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Active ingredients
Ezetimibe
Release form
Pills
Composition
Ezetimibe 10 mg Auxiliary substances: lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate.
Pharmacological effect
Lipid-lowering drug for oral administration. Selectively inhibits the absorption of cholesterol and some plant styrenes in the intestine. The mechanism of action of ezetimibe differs from the mechanism of action of other classes of lipid-lowering drugs (for example, statins, sequestrants of bile acids, fibrates, and plant styrenes). a decrease in the supply of cholesterol from the intestine to the liver, due to which the reserves of cholesterol in the liver are reduced and the excretion of cholesterol from the blood increases. Ezetrol does not increase the excretion of bile acids (unlike drugs that bind bile acids) and does not inhibit the synthesis of Xc in the liver (unlike statins). In a two-week clinical study in which 18 patients with hypercholesterolemia were included, Ezetrol reduced the absorption of Xc in the intestine by 54% compared to placebo. The statins reduce the synthesis of Xc in the liver. Due to two different mechanisms of action, the drugs of these two classes when administered together provide an additional decrease in the level of Xc. Ezetrol, administered in combination with statins, reduces the level of total Xc, Xc-LDL, apolipoprotein-B and triglycerides and increases the level of Xc-HDL in patients with hypercholesterolemia to a greater extent than ezetimibe or simvastatin administered separately. Clinical studies have shown that elevated The level of total Xc, Xc-LDL and apolipoprotein-B, the main protein component of LDL, contributes to the development of atherosclerosis. In addition, a low level of HD-C HDL is associated with the development of atherosclerosis. In epidemiological studies, it was found that cardiovascular morbidity and mortality are directly dependent on the level of total Xc and Xc-LDL and inversely on the level of Xc-HDL. As with LDL, cholesterol and triglyceride-rich lipoproteins, including VLDL, LDL and remnant, can also contribute to the development of atherosclerosis. A series of preclinical studies have been carried out to determine the selectivity of ezetimibe for inhibiting Xc absorption.Ezetimibe inhibited the absorption of 14C-cholesterol and did not affect the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, fat-soluble vitamins.
Pharmacokinetics
Absorption After ingestion, ezetimibe is rapidly absorbed and intensively conjugates in the small intestine and liver to form pharmacologically active phenolic glucuronide (ezetimib glucuronide). Сmax of ezetimib-glucuronide is achieved in 1-2 h, ezetimibe - in 4-12 h. Absolute bioavailability of ezetimibe cannot be determined, since this compound is practically insoluble in water. Simultaneous food intake (both with high fat content and low fat content) does not affect on the bioavailability of ezetimibe when administered orally at a dose of 10 mg. Distribution: The binding of plasma proteins of ezetimibe and ezetimib glucuronide is 99.7% and 88-92%, respectively. Metabolism Ezetimibe is metabolized mainly in the small intestine and liver by conjugation with glucuronide (Phase II reaction) followed by excretion with bile. The minimum oxidative metabolism (phase I reaction) is observed in all species studied. Ezetimibe and ezetimibe-glucuronide are the main substances detected in the blood plasma and constitute approximately 10-20% and 80-90% of the total content of the drug in plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly excreted from the plasma under conditions of intensive enterohepatic recirculation. Exit After ingestion of 20 mg of 14C-labeled ezetimibe, the total plasma level of ezetimibe was 93% of the total plasma radioactivity. After 48 hours, no radioactive traces of the drug were detected in the blood plasma. T1 / 2 of ezetimibe and ezetimib-glucuronide is about 22 hours. Within 10 days, about 78% of the total dose taken is excreted in the urine and 11% in the urine. Pharmacokinetics Special clinical cases of pharmacokinetic data for children under the age of 10 years are not available. 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, pharmacokinetic parameters in adolescents and adults did not differ. In elderly patients over the age of 65, plasma concentrations of total ezetimibe are about 2 times higher than in young people (18 to 45 years).The degree of reduction in LDL-C and the safety profile are comparable in elderly and young patients who received Ezetrol. After a single dose of the drug at a dose of 10 mg, the average AUC for total ezetimibe in patients with mild liver failure (5-6 points on the Child-Pugh scale ) increases about 1.7 times compared with healthy volunteers. Dose selection for patients with mild hepatic impairment is not required. In a 14-day study with ezetimibe at a dose of 10 mg / day in patients with moderate hepatic insufficiency (7–9 points on the Child-Pugh scale), the AUC for total ezetimibe was about 4 times more than healthy volunteers both on day 1 and day 14 of the study. After a single dose of ezetimib in a dose of 10 mg in patients with severe kidney disease (n = 8) (CC not more than 30 ml / min /1.73 m2) AUC for total ezetimibe increased about 1.5 times compared to eniyu from healthy volunteers (n = 9). This result is not clinically significant. Dose selection for patients with impaired renal function is not required. Plasma ezetimibe concentration is slightly higher (less than 20%) in women than in men. The decrease in LDL-C and the safety profile are comparable in patients of both sexes receiving ezetimibe treatment. Therefore, dose adjustment for men or women is not required.
Indications
- primary hypercholesterolemia; Esetrol is prescribed in combination with HMG-CoA reductase inhibitors (statins) or as monotherapy in addition to a diet to reduce elevated levels of total Xc, Xc-LDL, apolipoprotein B, and triglycerides, as well as to increase the level of Xc-HDL in patients with primary (heterozygous familial and nonfamily) hypercholesterolemia; homozygous familial hypercholesterolemia; Ezetrol in combination with statins is recommended to reduce elevated levels of total Xc, Xc-LDL; patients can also receive additional treatment, for example, LDL-apheresis; - homozygous sitosterolemia (or phytosterolemia); Ezetrol is recommended to reduce elevated levels of sitosterol and campesterol.
Contraindications
- moderate (7-9 points on the Child-Pugh scale) and severe (more than 9 points on the Child-Pugh scale) degree of liver failure; - lactose intolerance,lactase deficiency or glucose / galactose malabsorption syndrome; - children's age up to 18 years; - hypersensitivity to any of the components of the drug. receiving cyclosporine; simultaneous use with fibrates before obtaining additional data on the results of clinical studies is not recommended.
Precautionary measures
During treatment, psoriasis may worsen. During pheochromocytoma, propranolol can only be used after taking an alpha blocker. After a long course of treatment, propranolol should be discontinued gradually, under the supervision of a physician. during anesthesia, you must stop taking propranolol or find a remedy for anesthesia with minimal negative inotropic effects. The impact on the ability to drive vehicles and control mechanisms of patients whose activities require increased attention, the question of the use of propranolol on an outpatient basis should be addressed only after evaluating the individual response of the patient.
Use during pregnancy and lactation
Clinical data on the use of the drug Ezetrol during pregnancy are not available. Therefore, the use of Ezetrol during pregnancy is not recommended. In the event of pregnancy, the administration of Ezetrol should be discontinued. There is no data on the removal of ezetimibe in breast milk in women. If necessary, the use of the drug during lactation should stop breastfeeding. In experimental studies on animals with the introduction of ezetimib, no direct and indirect adverse effects on pregnancy, development of the embryo / fetus, childbirth and postnatal development have been identified. When ezetimibe was administered to pregnant rats in combination with lovastatin, simvastatin, pravastatin and atorvastatin, no teratogenic effects were observed. When administered to pregnant rabbits with a small frequency, defects in the skeleton of the fetus were noted. In studies in rats, it was found that ezetimibe is excreted in breast milk.In this regard, Ezetrol is not recommended for use in nursing mothers.
Dosage and administration
Patients should follow a lipid-lowering diet before starting treatment and during the whole period of treatment with Ezethrol. The drug is taken orally at any time of the day, regardless of the meal. The recommended dose of Ezetrol as monotherapy or in combination with statins is 10 mg 1 time / day. With concomitant therapy with sequestrants of fatty acids, the drug is administered at 10 mg 1 time / day less than 2 hours before taking fatty acid sequestrants or no earlier than 4 hours after taking them. Elderly patients and patients with impaired renal function do not need to select a dose. Selection of doses for patients with mild liver failure (5-6 ba Child-Pugh scale is also not required. With moderate (7–9 points on the Child-Pugh scale) and severe (more than 9 points on the Child-Pugh scale) liver failure, the use of Ezetrol is not recommended.
Side effects
In clinical studies with a duration of 8 to 14 weeks, in which 3366 patients were included, a good tolerability of Ezetrol was shown when taken at a dose of 10 mg / day as monotherapy or in combination with statins. The unwanted effects were mild and transient; The overall frequency of side effects and the frequency of drug withdrawal did not differ from those when taking a placebo. Patients taking Ezetrol as monotherapy (n = 1691) or in combination with a statin (n = 1675), in 1-10% of cases, the following undesirable effects associated with the action of the drug. In monotherapy with Ezetrol: headache, abdominal pain, diarrhea. In combination therapy with Ezetrol and a statin: headache, fatigue, abdominal pain, constipation, diarrhea, bloating, nausea, increased AST and ALT activity , myalgia. From the side of the lab -valued parameters: frequency of clinically significant increases in liver transaminases (ALT and / or ACT 3 or more times the ULN) was similar in monotherapy Ezetrolom (0.5%) and placebo (0.3%). In combination therapy, the frequency of a clinically significant increase in serum transaminases is 1.3% for patients taking Ezetrol along with a statin, and 0.4% for those taking a statin alone. Transaminase elevation is usually asymptomatic,is not accompanied by the development of cholestasis and passes both with continued treatment and after discontinuation of the drug. The frequency of occurrence of a clinically significant increase in CPK (≥10xHGN) in patients receiving Ezetrol as monotherapy was similar to this indicator in patients who received placebo or statin in monotherapy. When using Ezetrol in clinical practice, the following adverse reactions were noted: angioedema, skin rash, increased CPK, liver enzyme activity, hepatitis, thrombocytopenia, pancreatitis t, nausea, paresthesias; very rarely - myopathy, rhabdomyolysis.
Overdose
Several cases of overdose were reported, most of which were not accompanied by adverse reactions, and if they occurred, the adverse events were not serious. In clinical studies, in one of which 15 healthy volunteers were prescribed ezetimibe at a dose of 50 mg / day for 14 days, in another, 18 patients with primary hypercholesterolemia at a dose of 40 mg / day for 56 days were well tolerated. Treatment: in case of overdose, supportive and symptomatic therapy is carried out.
Interaction with other drugs
In preclinical studies, it was 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 by N-acetyltransferase,. ), glipizida, tolbutamida, midazolam and warfarin. Simultaneous administration of cimetidine with ezetimib does not affect the bioavailability of the latter. Simultaneous administration of antacid It 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 used simultaneously with Kolestiramine AUC, total ezetimibe (ezetimibe + ezetimibe-glucuronide) decreases by approximately 55%. An additional decrease in LDL-C LDL due to the addition of ezetimibe to colestiramine can be reduced by this interaction. In patients undergoing kidney transplantation, with CC more than 50 ml / min, constantly receiving cyclosporine, a single dose of Ezethrol in a dose of 10 mg was accompanied by an average 3.4-fold ( from 2.3 to 7.9 times) by increasing the AUC of ezetimibe.One patient who underwent kidney transplantation and with severe renal insufficiency (CC 13.2 ml / min / 1.73 m2), receiving complex therapy, including cyclosporine, showed a 12-fold increase in the concentration of ezetimibe, compared with the control group. In 12 healthy volunteers who received for 8 days ezetimibe at a dose of 20 mg / day concurrently with cyclosporine at a daily dose of 100 mg, on the 7th day an increase in cyclosporine AUC was found on average by 15% (from a decrease of 10% to an increase of 50%) compared with patients in whom cyclosporine was used as monotherapy at a dose of 100 mg / day. Simultaneous administration of fenofibrate or gemfibrozil increases the total concentration of ezetimibe approximately 1.5 and 1.7 times, respectively. However, this increase is not considered as clinically significant. The safety and efficacy of ezetimibe when used with fibrates has not been established. Fibrates can increase cholesterol secretion in bile, which can lead to gallstone disease. In preclinical studies on dogs, ezetimibe increased cholesterol levels in the gallbladder. Although the significance of this data for humans is unknown, the simultaneous administration of Ezetrol with fibrates before clinical trials is not recommended. When Ezetrol was taken simultaneously with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin and rosuvastatin, there was no clinically significant pharmacokinetic interaction.
special instructions
Before starting treatment, patients should switch to an appropriate lipid-lowering diet and continue to follow this diet during the entire period of therapy with Ezetrol. Note that if Ezetrol is prescribed together with lipid-lowering drugs of the statin class, you should carefully read the instructions for medical use of this statin. clinical trials with the simultaneous appointment of the drug Ezetrol and statins class drug patients had an increase in activity liver enzymes (3 times higher than VGN). When prescribing 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 did not exceed that compared with 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 trials, the incidence of CPK (≥10xHGN) was 0.2% in the Ezetrol group compared to 0.1% in the placebo group, and 0.1% in the Ezetrol combined-use group with a statin, compared to 0.4% in the statin monotherapy group. doses in excess of 10 mg in patients with moderate and severe hepatic insufficiency have not been studied, the prescription of Ezetrol is not recommended for such patients. Patients taking fenofibrate with Ezethrol should be warned of possible rice. the occurrence of gallstone disease and gallbladder disease. If the doctor suggests the possible development of these diseases, then therapy with Ezetrol should be discontinued. The safety and efficacy of prescribing ezetimibe in combination with other fibrates has not been established. Although the significance of this data for humans has not yet been established, the simultaneous administration of ezetimibe with fibrates is not recommended before obtaining additional data on the results of clinical studies. If it is necessary to administer Ezetrol with cyclosporine at the same time, you should take precautions and regularly monitor plasma concentrations of the latter.