Ezetrol, pills 10mg, 28pcs

Composition

1 tablet contains:

Active ingredient:  

ezetimibe 10 mg;

Auxiliary substances:  

croscarmellose sodium; 

lactose monohydrate;

magnesium stearate;

microcrystalline cellulose;

povidone;

sodium lauryl sulfate.

Pharmacological action

EZETROL is a selective representative of a new class of lipid-lowering drugs that reduce the absorption of cholesterol (CL) in the intestine, including CL of vegetable fats.

The mechanism of action of Ezetrol differs from the mechanism of action of other classes of lipid-lowering agents (for example, statins, bile acid sequestrants, fibrates). Unlike bile acid sequestrants, Ezetimibe does not increase bile acid excretion and does not inhibit CL synthesis in the liver, unlike statins.

When administered to the small intestine, Ezetimibe is localized at the border of the small intestine brush and slows down the absorption of CL, which leads to a decrease in the intake of CL from the intestine to the liver.

After 2 weeks of use, EZETROL reduces intestinal absorption of CL by 54% compared to placebo.

Pharmacokineticsabsorption

After oral use, ezetimibe is rapidly absorbed and intensively conjugates in the small intestine and liver with pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). The maximum plasma concentration (Cmax) is observed after 1-2 hours for ezetimibe-glucuronide and after 4-12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined, since this compound is practically insoluble in water.

Concomitant intake of food (both high-fat and low-fat) does not affect the bioavailability of ezetimibe when taken orally. EZETROL can be taken both during and between meals.

Distribution

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

Metabolism

Ezetimibe is mainly metabolized in the small intestine and liver by conjugation with glucuronide (phase II reaction), followed by biliary excretion. Minimal oxidative metabolism (phase I reaction) is observed at all stages of Ezetimibe transformation. Ezetimibe and ezetimibe-glucuronide are the main substances detected in blood plasma, and make up approximately 10-20% and 80-90% of the total drug content in plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma, and enterohepatic recirculation occurs.

The half-life (T 1/2) of ezetimibe and ezetimibe glucuronide is approximately 22 hours.

Deduction

Approximately 78% and 11% of the total dose taken is excreted in the faeces and urine, respectively, over a 10-day period.

Indications

-high cholesterol in the blood;- coronary heart disease; – atherosclerosis.

Use during pregnancy and lactation

Animal studies with ezetimibe did not reveal any direct or indirect adverse effects on pregnancy, embryo/fetus development, labor, or postnatal development. No teratogenic effects were observed when ezetimibe was administered to pregnant rats in combination with lovastatin, simvastatin, pravastatin or atorvastatin. When administered to pregnant rabbits, fetal skeletal defects were observed with a small frequency.

There are no clinical data on the use of Ezetrol during pregnancy. Therefore, the use of Ezetrol during pregnancy is not recommended. In case of pregnancy, Ezetrol should be discontinued.

In rat studies, ezetimibe was found to be excreted in breast milk. There are no data on the excretion of ezetimibe in breast milk in women. In this regard, Ezetrol is not recommended for use in nursing mothers. If the use of the drug is necessary, the patient should stop breastfeeding.

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 under 18 years of age;- hypersensitivity to any of the components of the drug.

When prescribing Ezetrol in combination with a statin to control contraindications, follow the instructions for using the prescribed statin.

Caution should be exercised when prescribing the drug to patients receiving cyclosporine; concomitant use with fibrates until additional data from clinical studies are obtained is not recommended.

Side effects

In clinical trials lasting from 8 to 14 weeks, which included 3366 patients, Ezetrol, administered at a dose of 10 mg per day in monotherapy or in combination with a statin, showed good tolerability.

Adverse effects were usually mild and transient; the overall frequency of side effects and the frequency of treatment discontinuations due to undesirable effects with Ezetrol did not differ from those with placebo.

In patients taking Ezetrol alone (n=5691) or in combination with a statin (n=1675), the most common (≥1/100,

Ezetimibe motor therapy: headache, abdominal pain, diarrhea.

Combination therapy with statin: headache, fatigue, abdominal pain, constipation, diarrhea, bloating, nausea, increased ALT and ACT, myalgia.

Laboratory parameters: the frequency of clinically significant increases in serum ALT and/or ACT enzymes 3 or more times higher than the upper limit of normal (ULN) was similar with Ezetrol alone (0.5%) and placebo (0.3%).

When studying the safety of combination therapy, the frequency of clinically significant increases in serum enzymes was 1.3% in patients taking Ezetrol in combination with a statin and 0.4% in patients taking statin alone.

The increase in serum enzymes was usually asymptomatic, was not accompanied by the occurrence of cholestasis, and passed both with continued treatment and after discontinuation of the drug.

The incidence of a clinically significant increase in creatine phosphokinase (CPK – ≥10×ULN) in patients receiving Ezetrol alone was similar to that in patients receiving placebo or statin alone.

Clinical experience of application

When using Ezetrol in clinical practice, the following adverse reactions have been reported: hypersensitivity reactions, including angioedema and skin rash; myalgia; increased CPK, liver enzymes, hepatitis, thrombocytopenia, pancreatitis, nausea. Very rarely-myopathy/rhabdomyolysis.

Interaction

Preclinical studies have shown that ezetimibe does not induce cytochrome P450 enzymes involved in drug metabolism. No clinically significant pharmacokinetic interactions were observed between ezetimibe and agents metabolized by cytochromes P4501A2,2D6,2C8,2C9 and ZA4 or N-acetyltransferase.

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

Antacids: concomitant use reduces the rate of absorption of ezetimibe, but does not affect its bioavailability. This decrease in the rate of absorption is not considered clinically significant.

Cholestyramine: concomitant use reduces the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) by approximately 55%. An additional reduction in LDL cholesterol due to the addition of ezetimibe to cholestyramine can be reduced by this interaction.

Cyclosporine: in kidney transplant patients with creatinine clearance >50 ml / min and treated with cyclosporine at a constant dose, a single dose of 10 mg of Ezetrol resulted in an increase in the AUC of Ezetrol by an average of 3.4 times (from 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), who received complex therapy, including cyclosporine, there was a 12-fold increase in the level of Ezetrol compared to the control group. In 12 healthy volunteers treated for 8 days ezetimibe at a dose of 20 mg / day concurrently with cyclosporine at a dose of 100 mg per day at day 7 revealed an increase in AUC of cyclosporine by 15% (from a decline of 10% to an increase of 51%) compared with patients in whom cyclosporine was used in monotherapy in a dose of 100 mg/day.

Fibrates: simultaneous reception of phenofibrate or gemfibrozil increases the total concentration ezetimibe approximately 1.5 and 1.7 times, respectively. However, these increases are not considered clinically significant.

The safety and efficacy of ezetimibe in combination with fibrates has not been established. Fibrates can increase the excretion of cholesterol in the bile, which can lead to gallstone disease. In a preclinical study in dogs, ezetimibe increased the level of cholesterol in the gallbladder. Although the significance of these data for humans is unknown, concomitant use of ezetimibe with fibrates prior to clinical trials is not recommended.

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

How to take it, course of use and dosage

Inside, at any time of the day, regardless of food intake.

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 Ezetrol®.

The recommended dose of Ezetrol in monotherapy or in combination with a statin is 10 mg once a day.

No dose adjustment is required for elderly patients (see “Pharmacokinetics”).

In case of liver failure

No dose adjustment is required for patients with mild hepatic insufficiency (Child-Pugh score 5-6). Treatment with ezetimibe is not recommended in patients with moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) liver dysfunction (see “Pharmacokinetics” and “Contraindications”).

In case of kidney failure

No dose adjustment is required for patients with impaired renal function (see “Pharmacokinetics”).

Concomitant therapy with fatty acid sequestrants

Ezetrol should be taken at a dose of 10 mg once a day no later than 2 hours before or no earlier than 4 hours after taking fatty acid sequestrants.

Overdose

Symptoms: Several cases of overdose have been reported, most of which were not associated with the occurrence of adverse events, and if they occurred, the adverse events were not serious.

In clinical trials, in one of which ezetimibe was administered to 15 healthy volunteers at a dose of 50 mg per day for 14 days, in the other-to 18 patients with primary hypercholesterolemia at a dose of 40 mg per day for 56 days, good tolerability of the drug was demonstrated.

Treatment: symptomatic and supportive therapy.

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.

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

Liver Enzymes

In controlled clinical trials with simultaneous use of Ezetrol and statin, patients showed an increase in liver enzymes (3 times higher than the upper limit of normal). If Ezetrol is given in combination with a statin, liver function monitoring should be performed at the beginning of treatment and then in accordance with the recommendations for this statin.

Skeletal musculature

In clinical trials, the incidence of myopathy or rhabdomyolysis associated with the use of Ezetrol did not exceed that in comparison with the corresponding control group (placebo or statin). However, myopathy and rhabdomyolysis are known adverse reactions of statins and other lipid-lowering agents. In clinical trials, the frequency of increased CPK activity, more than 10 times higher than the ULN, was 0.2% in the Ezetrol group compared to 0.1% in the placebo group, and 0.1% in the Ezetrol-statin combination group compared to 0.4% in the statin monotherapy group.

Liver failure

Since the effect of ezetimibe doses exceeding 10 mg in patients with moderate to severe hepatic insufficiency has not been studied, Ezetrol is not recommended for such patients.

Fibrates

The safety and efficacy of ezetimibe in combination with fibrates has not been established. Therefore, concomitant use of Ezetrol and fibrates is not recommended.

Cyclosporine

Precautions should be taken when prescribing ezetimibe to patients receiving cyclosporine. Cyclosporine concentrations should be monitored when Ezetrol and cyclosporine are co-administered.

Form of production

Tablets

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

2 years

Active ingredient

Ezetimibe

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Prevention of heart attacks and strokes, Atherosclerosis