

If Ezetimibe is used in combination with a statin, liver function monitoring should be performed at the beginning of treatment and then in accordance with the recommendations for that statin.

Most patients who experienced rhabdomyolysis were taking statins before starting ezetimibe. Nevertheless, rhabdomyolysis has been reported very rarely with the use of ezetimibe as monotherapy, and very rarely when ezetimibe was added to other drugs known to increase the risk of rhabdomyolysis.

All patients starting treatment with ezetimibe should be informed about the risk of myopathy and instructed to immediately report any unexplained muscle pain, tenderness, or weakness. If myopathy is suspected based on muscle symptoms or if CPK activity exceeds the upper limit of normal, ezetimibe, any statins, and any other concomitant drugs the patient is taking should be discontinued immediately.

Since the consequences of an increase in the AUC of total ezetimibe are unknown, Ezetimibe is not recommended for patients with moderate and severe hepatic impairment.

The safety and efficacy of using ezetimibe simultaneously with fibrates (except fenofibrate) have not been established. Concomitant use of ezetimibe with fibrates (except fenofibrate) is not recommended.

Patients taking fenofibrate concomitantly with ezetimibe should be warned about the possible risk of cholelithiasis and gallbladder diseases. If the doctor suspects the possible development of the above diseases in a patient, it is necessary to examine the gallbladder and prescribe alternative lipid-lowering therapy.

When prescribing ezetimibe to patients receiving cyclosporine, precautions should be taken. Regular monitoring of cyclosporine plasma concentration is necessary when ezetimibe and cyclosporine are used concomitantly.

When co-administered with warfarin, other coumarin anticoagulants, or fluindione, the INR level should be carefully monitored.

Use in pediatrics

The efficacy and safety of ezetimibe in children aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia were evaluated in a 12-week placebo-controlled clinical study. The adverse event profile in children receiving ezetimibe was comparable to the adverse event profile in adult patients receiving ezetimibe. This clinical study did not show any apparent effect on growth or sexual maturation in boys or girls. However, the effect of ezetimibe on growth and sexual maturation has not been studied in treatment lasting more than 12 weeks.

The efficacy and safety of ezetimibe taken concomitantly with simvastatin in children aged 10 to 17 years with heterozygous familial hypercholesterolemia were evaluated in controlled clinical trials in adolescent boys (Tanner stage II or higher) and in girls who were at least 1 year post-menarche.

In this limited controlled study, no apparent effect on growth or sexual maturation in adolescent boys and girls, or on the duration of the menstrual cycle in girls, was observed. However, the effect of ezetimibe on growth and sexual maturation over a treatment period >33 weeks has not been studied.

The safety and efficacy of ezetimibe when used concomitantly with simvastatin at doses above 40 mg/day in children aged 10 to 17 years have not been studied.

The safety and efficacy of ezetimibe when used concomitantly with simvastatin in children under 10 years of age have not been studied.

The long-term efficacy of ezetimibe in patients under 17 years of age in reducing morbidity and mortality in adulthood has not been studied.

Ezetimibe has not been studied in patients under 6 years of age.

Effect on ability to drive vehicles and operate machinery

Some adverse effects observed with the use of ezetimibe may affect the ability of some patients to drive vehicles and operate machinery.

Drug Interactions

Concomitant intake of antacids reduces the rate of absorption of ezetimibe but does not affect its bioavailability; the reduction in absorption rate is not clinically significant.

When used concomitantly with cholestyramine, the AUC of total ezetimibe (Ezetimibe + Ezetimibe-glucuronide) decreases by approximately 55%. The additional reduction in LDL-C from adding ezetimibe to cholestyramine may be reduced by this interaction.

In patients who have undergone kidney transplantation, with creatinine clearance greater than 50 ml/min, who are continuously receiving cyclosporine, a single dose of ezetimibe 10 mg was accompanied by an average 3.4-fold (range 2.3 to 7.9) increase in the AUC of ezetimibe. In one patient who had undergone kidney transplantation and had severe renal failure (creatinine clearance 13.2 ml/min/1.73 m²) receiving complex therapy including cyclosporine, a 12-fold increase in ezetimibe concentration was noted compared to the control group. In 12 healthy volunteers who received Ezetimibe at a dose of 20 mg/day for 8 days simultaneously with cyclosporine at a daily dose of 100 mg, on day 7, an average increase in the AUC of cyclosporine by 15% (range from a decrease of 10% to an increase of 50%) was detected compared to patients who received cyclosporine as monotherapy at a dose of 100 mg/day.

The safety and efficacy of using ezetimibe simultaneously with other fibrates have not been studied. Fibrates may increase the excretion of cholesterol in the bile, which can lead to cholelithiasis. In a preclinical study in dogs, Ezetimibe increased the concentration of cholesterol in the bile. Although the significance of these data for humans is not yet known, concomitant use of ezetimibe with fibrates (except fenofibrate) is not recommended until additional data from clinical studies are obtained. Concomitant use of ezetimibe and fenofibrate or gemfibrozil increases the concentration of total ezetimibe by approximately 1.5 and 1.7 times, respectively, but these increases are not considered clinically significant.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.