Ezetimibe - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Other lipid-lowering agents

Included in the formulation

Lipbon®

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EGIS ZAO Pharmaceutical Plant Hungary

Ezetrol®

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Schering-Plau N. Labo. Belgium

АТХ:

C.10.A.X.09 Ezetimibe

Pharmacodynamics:

A hypolipidemic agent. Selectively inhibits the absorption of cholesterol and certain plant styrenes in the intestine.

When entering the small intestine ezetimibe localized in the brush border of the small intestine and prevents the absorption of cholesterol, which leads to a decrease in the intake of cholesterol from the intestine to the liver, thereby reducing its stock in the liver and increasing excretion from the blood. Ezetimibe does not increase the excretion of bile acids (as opposed to drugs that bind bile acids) and does not inhibit the synthesis of cholesterol in the liver (as opposed to statins).

By reducing the absorption of cholesterol in the intestine ezetimibe reduces the flow of it into the liver. Statins reduce the synthesis of cholesterol in the liver. Due to two different mechanisms of action, the preparations of these two classes, when co-administered, provide an additional reduction in cholesterol.

Clinical studies have shown that an elevated level of total cholesterol, LDL cholesterol and apolipoprotein-B (the main protein component of LDL) contributes to the development of atherosclerosis.In addition, a lower level of HDL cholesterol is associated with the development of atherosclerosis. Epidemiological studies have established that cardiovascular morbidity and mortality are directly related to the level of total cholesterol and LDL cholesterol and in inverse relationship to the level of HDL cholesterol. Like LDL, lipoproteins, rich in cholesterol and triglycerides, including VLDL, LLPP and remnants, can also contribute to the development of atherosclerosis.

In a series of preclinical studies it was shown that ezetimibe inhibits the absorption of 14C-cholesterol and does not affect the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, fat-soluble vitamins A and D.

Pharmacokinetics:

Prodrug. Absorption is fast (increases with simultaneous use with fatty meat) and is 35-60%. Biotransformation in the small intestine and liver with the formation of an active metabolite (ezetimibe glucuronide). The connection with plasma proteins is more than 90% (ezetimibe and its metabolite); In plasma 10-20% of ezetimibe and 80-90% of ezetimibe of glucuronide are determined. Half-life22 hoursElimination with feces (69-78% mainly in the form of ezetimibe) and kidneys (9-11% in the form of ezetimibe glucuronide). Undergoes intestinal-hepatic recirculation.

Indications:

Primary hypercholesterolemia (in combination with statins or as a monotherapy in addition to diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides, and to increase HDL cholesterol in patients with primary hypercholesterolemia); homozygous familial hypercholesterolemia (in combination with statins is recommended to reduce the elevated level of total cholesterol, LDL cholesterol, it is also possible to use LDL-apheresis); homozygous sitosterolemia (or phytosterolemia) - an elevated level of plant sterols in plasma at elevated or normal cholesterol levels and a normal triglyceride content.

ICD-10

IV.E70-E90.E78.1 Pure hyperglyceridemia

IV.E70-E90.E78.0 Pure hypercholesterolemia

IV.E70-E90.E78.2 Mixed hyperlipidemia

Contraindications:

Hypersensitivity; the use of ezetimibe in combination with statin in patients with active liver disease or an unexplained persistent elevation in the levelhepatic transaminases; use in patients with moderate to severe hepatic impairment (7-9 or more on the Child-Pugh scale); appointment simultaneously with fibrates. Ezetimibe Do not use in children and adolescents under the age of 18 years. Pregnancy and lactation.

Carefully:

Patients receiving ciclosporin.

Pregnancy and lactation:

Action category for the fetus by FDA - C. There are no clinical data on the use of ezetimibe in pregnant women. In case of pregnancy, the drug should be discontinued.

There are no data on the isolation of ezetimibe with breast milk in women. In studies on rats, it was found that ezetimibe excreted in breast milk. Concerning ezetimibe it is not recommended for use in nursing mothers.

Dosing and Administration:

Before and during treatment, patients must observe a lipid-lowering diet. The recommended dose as a monotherapy and in combination with statins is 10 mg once a day.

With concomitant therapy, fatty acid sequestrants ezetimibe apply in a dose of 10 mg 1 time per day no later than 2 hours before the reception of sequestrants of fatty acids or no earlier than 4 hours after their administration.

Side effects:

With monotherapy: headache, abdominal pain, diarrhea.

With combined therapy with statin: headache, fatigue, abdominal pain, constipation, diarrhea, bloating, nausea, increased activity of AST and ALT, myalgia.

From the side laboratory indicators: it is possible to increase ALT and / or ACT activity ≥ 3 x HNG (more often when combined with statin), increase creatine phosphokinase activity ≥ 10 x HNG.

When applying in clinical practice: possible angioedema, skin rash, increased creatine phosphokinase, hepatic enzymes, hepatitis, thrombocytopenia, pancreatitis, nausea, myalgia; very rarely - myopathy, rhabdomyolysis.

Overdose:

Symptoms: reported several cases of overdose, most of which were not accompanied by the occurrence of undesirable phenomena, and in the event of their occurrence, undesirable phenomena were not serious.

In clinical studies, one of which ezetimibe 15 healthy volunteers were given at a dose of 50 mg per day for 14 days, in the other 18 patients with primary hypercholesterolemia at a dose of 40 mg per day for 56 days showed good tolerability of the drug.

Treatment: symptomatic and supportive therapy.

Interaction:

Cyclosporine. In patients undergoing kidney transplantation, with creatinine clearance> 50 ml / min, who received ciclosporin in a constant dose, a single administration of ezetimibe at a dose of 10 mg resulted in an increase in the system exposure of ezetimibe by an average of 3.4 times (2.3 to 7.9 times). In one patient after kidney transplantation and with severe renal insufficiency (creatinine clearance 13.2 ml / min / 1.73 m2) receiving complex therapy, including ciclosporin, there was a 12-fold increase in the level of ezetimibe compared with the control group. 12 healthy volunteers received within 8 days ezetimibe at a dose of 20 mg / day simultaneously with cyclosporine at a dose of 100 mg / day on day 7, an increase in systemic exposure to cyclosporine was found to increase by an average of 15% (from a decrease of 10% to an increase of 51%) compared with patients in whom ciclosporin was used in monotherapy at a dose of 100 mg per day.

Caution should be exercised when prescribing ezetimibe to patients receiving ciclosporin, in connection with the increase in the exposure of both ezetimibe and cyclosporine. The concentration of cyclosporine should be controlled with the simultaneous administration of ezetimibe and cyclosporine.The degree of increase in ezetimibe exposure may be higher in patients with severe renal insufficiency.

Fibrates. The safety and effectiveness of ezetimibe in combination with fibrates has not been established. Fibrates can increase the secretion of cholesterol with bile, which can lead to cholelithiasis. In preclinical research on dogs ezetimibe increased the level of cholesterol in the gallbladder. Although the significance of this data is unknown to a person, simultaneous administration of ezetimibe with fibrates prior to clinical trials is not recommended.

Fenofibrate. In case of suspicion of cholelithiasis in a patient receiving ezetimibe and fenofibrate, it is required to conduct a study of the gallbladder and prescribe another lipid-lowering therapy.

Kolestyramin. Simultaneous reception reduces the average system exposure of total ezetimibe (ezetimibe + glucuronide ezetimibe) by approximately 55%. Additional reduction in LDL cholesterol level due to the addition of ezetimibe to colestyramine can be reduced by this interaction.

Coumarin anticoagulants.When prescribing ezetimibe, patients who are on warfarin therapy need prothrombin time monitoring.

Special instructions:

If ezetimibe is prescribed in combination with statin, you should carefully read the instructions for the medical use of a particular statin.

Enzymes of the liver. In controlled clinical trials with the simultaneous administration of ezetimibe and statin in patients, an increase in the level of hepatic enzymes (3 times higher than the upper limit of the norm) was observed. If ezetimibe is prescribed in combination with statin, liver function monitoring should be performed at the beginning of treatment and further in accordance with the recommendations for this statin. If the level of ALT and / or AST is more than 3 times higher than the upper limit of the norm, consideration should be given to the abolition of ezetimibe and / or statin.

In clinical trials, the incidence of myopathy or rhabdomyolysis associated with the use of ezetimibe did not exceed that of the corresponding control group (placebo or statin). The risk of toxicity to skeletal muscle increases in the following cases: high doses of statin, age over 65, hypothyroidism, impaired renal function,and also depends on the particular statin used and the simultaneous use of other drugs. If suspected to develop myopathy or rhabdomyolysis, ezetimib and statin therapy should be discontinued immediately.

Instructions

Ezetimibe (Ezetimibum)