PHARMACOLOGICAL PROPERTIES

Pharmacodynamics.

Zeta ® is a representative of a new class of lipid-lowering substances that selectively inhibit the intestinal absorption of cholesterol and the corresponding plant sterols. The Zeta ® is orally active and has an action mechanism that is different from other classes of cholesterol-cholesterol drugs (for example, statins, bile acid sequestrants (resin), acid derivatives of fibrates and plant stanols). Molecular target of ezetimibe is the carrier of sterols Niemann-Pick Cl-Like 1 (NPC1L1), responsible for absorption of cholesterol and phytosterols in the intestine.

Ezetimibe is localized on the small intestine strip and inhibits the absorption of cholesterol, reducing the delivery of intestinal cholesterol to the liver; statins reduce the synthesis of cholesterol in the liver, and together these mechanisms provide an additional reduction in cholesterol. After 2 weeks of clinical use in 18 patients with hypercholesterolemia, Zete reduced the absorption of cholesterol by 54% compared with placebo.

A series of preclinical studies was conducted to determine the selectivity of ezetimibe for suppressing the absorption of cholesterol. Ezetimibe inhibited the absorption of [14 C] -cholesterol without affecting the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinylestradiol, or fat-soluble vitamins A and D.

Epidemiological studies have established that cardiovascular morbidity and mortality vary in direct proportion to the level of total cholesterol and LDL cholesterol and in the reverse - from the level of HDL cholesterol.

The effect of Zete on cardiovascular morbidity and mortality has not yet been demonstrated.

Pharmacokinetics.

Absorption. After oral administration, ezetimibe is rapidly absorbed and is actively conjugated to form a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). The average maximum concentration (max) in blood plasma is achieved in 1-2 hours for ezetimibe-glucuronide and after 4-12 hours for ezetimibe. Absolute bioavailability of ezetimibe can not be determined, since this compound is insoluble in water.

Simultaneous food intake (with a low or high fat content) does not affect the oral bioavailability of ezetimibe, in particular tablets of the Zete ® preparation at 10 mg. Zeta ® can be taken regardless of food intake.

Distribution. Ezetimibe and ezetimibe-glucuronide bind to plasma proteins by 99.7% and 88-92%, respectively.

Metabolism. The initial metabolism of ezetimibe occurs in the small intestine and liver by conjugation with glucuronide (a phase II reaction) followed by excretion with bile. Minimal oxidative metabolism (reaction of the I phase) was observed at all stages of the transformation. Ezetimibe and ezetimibe-glucuronide are the main substances that are detected in the blood plasma, and constitute approximately 10-20% and 80-90% of the total drug content in the plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly removed from the blood plasma during intestinal hepatic recirculation. The half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Conclusion. After the intake of 20 mg of 14 C-ezetimibe by the volunteers in the blood plasma, approximately 93% of the total ezetimibe was detected from the total radioactivity of the plasma. Approximately 78% and 11% of the received radioactive dose were excreted with feces and urine respectively for 10 days. After 48 h in the blood plasma levels of radioactivity, no detectable was observed.

Special populations.

children

Absorption and metabolism of ezetimibe are the same in children and adolescents (10-18 years). Clinical application in pediatric practice and in adult patients is limited to data on patients with GOSG, heterozygous familial hypercholesterolemia or sitosterolemia.

Elderly patients

In elderly patients (over 65 years of age), the plasma concentration of total ezetimibe is approximately twice that of younger patients (18-45 years of age). Decreased LDL cholesterol and safety profile are approximately the same in elderly patients and young patients taking ezetimibe. Therefore, for elderly patients there is no need for dose adjustment.

Patients with hepatic insufficiency

After a single dose of 10 mg of ezetimibe, the mean area under the plasma concentration-time curve (AUC) for total ezetimibe was 1.7 times higher in patients with mild hepatic insufficiency (5-6 on the Child-Pugh scale), than in healthy volunteers. During the 14-day study of the use of ezetimibe (10 mg per day) in patients with moderate hepatic insufficiency (7-9 on the Child-Pugh scale), the AUC values ​​for total ezetimibe increased approximately 4-fold for the 1 st and 14- and a day compared to such a rate in healthy volunteers. Patients with hepatic insufficiency of a mild degree of dose adjustment are not required. Since the effects of elevated ezetimibe in patients with moderate or severe hepatic impairment (more than 9 on the Child-Pugh scale) are unknown, the Zete ® preparation is not recommended for this category of patients (see "Features of Use" section).

Patients with renal insufficiency

After a single dose of 10 mg of ezetimibe in patients with severe renal insufficiency (n = 8, creatinine clearance ≤ 30 mL / min / 1.73 m 2), the mean AUC for total ezetimibe increased approximately 1.5-fold compared with that in healthy volunteers (n = 9). This result is not considered clinically relevant. For patients with impaired renal function, there is no need for dose adjustment.

One patient in this study (who had a kidney transplant and received multi-therapy, including cyclosporine) had a 12-fold increase in total ezetimibe.

Floor

The plasma concentration of total ezetimibe is somewhat higher (about 20%) in women than in men. Decreased LDL cholesterol and safety profile are approximately the same for men and women who are taking Zete ®. Therefore, there is no need for dose adjustment depending on sex.

INDICATIONS

Primary hypercholesterolemia.

Zeta ® in combination with a HMG-CoA reductase inhibitor (statins) is indicated as an adjunct therapy for a diet for patients with primary (heterozygous familial and non-family) hypercholesterolemia if therapy with only statins is insufficient.

Monotherapy with the Zete ® preparation is shown as an auxiliary therapy for a diet for patients with primary (heterozygous familial and non-family) hypercholesterolemia, for whom the use of statin is impractical or there is intolerance.

Homozygous familial hypercholesterolemia (GOSG).

Zetia® in combination with statins is indicated as an adjunct to diet for patients with GOSG. Patients may also receive additional treatment (eg, LDL apheresis).

Homozygous sitosterolemia (phytosterolemia).

Zeta ® is indicated as an adjuvant therapy to a diet for patients with homozygous familial sitosterolemia.

CONTRAINDICATIONS

Hypersensitivity to the active substance or to any auxiliary substance.

While taking Zetia® with any statin, you should read the instructions of this medication.
Joint therapy with Zete ® with statins is contraindicated during pregnancy and lactation, as well as patients with liver disease in the acute stage or unexplained long-term increases in the level of serum transaminases.

INTERACTION WITH OTHER DRUGS AND OTHER TYPES OF INTERACTION

The study of interaction with other medicinal products was carried out only with the participation of adults.

Preclinical studies have shown that ezetimibe does not induce enzymes of the cytochrome P450 system that the drug is metabolized. There were no clinically significant pharmacokinetic interactions between ezetimibe and drugs that are metabolized by enzymes of the cytochrome P450 1A2, 2D6, 2C8, 2C9 and 3A4 system or N-acetyltransferase.

In clinical trials of drug interactions, ezetimibe did not interfere with the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinylestradiol and levonorgestrel), glipizide, tolbutamide, or midazolane in combination therapy. Cimetidine with combined therapy with ezetimibe did not affect the bioavailability of ezetimibe.

Antacids. Simultaneous reception of antacids leads to a decrease in the degree of absorption of ezetimibe, but does not affect its bioavailability. Such a decrease in the degree of absorption can not be considered clinically significant.

Cholestyramine. When combined with cholestyramine, the mean area under the plasma concentration-time curve (AUC) of total ezetimibe (ezetimibe and ezetimibe-glucuronide) decreased by about 55%. When Zetia® is added to colestyramine, a gradual decrease in low density lipoprotein cholesterol (LDL cholesterol) may slow down.

Fibrates. In patients taking Zetia® and fenofibrate, there is a risk of developing cholelithiasis and cholelithiasis.

If there is a suspicion of cholelithiasis in the patient, taking Zetia® and fenofibrate, a screening of the gallbladder is indicated, and therapy should be stopped.

Simultaneous reception of fenofibrate or gemfibrozil moderately increases the concentration of total ezetimibe (approximately 1.5-1.7 times, respectively).

Combined therapy with Zetia® and other fibrates has not been studied.

Fibrates can increase the release of cholesterol in the bile, which leads to cholelithiasis. In animal studies, ezetimibe sometimes increased cholesterol levels in the gallbladder, but not in all species. The risk of stone formation associated with the therapeutic use of the Zete ® preparation can not be detected.

Statins. No clinically significant pharmacokinetic interaction was detected with the combined use of ezetimibe with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.

Cyclosporine. In a study involving 8 patients after kidney transplantation with creatinine clearance> 50 mL / min with a stable dose of cyclosporine, a single dose of Zetia® 10 mg leads to an increase of 3.4 times (range 2.3 to 7.9 times) of the mean AUC of total ezetimibe compared with the corresponding indicator in the control population of healthy patients receiving only ezetimibe, in another study (n = 17). In another study, a patient with a transplanted kidney and severe renal failure who received cyclosporine and many other medicines had a 12-fold increase in the total ezetimibe exposure compared to control patients receiving only ezetimibe. During a cross-over study with two periods involving 12 healthy volunteers, the daily administration of 20 mg of ezetimibe for 8 days with a single dose of 100 mg of cyclosporine on day 7 resulted in an increase in AUC of cyclosporine by an average of 15% (range from a decrease of 10% to an increase of 51%) compared with the corresponding index with the administration of a single dose of 100 mg of cyclosporine. A controlled study of the effect of simultaneous administration of ezetimibe on cyclosporine exposure in patients with a transplanted kidney was not performed. Caution should be taken to start taking Zetia® in patients who take cyclosporine. In patients taking cyclosporine and Zete ®, the concentration of cyclosporine should be checked.

Anticoagulants. The simultaneous use of ezetimibe (10 mg once daily) had no significant effect on the bioavailability of warfarin and prothrombin time in a study involving 12 healthy adult males. However, there have been post-registration reports of an increase in the International Normalized Ratio (INR) in patients to whom Zetia® was added to warfarin or fluindione. When Zetia® is added to warfarin, another coumarin anticoagulant or fluindione, it is necessary to monitor INR properly.

FEATURES OF APPLICATION

When concurrently taking Zete ® with statins, you should read the instructions for using this statin.

Liver enzymes

During controlled clinical trials, patients who received the combination of statins and Zetia® experienced a gradual increase in transaminase levels (≥ 3 times the upper limit of the norm). When taking Zetia® with statins, functional liver tests should be performed at the beginning of therapy and in accordance with the statin recommendations.

Skeletal muscles

Post-marketing research reported cases of myopathy and rhabdomyolysis with Zetiyau®. The majority of patients who developed rhabdomyolysis took the statin concomitantly with the drug. However, cases of rhabdomyolysis have been reported very rarely with monotherapy with Zetia®, and in the case of the addition of Zetiyau® to other agents known to be associated with an increased risk of rhabdomyolysis. If you suspect myopathy, which is manifested by muscle symptoms or an increase in the level of CK more than 10 times the upper limit of the norm, you should immediately stop taking Zetiyau®, any statin and any of the other drugs that the patient takes at a time. All patients starting treatment with Zetia® should be informed of the risk of myopathy and the need to report urgently on the appearance of muscle pain, lethargy, or weakness of unclear etiology.

Liver failure

Since the effects of elevated ezetimibe in patients with moderate to severe hepatic insufficiency are not known, the Zete ® preparation is not recommended for this category of patients.

Fibrates

The safety and efficacy of Zete ® with fibrates have not been investigated.

If there is a suspicion of cholelithiasis in the patient, Zete ® and fenofibrate are taken, a gallbladder examination is indicated, and such therapy should be discontinued.

Ciclosporin

Caution should be started with the Zete ® preparation for patients taking cyclosporine. In patients taking cyclosporine and Zete ®, the concentrations of cyclosporin should be monitored.

Anticoagulants

If Zete ® is used against the background of taking warfarin, another coumarin anticoagulant, or fluindione, the international normalized ratio (MNO) should be properly monitored.

Excipients

Patients with rare hereditary forms of intolerance to galactose, congenital insufficiency of lactase or glucose / galactose malabsorption syndrome should not use this medication.

Application to pediatric patients

The efficacy and safety of Zete ®, intended in combination with simvastatin for patients aged 10-17 years with heterozygous familial hypercholesterolemia, were evaluated in a controlled clinical trial involving boys (Tanner Stage II or higher) and girls (at least one year after menarche ).

During this limited controlled study, there was no significant effect on the growth and puberty of boys and girls in adolescence and no effect on the length of the menstrual cycle in girls. However, the effect of ezetimibe on growth and puberty during the treatment period of more than 33 weeks has not been studied.The safety and efficacy of Zete ®, intended in combination with simvastatin at a dose of more than 40 mg per day, patients aged 10 to 17 years, were not studied.

Have not studied the use of Zete ® by patients under the age of 10 years and girls in the first menstruation.

The long-term effectiveness of Zete® therapy in patients under the age of 17 to reduce morbidity and mortality in adulthood has not been investigated.

Use during pregnancy or lactation.

Therapy with Zete ® in combination with statins is contraindicated during pregnancy and lactation. Clinical data on the use of Zetia® during pregnancy are not available.

The ability to influence the reaction rate when driving vehicles or other mechanisms.

Studies on the effect on the ability to drive and other mechanical means have not been carried out. But it should be borne in mind that it was reported dizziness when driving a car and other mechanisms.

METHOD OF USE AND DOSES

During the entire course of Zete® treatment, the patient should adhere to a standard lipid-lowering diet.

The recommended dose of Zete ® is 10 mg (1 tablet) per day, regardless of food intake.

When adding Zetia® to a statin, you should continue taking the dose of a statin that has already been prescribed. In this case, you should read the instructions for the use of this statin.

Simultaneous use of bile acid with SECURITY

Zetia® should be taken no later than 2:00 before or no earlier than 4:00 after the introduction of SECTIONAL BILLS.

Patients of advanced age.

Older patients do not need a dose adjustment.

Patients with impaired hepatic function

For patients with mild hepatic insufficiency (5-6 points on the Child-Pugh scale), dose adjustment is not required. Treatment with Zetia® It is not recommended for patients with moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 on the Child-Pugh scale) liver failure.

Admission of patients with impaired renal function

Patients with renal insufficiency do not need dose adjustment.

Children.

At the beginning of treatment, specialist supervision is necessary.

Children aged 10 years (puberty: boys - stage Tanner II and above, girls - not less than a year after menarche) do not need a dose adjustment, but clinical experience in children (aged 10 to 17 years) is limited.

When taking Zete ® with simvastatin, you should read the dosage instructions for children from 10 to 17 years.

Children under 10 years of age: Zetia® is not recommended for children under 10 years of age due to a lack of safety and efficacy data.

OVERDOSE

Several cases of overdose with Zetia® have been reported; in most cases, an overdose did not lead to undesirable events. The undesirable phenomena that were observed were not serious. In case of an overdose, symptomatic and supportive measures should be taken.

ADVERSE REACTIONS

Children aged 10 to 17 years:

In the study with the participation of adolescents aged 10 to 17 years with heterozygous familial hypercholesterolemia (N = 248), ALT and / or AST (> 3 times the upper limit of the norm) were observed in 3% (4 patients) of the ezetimibe / simvastatin group compared with 2% (2 patients) in the simvastatin monotherapy group; these indicators were 2% (2 patients) and 0% for the increase in CK (CK) ≥ 10 times from the upper limit of the norm. Myopathy was not reported.

In this study, no liquid adverse reactions to the drug were compared.

Data from laboratory studies.

During controlled clinical trials of monotherapy, a clinically significant increase in serum transaminases (ALT and / or AST -> 3 times the upper limit of the norm) was similar in Zetia® (0.5%) and placebo (0.3%). In studies of combined therapy, the incidence rate was 1.3% in patients concomitant with Zetia® and statin, and 0.4% in patients taking only statin. This increase was usually asymptomatic, not associated with cholestasis, and the indicators returned to baseline after the withdrawal of therapy or continued treatment.

Clinical studies showed a clinically significant increase in CKD (≥10 times the upper limit of the norm) in 0.2% (in 4 of 1674) of patients taking only Zeta ® compared to 0.1% (in 1 of 786) of the patients taking placebo, and in 0.1% (1/917) of patients taking Zetia® concomitant with statins, according to

COMPOSITION
active substance: ezetimib;

1 tablet contains 10 mg of ezetimibe;

auxiliary substances: lactose, microcrystalline cellulose, povidone (K29-32), sodium croscarmellose, sodium lauryl sulfate, magnesium stearate.

MEDICINAL FORM
Pills.

Basic physical and chemical properties: capsule-like tablets from white to almost white with an impression "414" on the one hand.

PHARMACOLOGICAL GROUP
Other lipid modifying agents. ATX Code C10A X09.