Ezemirt (Tablets) Instructions for Use

Marketing Authorization Holder

Grotex, LLC (Russia)

ATC Code

C10AX09 (Ezetimibe)

Active Substance

Ezetimibe (Rec.INN registered by WHO)

Dosage Form

Ezemirt

Tablets 10 mg

Dosage Form, Packaging, and Composition

Tablets

10 pcs. – blister packs – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs (10 pcs.) – cardboard packs (100 pcs.) – By prescription
10 pcs. – blister packs (2 pcs.) – cardboard packs (20 pcs.) – By prescription
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blister packs (4 pcs.) – cardboard packs (40 pcs.) – By prescription
10 pcs. – blister packs (5 pcs.) – cardboard packs (50 pcs.) – By prescription
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blister packs (7 pcs.) – cardboard packs (70 pcs.) – By prescription
10 pcs. – blister packs (8 pcs.) – cardboard packs (80 pcs.) – By prescription
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – By prescription
120 pcs. – bottles – cardboard packs (120 pcs.) – By prescription
14 pcs. – blister packs – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs (10 pcs.) – cardboard packs (140 pcs.) – By prescription
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (3 pcs.) – cardboard packs (42 pcs.) – By prescription
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – By prescription
14 pcs. – blister packs (5 pcs.) – cardboard packs (70 pcs.) – By prescription
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – By prescription
14 pcs. – blister packs (7 pcs.) – cardboard packs (98 pcs.) – By prescription
14 pcs. – blister packs (8 pcs.) – cardboard packs (112 pcs.) – By prescription
14 pcs. – blister packs (9 pcs.) – cardboard packs (126 pcs.) – By prescription
150 pcs. – bottles – cardboard packs (150 pcs.) – By prescription
180 pcs. – bottles – cardboard packs (180 pcs.) – By prescription
210 pcs. – bottles – cardboard packs (210 pcs.) – By prescription
240 pcs. – bottles – cardboard packs (240 pcs.) – By prescription
270 pcs. – bottles – cardboard packs (270 pcs.) – By prescription
30 pcs. – bottles – cardboard packs (30 pcs.) – By prescription
300 pcs. – bottles – cardboard packs (300 pcs.) – By prescription
60 pcs. – bottles – cardboard packs (60 pcs.) – By prescription
7 pcs. – blister packs – cardboard packs (7 pcs.) – By prescription
7 pcs. – blister packs (10 pcs.) – cardboard packs (70 pcs.) – By prescription
7 pcs. – blister packs (2 pcs.) – cardboard packs (14 pcs.) – By prescription
7 pcs. – blister packs (3 pcs.) – cardboard packs (21 pcs.) – By prescription
7 pcs. – blister packs (4 pcs.) – cardboard packs (28 pcs.) – By prescription
7 pcs. – blister packs (5 pcs.) – cardboard packs (35 pcs.) – By prescription
7 pcs. – blister packs (6 pcs.) – cardboard packs (42 pcs.) – By prescription
7 pcs. – blister packs (7 pcs.) – cardboard packs (49 pcs.) – By prescription
7 pcs. – blister packs (8 pcs.) – cardboard packs (56 pcs.) – By prescription
7 pcs. – blister packs (9 pcs.) – cardboard packs (63 pcs.) – By prescription
90 pcs. – bottles – cardboard packs (90 pcs.) – By prescription

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 the absorption of cholesterol 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 of these two classes, when co-administered, provide an additional reduction in cholesterol levels.

Clinical studies have shown that elevated levels of total cholesterol, LDL cholesterol, and apolipoprotein B – the main protein component of LDL – contribute to the development of atherosclerosis. Furthermore, a reduced level of HDL cholesterol 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 cholesterol and inversely dependent on the level of HDL cholesterol. Like LDL, cholesterol- and triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also contribute to the development of 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 because 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.

The plasma protein binding of 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, approximately 78% of the total administered dose is excreted in the feces, and about 11% in the urine.

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.

Indications

Primary hypercholesterolemia (in combination with statins or as monotherapy in addition to diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides, and to increase HDL cholesterol levels in patients with primary hypercholesterolemia); homozygous familial hypercholesterolemia (in combination with statins, indicated to reduce elevated concentrations of total cholesterol and LDL cholesterol 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, 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 (CKD). 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 CKD.

ICD codes

Dosage Regimen

Follow a hypolipidemic diet before initiating and throughout therapy.

Take the recommended dose of 10 mg once daily. This applies to both monotherapy and use in combination with statins.

Administer the tablet at any time of day, with or without food.

When co-administering with a bile acid sequestrant, take Ezemirt at least 2 hours before or at least 4 hours after taking the sequestrant.

For pediatric patients 6 years of age and older, the 10 mg once daily dose is also standard; no adjustment is required.

No dose adjustment is necessary for elderly patients or for patients with mild hepatic impairment or renal impairment.

Do not use in patients with moderate or severe hepatic impairment.

If used concomitantly with a statin, adhere to the liver function monitoring schedule specified for that statin.

Discontinue therapy immediately if unexplained muscle pain, tenderness, or weakness occurs.

Adverse Reactions

Metabolism disorders infrequent – decreased appetite.

Cardiovascular system infrequent – flushing, increased blood pressure.

Respiratory system infrequent – cough.

Digestive system frequent – abdominal pain, diarrhea, flatulence; infrequent – dyspepsia, gastroesophageal reflux, nausea, increased ALT, AST, GGT activity.

Musculoskeletal system infrequent – arthralgia, muscle spasms, neck pain, increased serum CPK activity.

General disorders frequent – fatigue; infrequent – 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 ezetimibe administration did not reveal direct or indirect adverse effects on pregnancy, embryonic/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. 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 thereafter 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 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 increased AUC of total ezetimibe are unknown, Ezetimibe is not recommended for patients with moderate and severe hepatic impairment.

The safety and efficacy of ezetimibe used concomitantly 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 disease. 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 concentrations is necessary when ezetimibe and cyclosporine are used concomitantly.

During concomitant therapy 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 trial. The adverse event profile in children receiving ezetimibe was comparable to the adverse event profile in adult patients receiving ezetimibe. This clinical trial did not show a clear effect on growth or puberty in boys or girls. However, the effect of ezetimibe on growth and puberty has not been studied for treatment durations longer 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 clear effect on growth or puberty was observed in adolescent boys and girls, nor on the duration of the menstrual cycle in girls. However, the effect of ezetimibe on growth and puberty over a treatment period of >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 administration 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 cholesterol from adding ezetimibe to cholestyramine may be reduced by this interaction.

In patients who had undergone kidney transplantation, with creatinine clearance greater than 50 ml/min, who were 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 receiving ezetimibe 20 mg/day for 8 days concomitantly with cyclosporine at a daily dose of 100 mg, on day 7, an average 15% increase (range from a 10% decrease to a 50% increase) in the AUC of cyclosporine was detected compared to patients who received cyclosporine as monotherapy at a dose of 100 mg/day.

The safety and efficacy of ezetimibe used concomitantly 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 30°C (86°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.