Ezetimibe-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

C10AX09 (Ezetimibe)

Active Substance

Ezetimibe (Rec.INN registered by WHO)

Dosage Form

Ezetimibe-SZ

Tablets 10 mg: 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

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

Excipients: lactose monohydrate (milk sugar), microcrystalline cellulose 102, croscarmellose sodium (primellose), povidone K30 (medium molecular weight polyvinylpyrrolidone), sodium lauryl sulfate, sodium carboxymethyl starch, magnesium stearate.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent – cholesterol absorption inhibitor

Pharmacotherapeutic Group

Hypolipidemic agents; other hypolipidemic agents

Pharmacological Action

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

Mechanism of action and pharmacodynamic effects

The drug Ezetimibe-SZ is effective when taken orally. The mechanism of action of ezetimibe differs from the mechanism of action 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 a transport protein (Niemann-Pick C1-Like 1, NPC1L1), responsible for the intestinal absorption of cholesterol and phytosterols.

Ezetimibe localizes in the brush border of the small intestine and inhibits the absorption of CH, leading to a decrease in the flow of CH from the intestine to the liver, thereby reducing CH stores in the liver and increasing the clearance 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).

Clinical efficacy and safety

In a 2-week clinical study that included 18 patients with hypercholesterolemia, Ezetimibe reduced intestinal CH absorption by 65% compared with placebo. By inhibiting intestinal CH absorption, Ezetimibe reduces the delivery of CH to the liver. Statins reduce the synthesis of CH in the liver. When used concomitantly, drugs from these two groups provide an additional reduction in CH concentration. The drug Ezetimibe-SZ, taken concomitantly with statins, reduces the concentration of TC, LDL-C, apo-B, non-HDL-C, and TG, and also increases the concentration of HDL-C in the blood plasma in patients with hypercholesterolemia to a greater extent than Ezetimibe or a statin taken in monotherapy. Concomitant use of ezetimibe with fenofibrate reduces the concentration of TC, LDL-C, apo-B, TG, and non-HDL-C, and also increases the concentration of HDL-C in the blood plasma in 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. In addition, a reduced concentration of HDL-C is also associated with the development of atherosclerosis. The results of epidemiological studies have shown that cardiovascular morbidity and mortality are directly dependent on the concentrations of TC and LDL-C and inversely dependent on the concentration of HDL-C. Like LDL, cholesterol- and TG-rich lipoproteins, including very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also contribute to the development of atherosclerosis.

A series of preclinical studies were conducted to determine the selectivity of ezetimibe with respect to the inhibition of cholesterol absorption. Ezetimibe inhibited the absorption of [¹⁴C]-cholesterol and had no effect on the absorption of TG, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.

Pharmacokinetics

Absorption

After oral administration, Ezetimibe is rapidly absorbed and extensively metabolized in the small intestine and liver by conjugation to a pharmacologically active phenolic glucuronide (Ezetimibe-glucuronide). The C_max of Ezetimibe-glucuronide in plasma is observed after 1-2 hours, and of ezetimibe after 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 the preparation of injectable solutions. Food intake (with low or high fat content) did not affect the bioavailability of ezetimibe when the drug Ezetimibe-SZ was taken orally in the form of 10 mg tablets. The drug Ezetimibe-SZ can be taken regardless of meals.

Distribution

Ezetimibe and Ezetimibe-glucuronide are bound to plasma proteins by 99.7% and 88-92%, respectively.

Metabolism

The metabolism of ezetimibe occurs mainly in the small intestine and liver by conjugation with glucuronide (phase II reaction) followed by biliary excretion. Ezetimibe is minimally subjected to oxidative metabolism (phase I reaction). Ezetimibe and Ezetimibe-glucuronide (the main derivatives of ezetimibe determined 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 in the process of enterohepatic recirculation. The T_1/2 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) of the total radioactive products was found in plasma. Within 10 days, approximately 78% of the administered radioactive products were excreted through the intestine with bile, 11% through the kidneys. After 48 hours, no radioactive products were detected in plasma.

Pharmacokinetics in special patient groups

Elderly patients. In elderly patients (over 65 years of age), the plasma concentration of total ezetimibe is approximately 2 times higher than in younger patients (from 18 to 45 years). The degree of LDL-C reduction and the safety profile were comparable in elderly and younger patients receiving Ezetimibe. Dose adjustment of the drug is not required for elderly patients.

Renal impairment. After a single dose of ezetimibe 10 mg in patients with severe renal impairment (n=8; CrCl not more than 30 ml/min/1.73 m²), the AUC value of total ezetimibe increased approximately 1.5 times compared with healthy volunteers (n=9). This result is not clinically significant. Dose adjustment of the drug is not required for patients with impaired renal function. In a patient after kidney transplantation receiving complex therapy, including cyclosporine, the AUC value of total ezetimibe increased 12-fold.

Hepatic impairment. After a single dose of ezetimibe 10 mg, the mean AUC value of total ezetimibe was 1.7 times greater in patients with mild hepatic impairment (5-6 points on the Child-Pugh scale) than in healthy volunteers. In a 14-day study of ezetimibe at a dose of 10 mg/day involving patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale), the mean AUC value of total ezetimibe increased 4-fold on day 1 and day 14 compared with healthy volunteers. For patients with mild hepatic impairment, dose adjustment of the drug is not required. Since the consequences of an increase in the AUC value of total ezetimibe are unknown, Ezetimibe is not recommended for patients with moderate and severe hepatic impairment (> 9 points on the Child-Pugh scale) (see section “With caution”).

Gender. The plasma concentration of total ezetimibe is slightly higher in women (< 20%) than in men. The degree of LDL-C reduction and the safety profile are the same in men and women taking Ezetimibe, so dose adjustment of the drug is not required for male or female patients.

Children. The pharmacokinetic parameters of ezetimibe were the same in children over 6 years of age and adults. Pharmacokinetic data for children under 6 years of age are not available.

Indications

The drug Ezetimibe-SZ is indicated for use in adults and children aged 6 years and older.

Primary hypercholesterolemia

• In combination with HMG-CoA reductase inhibitors (statins) or in monotherapy in addition to diet to reduce elevated concentrations of TC, LDL-C, apo-B, TG, and non-HDL-C (calculated as the difference between TC concentration and HDL-C concentration), and to increase HDL-C concentration in adults and adolescents (10-17 years) with primary (heterozygous familial and non-familial) hypercholesterolemia;
• In combination with fenofibrate in addition to diet to reduce elevated concentrations of TC, LDL-C, apo-B, and non-HDL-C in patients with mixed hypercholesterolemia.

Prevention of cardiovascular diseases

• In combination with statins to reduce 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 coronary artery disease;

Prevention of major cardiovascular complications in patients with chronic kidney disease

• In combination with simvastatin to reduce 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

• In combination with a statin is indicated to reduce elevated concentrations of TC and LDL-C in adults and adolescents (10-17 years) with homozygous familial hypercholesterolemia. Patients may also receive adjunctive treatment (e.g., LDL apheresis).

Homozygous sitosterolemia (phytosterolemia)

• To reduce elevated concentrations of sitosterol and campesterol in patients with homozygous familial sitosterolemia.

ICD codes

Dosage Regimen

Before starting treatment, patients should switch to an appropriate lipid-lowering diet and continue to follow this diet throughout the entire period of therapy with the drug Ezetimibe-SZ.

The drug is taken orally at any time of the day, regardless of meals.

Use in patients with primary hypercholesterolemia

The dose of the drug Ezetimibe-SZ in monotherapy or in combination with a statin or fenofibrate is 10 mg once/day. The dose of fenofibrate should not exceed 160 mg once/day when used concomitantly with the drug Ezetimibe-SZ.

Use in patients with coronary artery disease

Combination therapy with statins. For additional reduction of cardiovascular events in patients with coronary artery disease, the drug Ezetimibe-SZ at a dose of 10 mg can be used with a statin with a proven effect on reducing the risk of cardiovascular complications.

Combination therapy with bile acid sequestrants

The drug Ezetimibe-SZ should be taken at a dose of 10 mg once/day at least 2 hours before or 4 hours after taking bile acid sequestrants.

Use in patients with impaired renal function/chronic kidney disease

Monotherapy. For patients with impaired renal function, dose adjustment of the drug is not required (see section “Pharmacokinetics”, subsection “Pharmacokinetics in special patient groups”).

Combination therapy with simvastatin. For patients with mild renal impairment (GFR not less than 60 ml/min/1.73 m²), dose adjustment of the drug Ezetimibe-SZ or simvastatin is not required. For patients with renal impairment and GFR less than 60 ml/min/1.73 m², the drug Ezetimibe-SZ is prescribed at a dose of 10 mg and simvastatin at a dose of 20 mg once/day in the evening. In these patients, the use of simvastatin at a higher dose requires careful monitoring (see section “Pharmacokinetics”).

Elderly patients (≥65 years)

Dose adjustment of the drug is not required (see section “Pharmacokinetics”).

Patients with impaired liver function

For patients with mild hepatic impairment (5-6 points on the Child-Pugh scale), dose adjustment of the drug is not required. The use of the drug Ezetimibe-SZ 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) hepatic impairment (see sections “Pharmacokinetics” and “Special instructions”).

Use in children and adolescents from 6 to 18 years

The dosage regimen for children from 6 to 18 years does not differ from the dosage regimen for adults.

Use in children from 0 to 6 years

The safety and efficacy of ezetimibe in children aged 0 to 6 years have not been established to date. The use of the drug Ezetimibe-SZ in children under 6 years of age is contraindicated.

Adverse Reactions

Summary of the safety profile

In clinical studies in which patients took Ezetimibe at a dose of 10 mg/day in monotherapy, or in combination with a statin or in combination with fenofibrate, adverse reactions were usually mild and transient; the overall incidence of adverse effects and the incidence of treatment discontinuation due to adverse effects when taking ezetimibe did not differ from these indicators when taking placebo.

Tabulated summary of adverse reactions

Adverse reactions are distributed by system-organ class with an indication of the frequency of their occurrence: common (≥1/100, but <1/10), uncommon (≥1/1000, but <1/100), rare (≥1/10000, but <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

When using the drug Ezetimibe-SZ in monotherapy

The following common or uncommon adverse reactions were observed when taking ezetimibe in monotherapy or when taking ezetimibe concomitantly with a statin.

Table 1. Adverse reactions when taking ezetimibe in monotherapy

Description of selected adverse reactions

When taking ezetimibe concomitantly with fenofibrate

Gastrointestinal disorders: common – abdominal pain.

In a multicenter, double-blind clinical study lasting up to 1 year involving patients with mixed hyperlipidemia, the frequency of consecutive clinically significant increases (more than 3 times the ULN) in serum hepatic transaminase activity was 4.5% in the group of patients taking fenofibrate in monotherapy, and 2.7% in the group of patients taking Ezetimibe concomitantly with fenofibrate. The frequency of cholecystectomy was 0.6% in the group of patients taking fenofibrate in monotherapy, and 1.7% in the group of patients taking Ezetimibe concomitantly with fenofibrate (see section “Special instructions”). There was no increase in CPK activity (more than 10 times the ULN) in any of the treatment groups in this study.

Patients with coronary artery disease

In the IMPROVE-IT clinical trial (a study of the reduction of the risk of cardiovascular events), 18,144 patients with coronary artery disease took simvastatin + Ezetimibe at a dose of 40 mg + 10 mg (n=9067; of which 6% of patients had their dose titrated to 80 mg + 10 mg) or simvastatin at a dose of 40 mg (n=9077; of which 27% of patients had their dose titrated to 80 mg). The safety profile of the drugs in the two groups was similar throughout the entire observation period (median observation duration was 6 years). The frequency of drug discontinuation due to adverse events was 10.6% in the group of patients taking simvastatin + Ezetimibe, and 10.1% in the group of patients taking simvastatin. The frequency of myopathy was 0.2% in the group of patients taking simvastatin + Ezetimibe, and 0.1% in the group of patients taking simvastatin, 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 frequency of rhabdomyolysis was 0.1% in the group of patients taking simvastatin + Ezetimibe, and 0.2% in the group of patients taking simvastatin, 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 impairment, two consecutive increases in CPK activity from 5 to 10 times the ULN with signs of renal impairment, or CPK activity of at least 10,000 IU/ml without signs of renal impairment. The frequency of consecutive increases in hepatic transaminase activity (at least 3 times the ULN) was 2.5% in the group of patients taking simvastatin + Ezetimibe, and 2.3% in the group of patients taking simvastatin (see section “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 frequency of hospitalization with 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 the SHARP clinical study (Study of Heart and Renal Protection) involving 4650 patients taking a fixed-dose combination hypolipidemic drug containing ezetimibe (10 mg) and simvastatin (20 mg) once daily, and 4620 patients taking placebo, the safety profiles were comparable throughout the observation period (median observation duration was 4.9 years). This clinical study recorded only serious adverse events and discontinuation of the drug due to adverse events. The frequency of drug discontinuation was comparable in both groups (10.4% in the group of patients taking the fixed-dose combination of ezetimibe and simvastatin, and 9.8% in the group of patients taking placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in the group of patients taking the fixed-dose combination of ezetimibe and simvastatin, and 0.1% in the group of patients taking placebo.

Consecutive increases in hepatic transaminase activity (more than 3 times the upper limit of normal) were observed in 0.7% of patients taking the fixed-dose combination of ezetimibe and simvastatin, and in 0.6% of patients taking placebo. This clinical study did not show a statistically significant increase in the frequency of such adverse events as malignant neoplasms (9.4% in the group of patients taking the fixed-dose combination of ezetimibe and simvastatin, and 9.5% in the group of patients taking placebo), hepatitis, cholecystectomy, or complications of cholelithiasis or pancreatitis.

Laboratory parameters

In controlled clinical studies, the frequency of consecutive clinically significant increases in serum hepatic transaminase activity (ALT and/or AST activity 3 or more times the upper limit of normal) was comparable with ezetimibe monotherapy (0.5%) and placebo (0.3%). In the safety assessment of combination therapy, the frequency of clinically significant increases in serum hepatic transaminase activity was 1.3% in patients taking Ezetimibe concurrently with a statin and 0.4% in patients taking statin monotherapy. The increase in serum transaminase activity was usually asymptomatic, not accompanied by cholestasis, and returned to baseline both with continued treatment and after drug discontinuation.

The frequency of clinically significant increases in CK activity (10 or more times the upper limit of normal) in patients taking Ezetimibe monotherapy was similar to that in patients taking placebo or statin monotherapy.

Post-marketing experience

The following adverse reactions have been reported during post-marketing use of ezetimibe without specification of a causal relationship.

Children and adolescents aged 6 to 17 years

In a 12-week controlled clinical study involving children aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia (n=138), the safety and tolerability profile of ezetimibe was comparable to the profile in adult patients receiving Ezetimibe.

In a controlled clinical study involving children aged 10 to 17 years with heterozygous familial hypercholesterolemia (n=248) taking combination therapy with ezetimibe and simvastatin, the safety and tolerability profile was comparable to the safety profile in adult patients receiving combination therapy with ezetimibe and simvastatin.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk ratio. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to ezetimibe or to any of the excipients included in the drug;
• Moderate and severe hepatic impairment (≥ 7-9 or more points on the Child-Pugh scale) (see sections “Dosage Regimen”, “Pharmacological Properties”, “Pharmacokinetics”);
• Children under 6 years of age;
• Galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

When prescribing Ezetimibe-SZ concurrently with a statin or fenofibrate, the instructions for use of the additionally prescribed drugs must be followed.

Use in Pregnancy and Lactation

Pregnancy

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

There are no clinical data on the use of Ezetimibe-SZ during pregnancy, so caution should be exercised when prescribing the drug to pregnant women. If pregnancy occurs, Ezetimibe-SZ should be discontinued.

When using Ezetimibe-SZ and a statin concurrently, the instructions for use of that statin must be followed.

Breastfeeding period

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

Use in Hepatic Impairment

The use of the drug is contraindicated in patients with moderate and severe hepatic impairment.

For patients with mild hepatic impairment, dose adjustment of the drug is not required.

Use in Renal Impairment

When conducting monotherapy with the drug for patients with impaired renal function, dose adjustment of the drug is not required.

When conducting combination therapy with simvastatin for patients with mild renal impairment (GFR not less than 60 ml/min/1.73 m²), dose adjustment of Ezetimibe-SZ or simvastatin is not required. For patients with impaired renal function and GFR less than 60 ml/min/1.73 m², Ezetimibe-SZ is prescribed at a dose of 10 mg and simvastatin at a dose of 20 mg once daily in the evening.

Pediatric Use

The use of the drug is contraindicated in children under 6 years of age.

Geriatric Use

For elderly patients, dose adjustment of the drug is not required.

Special Precautions

Caution should be exercised when using Ezetimibe-SZ concurrently with fibrates, cyclosporine, and indirect anticoagulants (including warfarin and fluindione). Patients taking Ezetimibe-SZ and fenofibrate concurrently should be aware of the possible risk of gallbladder disease.

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

If Ezetimibe-SZ is prescribed in combination with a statin or fenofibrate, the instructions for use of the additionally prescribed drug should be carefully read.

Liver enzymes

In controlled clinical studies with concurrent use of ezetimibe and a statin, patients experienced consecutive increases in hepatic transaminase activity – ALT and AST (3 or more times the upper limit of normal). If Ezetimibe-SZ 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 section “Adverse Reactions”).

In the IMPROVE-IT clinical study, 18144 patients with coronary artery disease were randomized and took simvastatin + Ezetimibe at a dose of 40 mg + 10 mg daily (n=9067) or simvastatin at a dose of 40 mg daily (n=9077) (median observation duration was 6 years). The frequency of consecutive increases in hepatic transaminase activity (at least 3 times the upper limit of normal) was 2.5% in the group of patients taking simvastatin + Ezetimibe, and 2.3% in the group of patients taking simvastatin (see section “Adverse Reactions”).

In a controlled clinical study involving patients with chronic kidney disease, the frequency of consecutive increases in hepatic transaminase activity (3 or more times the upper limit of normal) was 0.7% in the group of patients taking the fixed-dose combination hypolipidemic drug containing ezetimibe (10 mg) and simvastatin (20 mg) once daily, and 0.6% in the group of patients taking placebo (see section “Adverse Reactions”).

Skeletal muscle

In clinical studies, the incidence of myopathy or rhabdomyolysis associated with the use of ezetimibe did not exceed that in 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 increased CK activity (more than 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 of concurrent use of ezetimibe and a statin compared to 0.4% in the statin monotherapy group.

During the post-marketing period of ezetimibe use, reports of cases of myopathy and rhabdomyolysis have been received, regardless of the cause of their development. Most patients who developed rhabdomyolysis were taking statins before starting ezetimibe. Nevertheless, very rare reports of rhabdomyolysis with ezetimibe monotherapy and with concurrent use of ezetimibe and drugs known to be associated with an increased risk of rhabdomyolysis have been reported.

All patients prescribed Ezetimibe-SZ should be warned about the risk of developing myopathy and rhabdomyolysis and should report any unexplained muscle pain, tenderness, or weakness to their doctor. If myopathy is diagnosed or suspected, the use of Ezetimibe-SZ and any statin taken concurrently with Ezetimibe-SZ should be discontinued immediately. The presence of these symptoms and an increase in CK activity (more than 10 times the upper limit of normal) indicates the development of myopathy.

In the IMPROVE-IT clinical study, 18144 patients with coronary artery disease were randomized and took simvastatin + Ezetimibe at a dose of 40 mg + 10 mg daily (n=9067) or simvastatin at a dose of 40 mg daily (n=9077) (median observation duration was 6 years). The incidence of myopathy was 0.2% in the group of patients taking simvastatin + Ezetimibe, and 0.1% in the group of patients taking simvastatin, where myopathy was defined as unexplained muscle weakness or muscle pain accompanied by an increase in CK activity of at least 10 times the upper limit of normal or two consecutive increases in CK activity from 5 to 10 times the upper limit of normal. The incidence of rhabdomyolysis was 0.1% in the group of patients taking simvastatin + Ezetimibe, and 0.2% in the group of patients taking simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or muscle pain accompanied by an increase in CK activity of at least 10 times the upper limit of normal with signs of impaired renal function, two consecutive increases in CK activity from 5 to 10 times the upper limit of normal with signs of impaired renal function, or CK activity of at least 10,000 IU/ml without signs of impaired renal function (see section “Adverse Reactions”).

In a clinical study involving patients with chronic kidney disease, the incidence of myopathy/rhabdomyolysis was 0.2% in the group of patients taking the fixed-dose combination hypolipidemic drug containing ezetimibe (10 mg) and simvastatin (20 mg) daily, and 0.1% in the group of patients taking placebo (see section “Adverse Reactions”).

Hepatic impairment

Since the consequences of an increased AUC of total ezetimibe are unknown, Ezetimibe-SZ is not recommended for patients with moderate and severe hepatic impairment (see sections “Pharmacokinetics” and “Contraindications”).

Fibrates

The safety and efficacy of using ezetimibe concurrently with fibrates (except fenofibrate) have not been established. Concurrent use of Ezetimibe-SZ with fibrates (except fenofibrate) is not recommended (see section “Drug Interactions”).

Fenofibrate

Patients taking fenofibrate concurrently with Ezetimibe-SZ should be warned about the possible risk of cholelithiasis and gallbladder disease. If the doctor suspects the possible development of the above-mentioned diseases in a patient, gallbladder examinations should be performed and alternative lipid-lowering therapy should be prescribed (see section “Adverse Reactions” and the instructions for use of fenofibrate).

Cyclosporine

Precautions should be taken when prescribing ezetimibe to patients taking cyclosporine. Regular monitoring of cyclosporine plasma concentration is necessary when using Ezetimibe-SZ and cyclosporine concurrently (see sections “Special Precautions” and “Drug Interactions”).

Indirect anticoagulants

When using Ezetimibe-SZ concurrently with indirect anticoagulants, including warfarin or fluindione, INR values should be monitored (see section “Drug Interactions”).

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 12-week 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 a clear effect on growth or puberty in boys or girls. However, the effect of ezetimibe on growth and puberty has not been studied with treatment lasting more than 12 weeks (see sections “Dosage Regimen”, “Adverse Reactions”).

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 controlled clinical study in adolescent boys and girls who were at least one year post-menarche. The adverse event profile in adolescents receiving Ezetimibe and up to 40 mg/day simvastatin was comparable to the adverse event profile in adult patients receiving Ezetimibe and simvastatin. This clinical study did not show a clear effect on growth or puberty in adolescent boys or girls or any effect on the duration of the menstrual cycle in girls (see sections “Dosage Regimen”, “Adverse Reactions”).

Excipients

Ezetimibe-SZ contains lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on 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 the use of Ezetimibe-SZ may affect the ability of some patients to drive vehicles and operate machinery (see section “Adverse Reactions”). Caution should be exercised when driving vehicles or engaging in activities requiring increased concentration and speed of psychomotor reactions while taking Ezetimibe-SZ.

Overdose

Symptoms

Several cases of overdose have been reported, most of which were not accompanied by adverse events, and in cases where they occurred, the adverse events were not serious.

In clinical studies in which 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, the drug was well tolerated.

Treatment

In case of overdose, symptomatic treatment and supportive therapy should be provided.

Drug Interactions

Cytochrome P450 system

Preclinical studies have shown that Ezetimibe does not induce cytochrome P450 isoenzymes involved in drug metabolism. No clinically significant pharmacokinetic interaction was observed between ezetimibe and agents metabolized by cytochrome P450 isoenzymes 1A2, 2D6, 2C8, 2C9, and 3A4 or N-acetyltransferase.

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

Antacids

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

Cholestyramine

Concomitant administration of cholestyramine reduces the mean AUC of total ezetimibe (Ezetimibe + Ezetimibe-glucuronide) by approximately 55%. The effect of additional reduction in LDL-C concentration due to concurrent use of ezetimibe and cholestyramine may be reduced by this interaction.

Cyclosporine

In patients with a history of kidney transplantation and a creatinine clearance greater than 50 ml/min who were taking a constant dose of cyclosporine, a single dose of 10 mg ezetimibe led to an average 3.4-fold increase (range 2.3 to 7.9-fold) in the AUC of total ezetimibe compared to this parameter in healthy volunteers.

In one patient after kidney transplantation with severe renal impairment (creatinine clearance 13.2 ml/min/1.73 m²) who was taking complex therapy, including cyclosporine, a 12-fold increase in the concentration of total ezetimibe was observed compared to the control group.

In a two-period crossover study involving 12 healthy volunteers who took 20 mg of Ezetimibe once daily for 8 days with a single 100 mg dose of cyclosporine on day 7 of ezetimibe therapy, an average 15% increase (range from a 10% decrease to a 51% increase) in the cyclosporine AUC value was found compared to this parameter in healthy volunteers who took a single 100 mg dose of cyclosporine as monotherapy (see the “Caution” section).

Fibrates

The safety and efficacy of using ezetimibe concomitantly with fenofibrate have been evaluated in clinical studies (see the “Adverse Reactions” section). The safety and efficacy of using ezetimibe concomitantly with other fibrates have not been studied.

Fibrates may increase the biliary excretion of cholesterol, which can lead to cholelithiasis. In a preclinical study in dogs, Ezetimibe increased the concentration of cholesterol in bile. Although the significance of these data for humans is not yet known, the concomitant use of ezetimibe with fibrates (except for fenofibrate) is not recommended until additional data from clinical studies are obtained.

Concomitant administration of ezetimibe and fenofibrate or gemfibrozil increases the concentration of total ezetimibe by approximately 1.5-fold and 1.7-fold, respectively; however, these increases are not considered clinically significant.

Statins

No clinically significant pharmacokinetic interaction was observed when ezetimibe was co-administered with atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, and rosuvastatin.

Oral Anticoagulants

Concomitant use of ezetimibe 10 mg once daily and warfarin had no significant effect on the bioavailability of warfarin or prothrombin time in a study involving 12 healthy volunteers.

In the post-registration period, reports were received of an increase in INR in patients taking Ezetimibe concomitantly with warfarin or fluindione. These patients were also taking other medications (see the “Special Instructions” section).

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.