Composition, form of production and packaging
Tablets of capsular form, from white to almost white, with engraving "414" on one side.
ezetimibe 10 mg
Excipients: lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate.
7 pcs. - blisters (1) - cardboard boxes.
* 7 pcs. - blisters (2) - cardboard boxes.
7 pcs. - blisters (3) - cardboard boxes.
* 7 pcs. - blisters (4) - cardboard boxes.
10 pieces. - blisters (1) - cardboard boxes.
10 pieces. - blisters (2) - cardboard boxes.
10 pieces. - blisters (3) - cardboard boxes.
10 pieces. - blisters (4) - cardboard boxes.
* - This variant of the drug package is presented in the Russian Federation.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
Lipid-lowering drug for oral administration. Selectively inhibits the absorption of cholesterol and certain plant styrenes in the intestine. The mechanism of action of ezetimibe differs from the mechanism of action of other classes of lipid-lowering agents (for example, statins, bile acid sequestrants, fibrates and plant styrenes).
When entering the small intestine, ezetimibe is localized in the brush border of the small intestine and prevents the absorption of cholesterol (Xc), which leads to a decrease in the intake of Xc from the intestine to the liver, thereby reducing the Xc in the liver and increasing the excretion of Xc from the blood. Ezetrol В® does not increase the excretion of bile acids (as opposed to drugs that bind bile acids) and does not inhibit the synthesis of Xc in the liver (as opposed to statins). In a two-week clinical trial in which 18 patients with hypercholesterolemia were included, EzetrolВ® reduced Xc absorption in the intestine by 54% compared with placebo.
Statins reduce the synthesis of Xc in the liver. Due to two different mechanisms of action, the preparations of these two classes, when co-administered, provide an additional decrease in the level of Xc. EzetrolВ®, administered in combination with statins, reduces the level of total Xc, Xc-LDL, apolipoprotein-B and triglycerides, and increases HDL-C level in patients with hypercholesterolemia more than ezetimibe or simvastatin administered separately.
Clinical studies have shown that an increased level of total cholesterol, Xc-LDL and apolipoprotein-B, the main protein component of LDL, promotes the development of atherosclerosis. In addition, a lower level of X-HDL is associated with the development of atherosclerosis. In epidemiological studies, it is established that cardiovascular morbidity and mortality are directly related to the level of total Xc and Xc-LDL and in inverse relationship to the level of HDL-C. Like LDL, lipoproteins, rich in cholesterol and triglycerides, including VLDL, LLPP and remnants, can also contribute to the development of atherosclerosis.
To determine the selectivity of ezetimibe against inhibition of Xs absorption, a series of preclinical studies was performed. Ezetimibe inhibited the absorption of 14 C-cholesterol and had no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinylestradiol, fat-soluble vitamins.
After ingestion, ezetimibe is rapidly absorbed and intensively conjugated in the small intestine and liver to form a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). C max ezetimibe-glucuronide is achieved after 1-2 h, ezetimibe - after 4-12 h. Absolute bioavailability of ezetimibe can not be determined, since this compound is practically insoluble in water.
Simultaneous food intake (both with a high fat content and low-fat) does not affect the bioavailability of ezetimibe when ingested at a dose of 10 mg.
Binding to blood plasma proteins of ezetimibe and ezetimibe-glucuronide is 99.7% and 88-92%, respectively.
Ezetimibe is metabolized mainly in the small intestine and liver by conjugation with glucuronide (phase II reaction) followed by excretion with bile. Minimal oxidative metabolism (reaction of the I phase) is observed in all the species studied. Ezetimibe and ezetimib-glucuronide are the main substances detected in the blood plasma, and are about 10-20% and 80-90% of the total plasma content, respectively. Ezetimibe and ezetimibe-glucuronide are slowly removed from the plasma under conditions of intense intestinal hepatic recirculation.
After ingestion of 20 mg of labeled 14C-ezetimibe, the total level of ezetimibe in the blood plasma was 93% of the total radioactivity of the blood plasma. After 48 hours, radioactive traces of the drug in the blood plasma were not determined.
T 1/2 of ezetimibe and ezetimibe-glucuronide is about 22 hours.
Within 10 days of the total number of doses taken with feces, about 78% is removed, with urine about 11%.
Pharmacokinetics in special clinical cases
Pharmacokinetic data for children under the age of 10 years are absent. Absorption and metabolism of ezetimibe in children, adolescents aged 10-18 years and adults are the same. According to the measurement of the concentration of total ezetimibe, the pharmacokinetic parameters in adolescents and adults did not differ.
In elderly patients over the age of 65 years, the concentration of total ezetimibe in the blood plasma is approximately 2 times higher than in young patients (18 to 45 years of age). The degree of decrease in the level of LDL-C and the safety profile are comparable in elderly and young patients treated with Ezetrol В® .
After a single dose of 10 mg, the mean AUC for total ezetimibe in patients with mild liver failure (5-6 points on the Child-Pugh scale) increases approximately 1.7-fold compared to healthy volunteers. Dose selection for patients with mild hepatic insufficiency is not required.
In a 14-day study, when taking ezetimibe at a dose of 10 mg / day in patients with moderate hepatic insufficiency (7-9 on the Child-Pugh scale), the AUC for total ezetimibe was approximately 4 times greater than in healthy volunteers, th day, and on the 14th day of the study.
After a single dose of 10 mg ezetimibe in patients with severe kidney disease (n = 8) (QC not more than 30 ml / min / 1.73 m 2 ), AUC for total ezetimibe increased approximately 1.5-fold compared to healthy volunteers (n = 9 ). This result is not clinically relevant. The choice of a dose for patients with impaired renal function is not required.
The concentration of ezetimibe in the blood plasma is slightly higher (less than 20%) in women than in men. Reducing the level of LDL-C and the safety profile is comparable in patients of both sexes receiving ezetimibe treatment. Therefore, correction of the dose of the drug for men or women is not required.
- primary hypercholesterolemia; Ezetrol В® is prescribed in combination with HMG-CoA reductase inhibitors (statins) or as a monotherapy in addition to diet to reduce the elevated levels of total cholesterol, LDL-C, apolipoprotein B and triglycerides, as well as to increase HDL-C level in patients with primary (heterozygous familial and non-family) hypercholesterolemia;
homozygous familial hypercholesterolemia; Ezetrol В® in combination with statins is recommended to reduce the elevated level of total Xc, Xc-LDL; patients can also receive additional treatment, for example, LDL-apheresis;
- homozygous sitosterolemia (or phytosterolemia); Ezetrol В® is recommended to reduce the elevated levels of sitosterol and campesterol.
Before the start of treatment and during the entire period of Ezetrol therapy, patients should observe a lipid-lowering diet. The drug is taken orally at any time of the day, regardless of food intake.
The recommended dose of Ezetrol В® as a monotherapy or in combination with statins is 10 mg 1 time / day.
With the concomitant therapy of fatty acid sequestrants, the drug is prescribed 10 mg once a day at least 2 hours before the intake of sequestrants of fatty acids or no earlier than 4 hours after their administration.
In elderly patients and patients with impaired renal function, dose selection is not required.
The selection of doses for patients with mild liver failure (5-6 points on the Child-Pugh scale) is also not required. At moderate (7-9 points on the scale Child-Pugh) and severe (more than 9 points on the Child-Pugh scale) of liver failure, the use of Ezetrol В® is not recommended.
In clinical studies of 8 to 14 weeks duration, in which 3366 patients were included, Ezetrol was well tolerated when taken at a dose of 10 mg / day as monotherapy or in combination with statins. The undesirable effects were mild and transient; The overall incidence of side effects and the frequency of drug withdrawal were not different from those with placebo.
In patients who took Ezetrol В® in the form of monotherapy (n = 1691) or in combination with statin (n = 1675), in 1-10% of cases the following undesirable effects associated with the action of the drug were detected.
When monotherapy with Ezetrol: headache, abdominal pain, diarrhea.
With combined therapy with Ezetrol and statin: headache, fatigue, abdominal pain, constipation, diarrhea, bloating, nausea, increased activity of AST and ALT, myalgia.
On the part of laboratory indicators: the frequency of clinically significant increase in hepatic transaminases (ALT and / or ACT 3 or more times higher than UGN) was similar for Ezetrol alone (0.5%) and placebo (0.3%). With combined therapy, the incidence of clinically significant increases in serum transaminases is 1.3% for patients taking Ezetrol В® together with statin, and 0.4% for those taking only statins. The increase in transaminases is usually asymptomatic, is not accompanied by the development of cholestasis and passes both during the continuation of treatment and after the drug is discontinued.
The frequency of clinically significant increase in CK (? 10xVGN) in patients treated with Ezetrol В® as monotherapy was similar to that in patients treated with placebo or statin as monotherapy.
When using Ezetrol in clinical practice, the following adverse reactions were noted: angioedema, skin rash, increased CK, hepatic enzyme activity, hepatitis, thrombocytopenia, pancreatitis, nausea, paresthesia; very rarely - myopathy, rhabdomyolysis.
- moderate (7-9 points on the Child-Pugh scale) and severe (more than 9 on the Child-Pugh scale) degree of hepatic insufficiency;
- lactose intolerance, lactase deficiency or glucose malabsorption / galactose syndrome;
- children's age till 18 years;
- Hypersensitivity to any of the components of the drug.
When appointing Ezetrol in combination with statin for the control of contraindications, it is necessary to follow the instructions for the administration of the prescribed statin.
Caution should be given to patients receiving cyclosporine; simultaneous use with fibrates to obtain additional data on the results of clinical studies is not recommended.
PREGNANCY AND LACTATION
Clinical data on the use of Ezetrol В® in pregnancy are absent. Therefore, the use of Ezetrol during pregnancy is not recommended. In case of pregnancy, Ezetrol should be stopped.
Data on the excretion of ezetimibe with breast milk in women is not available. If it is necessary to use the drug during lactation, breastfeeding should be stopped.
In experimental studies on animals with the introduction of ezetimibe, no direct and indirect adverse effects on pregnancy, embryo / fetal development, childbirth and postnatal development have been identified. When pregnant rats were injected with ezetimibe in combination with lovastatin, simvastatin, pravastatin and atorvastatin, teratogenic effects were not observed. When pregnant rabbits were injected with a small frequency, defects in the development of the skeleton in the fetus were noted.
In studies on rats it was found that ezetimibe is excreted in breast milk. In this regard, Ezetrol В® is not recommended for use in nursing mothers.
Before starting treatment, patients should proceed to the appropriate lipid-lowering diet and continue to follow this diet during the entire period of therapy with EzetrolВ®.
It should be borne in mind that if Ezetrol В® is prescribed together with hypolipidemic drugs of the statin class, it is necessary to carefully read the instruction for the medical use of this statin.
In controlled clinical trials, concomitant administration of Ezetrol В® and a statin drug in patients showed an increase in hepatic enzyme activity (3 times higher than UGN). In the appointment of this combination, liver function monitoring should be performed at the beginning of treatment and further in accordance with the recommendations for this statin.
In clinical studies, the incidence of myopathy or rhabdomyolysis associated with the use of Ezetrol В® did not exceed the level of the corresponding control group (placebo or statin). However, myopathy and rhabdomyolysis are known undesirable side effects of statins and other lipid-lowering drugs. In clinical studies, the frequency of increase in CK (? 10xVGN) was 0.2% in the Ezetrol group compared with 0.1% in the placebo group, and 0.1% in the combined Ezetrol group with statin, compared with 0.4% in the statin monotherapy group.
Since the use of ezetimibe in doses exceeding 10 mg in patients with moderate to severe hepatic impairment has not been studied, the use of Ezetrol В® in such patients is not recommended.
Patients taking fenofibrate along with Ezetrol В® should be warned about the possible risk of gallstone disease and gallbladder disease. If the doctor assumes the possible development of these diseases, then therapy with Ezetrol В® should be discontinued.
The safety and efficacy of prescribing ezetimibe in combination with other fibrates has not been established. Although the significance of these data for human is not yet established, the simultaneous administration of ezetimibe with fibrates to obtaining additional data from the results of clinical studies is not recommended.
If it is necessary to simultaneously prescribe Ezetrol with cyclosporine, precautions should be taken and regular monitoring of plasma concentrations in blood plasma should be performed.
Several cases of overdose have been reported, most of which were not accompanied by adverse reactions, and in the event of their occurrence, adverse events were not serious.
In clinical studies, in one of which ezetimibe was administered to 15 healthy volunteers at a dose of 50 mg / day for 14 days, in the other 18 patients with primary hypercholesterolemia at a dose of 40 mg / day for 56 days were shown good tolerability.
Treatment: in case of an overdose, supportive and symptomatic therapy is performed.
Pre-clinical studies have shown that ezetimibe does not induce cytochrome P450 isoenzymes. There was no clinically significant pharmacokinetic interaction between ezetimibe and drugs that are metabolized by cytochrome P450 1A2, 2D6, 2C8, 2C9, and 3A4 isoenzymes or N-acetyltransferase.
Ezetimibe does not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, midazolam and warfarin.
Simultaneous reception of cimetidine with ezetimibe does not affect the bioavailability of the latter.
Simultaneous administration of antacids reduces the rate of absorption of ezetimibe, but does not affect its bioavailability and, consequently, a decrease in the rate of absorption is not clinically significant.
When combined with colestyramine AUC, the total ezetimibe (ezetimibe + ezetimibe-glucuronide) decreases by approximately 55%. An additional decrease in LDL-C-cholesterol due to the addition of ezetimibe to colestyramine can be reduced by this interaction.
In patients who underwent kidney transplantation with SC more than 50 ml / min, constantly receiving cyclosporine, a single Ezetrol 10 mg dose was followed by an average of 3.4-fold (2.3 to 7.9 times) increase in AUC ezetimibe. One patient who underwent kidney transplantation and severe renal insufficiency (13.2 mL / min / 1.73 m 2 CK) who received complex therapy including cyclosporine had a 12-fold increase in ezetimibe concentration 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 in a daily dose of 100 mg, on the 7th day, an increase in AUC of cyclosporine was observed on average 15% (from a decrease of 10% to an increase of 50%) compared with patients in whom cyclosporine was used as a monotherapy in a dose of 100 mg / day.
Simultaneous reception of fenofibrate or gemfibrozil increases the total concentration of ezetimibe by approximately 1.5 and 1.7 times, respectively. However, this increase is not considered clinically significant.
The safety and effectiveness of ezetimibe when used with fibrates is not established. Fibrates can increase the release of cholesterol into the bile, which can lead to cholelithiasis. In pre-clinical studies on dogs, ezetimibe increased the cholesterol level in the gallbladder. Although the significance of this data is unknown to a person, simultaneous administration of Ezetrol with fibrates prior to clinical trials is not recommended.
With the simultaneous administration of Ezetrol with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin and rosuvastatin, clinically significant pharmacokinetic interaction was not observed.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 2 years.