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

Active substanceEzetimibeEzetimibe

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Lipbon®

pills inwards

EGIS ZAO Pharmaceutical Plant Hungary

Ezetrol®

pills inwards

Schering-Plau N. Labo. Belgium

Dosage form: & nbsppills

Composition:

Composition on 1 tablet:

Active substance: ezetimibe 10 mg.

Excipients: microcrystalline cellulose 30.3 mg, mannitol 30.3 mg, croscarmellose sodium 19.0 mg, low-substituted giprolose 10.0 mg, povidone-K25 5.0 mg, sodium lauryl sulfate 4.4 mg, magnesium stearate 1.0 mg.

Description:

The oblong flat tablets are white or almost white in color, engraved with a stylized letter E and number 611 on one side of the tablet, with little or no odor.

Pharmacotherapeutic group:The lipid-lowering agent is an inhibitor of cholesterol absorption

ATX: & nbsp

C.10.A.X.09 Ezetimibe

Pharmacodynamics:

Ezetimibe is the representative of a new class of lipid-lowering agents that selectively inhibit the absorption of cholesterol (cholesterol) and certain plant styrenes in the intestine.

Mechanism of action

Lipobon ® is effective for oral administration. The mechanism of action of ezetimibe differs from the mechanism of action of other classes of lipid-lowering agents (for example, inhibitors of HMG-CoA reductase (statins), bile acid sequestrants, fibrates and plant styrenes). The target molecule of the drug ezetimibe is a sterol transporter (Niemann-Pick C1-Like, NPC1L1), responsible for the absorption of sterols and phytosterols in the small intestine.

Ezetimibe is localized in the brush border of intestines Carr and prevents the absorption of cholesterol, leading to a reduction of intestinal cholesterol proceeds in the liver, thereby reducing cholesterol reserves in the liver and enhanced excretion of blood cholesterol. Ezetimibe does not enhance the excretion of bile acids (as opposed to drugs that bind bile acids) and does not inhibit the synthesis of cholesterol in the liver (in contrast to statins). Statins reduce the synthesis of cholesterol in the liver. Due to two different mechanisms of action, the preparations of these two groups, when co-administered, provide an additional reduction in the concentration of cholesterol.

Pharmacodynamic effects

Ezetemib in combination with a statin reduces the concentration of total cholesterol (TC), low density lipoprotein cholesterol (LDL), apolipoprotein B (apo-B), and triglycerides (TG) and increases the concentration of cholesterol in high density lipoprotein (HDL) in hypercholesterolemic patients greater than ezetimibe or simvastatin, appointed separately.

Clinical efficacy and safety

Clinical studies have shown that increased concentrations of OX, LDL cholesterol and apo-B, the main protein component of LDL, contribute to the development of atherosclerosis. In addition, a reduced concentration of LDL cholesterol is associated with the development of atherosclerosis. The results of the research have established that cardiovascular morbidity and mortality rates are directly related to the concentrations of OX and LDL cholesterol and in inverse relationship to the concentration of HDL cholesterol. Like LDL, lipoproteins rich in cholesterol and TG, including very low-density lipoproteins (VLDL), intermediate-density lipoproteins (ALTs), and remnants, can also contribute to the development of atherosclerosis.

To determine the selectivity of ezetimibe against inhibition of suction of cholesterol, a series of preclinical studies was performed.

Ezetimibe inhibited absorption [¹⁴C] cholesterol and had no effect on the absorption of TG, fatty acids, bile acids, progesterone, ethinyl estradiol and fat-soluble vitamins.

Pharmacokinetics:

Suction

After oral administration ezetimibe rapidly absorbed and intensively metabolized in the small intestine and liver into pharmacologically active phenolic glucoronide (ezetimibe-glucuronide). Maximum concentration in blood plasma (C_max) ezetimib-glucuronide is observed after 1-2 hours, ezetimibe - after 4-12 hours. Absolute bioavailability of ezetimibe can not be determined, since this compound is practically insoluble in water. Simultaneous intake of food (both oily and non-fatty) does not affect the bioavailability of ezetimibe when taken inside the drug at a dose of 10 mg. Lipbon can be used regardless of the time of meal.

Distribution

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

Metabolism

The primary metabolism of ezetimibe occurs in the small intestine and liver by conjugation with glucuronide (a phase II reaction), followed by isolation with bile. Minimal oxidative metabolism (reaction of the I phase) was observed at all stages of ezetimibe transformation. Ezetimibe and ezetimib-glucuronide, the main derivatives of the drug, are 10-20% and 80-90% of the total concentration of ezetimibe in the blood plasma, respectively. Ezetimibe and ezetimib-glucuronide are slowly removed from the blood plasma during intestinal hepatic recirculation. Half-life (T_1/2) for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Excretion

After ingestion of 20 mg of ezetimibe labeled ¹⁴C, 93% of the total ezetimibe from the total concentration of radioactive products was detected in the blood plasma. Approximately 78% and 11% of appropriately taken radioactive products were excreted through the intestine and kidneys within 10 days. After 48 hours no radioactive products were detected in the blood plasma.

Pharmacokinetics in specific patient groups

Children

Absorption and metabolism of ezetimibe in children, adolescents (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 do not differ. Pharmacokinetic data for children under 10 years are absent.

The clinical experience of using ezetimibe in children and adolescents (9-17 years) is limited to observations of patients with homozygous and heterozygous familial hypercholesterolemia and sitosterolemia.

Elderly patients

In elderly patients (over 65 years of age), the total ezetimibe concentration in the blood plasma is approximately 2 times higher than in young patients (18 to 45 years of age).The degree of decrease in LDL cholesterol concentration and the safety profile are comparable in elderly and young patients who received ezetimibe.

Patients with hepatic insufficiency

After a single dose of 10 mg ezetimibe, the average area under the concentration-time curve (AUC) for total ezetimibe in patients with mild liver failure (5-6 on the Child-Pugh scale) was approximately 1.7 times higher compared with that of healthy volunteers. In a 14-day study of ezetimibe at a dose of 10 mg per day in patients with moderate hepatic insufficiency (7-9 on the Child-Pugh scale), the mean AUC for total ezetimibe increased 4-fold at day 1 and day 14 compared with those in patients with preserved liver function.

For patients with mild hepatic insufficiency, dose adjustment is not required. Since the consequences of an increased concentration of total ezetimibe are unknown, ezetimibe is not recommended for patients with moderate to severe hepatic impairment (more than 9 on the Child-Pugh scale) (see "With caution").

Patients with renal insufficiency

After a single administration of ezetimibe at a dose of 10 mg in patients with severe impairment of function of the nightsn= 8; Creatinine clearance (CC) less than 30 ml / min / 1.73 m²). AUC for total ezetimibe increased approximately 1.5-fold compared to healthy volunteers (n = 9). This result is not clinically significant. The choice of a dose for patients with impaired renal function is not required.

Floor

The total concentration of ezetimibe is slightly higher (less than 20%) in women than in men. The level of LDL-lowering and the safety profile are approximately the same for men and women taking ezetimibe.

Indications:

Primary hypercholesterolemia

Lipobon® is prescribed in monotherapy (as an adjunct in addition to diet) or in combination with statins in addition to diet in patients with primary (heterozygous familial and non-family) hypercholesterolemia.

Homozygous familial hypercholesterolemia

Lipobon® in combination with statin is recommended to reduce elevated concentrations of OX and LDL cholesterol in patients with homozygous familial hypercholesterolemia. Patients may also receive supportive treatment (eg, LDL-apheresis).

Contraindications:

- Hypersensitivity to any of the components of the drug.

- When prescribing Lipobon® in combination with statin for contraindications, instructions for the administration of the prescribed statin should be followed.

- The use of Lipobon® in combination with statin is contraindicated in pregnancy and breastfeeding.

- Lipobon® is not recommended for patients with moderate to severe hepatic impairment (7-9 or more on the Child-Pugh scale - see the sections "Pharmacokinetics", "Dosage and Administration").

- Lipobon® in combination with statin is contraindicated in patients with active liver disease or with unexplained increased activity of liver transaminases.

- Children under 18 years.

- Lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Carefully:

When Lipobon® is prescribed to patients receiving ciclosporin, indirect anticoagulants (including warfarin and fluindione) caution should be used (see section "Interaction with other drugs").

Simultaneous administration of Lipobon® with fibrates until additional data are available from clinicalresearch is not recommended.

Pregnancy and lactation:

There are no clinical data on the use of ezetimibe during pregnancy. Therefore, the use of Lipobon® in pregnancy is not recommended. When diagnosing pregnancy, Lipobon® should be discontinued. With the simultaneous use of Lipobon® and statin, instructions for the use of this statin should be followed.

There is no data on the isolation of ezetimibe with breast milk. In this regard, Lipobon® is not recommended for use in nursing mothers. If the drug is necessary, the patient should stop breastfeeding.

Dosing and Administration:

Before starting treatment, patients should proceed to the appropriate hypocholesterolemic diet and continue to follow this diet during the entire period of therapy with Lipobon®.

The drug is taken orally, at any time of the day, regardless of the time of ingestion. The recommended dose of Lipobon® in monotherapy or in combination with statin is 10 mg once a day.

In elderly patients

Dosage for elderly patients is not required.

With hepatic insufficiency

Dosing for patients with mild liver failure (5-6 points on the Child-Pugh scale) is not required. Lipobon® is not recommended for patients with moderate (7-9 points on the Child-Pugh scale) and severe (more than 9 on the Child-Pugh scale) impaired liver function (see sections "Pharmacokinetics" and "Contraindications").

With renal insufficiency

The selection of doses for patients with impaired renal function is not required (see the section "Pharmacokinetics").

With concomitant therapy with bile acid sequestrants

The drug Lipobon® should be taken at a dose of 10 mg 1 time per day no later than 2 hours before and no earlier than 4 hours after taking the sequestrants of fatty acids.

Side effects:

In clinical studies lasting from 8 to 14 weeks, in which 3366 patients were included, ezetimibe at a dose of 10 mg per day in monotherapy or in combination with statin showed good tolerability. Undesirable affects were usually mild and transient. The overall incidence of adverse events and the frequency of discontinuation due to adverse effects with ezetimibe did not differ from those for placebo.

Undesirable reactions are described below in organ systems and frequency. Frequency of collateral

effects is given in accordance with the following scale according to the classification of the World

health organizations:

very often: ≥ 1/10:

often: ≥ 1/100 - <1/10:

infrequently: ≥ 1/1000 - <1/100;

rarely: ≥ 1 / 10000- <1/1000;

very rarely, including individual cases: <1/10000.

In patients who took ezetimibe in mop therapy, the most frequent were the following undesirable effects: headache, fatigue, abdominal pain, diarrhea, flatulence.

In patients who took ezetimibe in monotherapy, infrequently met: dyspepsia, gastroesophageal reflux, cough, "flushes" of blood to the skin of the face, increased blood pressure, pain in the neck. pain, increased activity of gamma-glutamyltransferase, a violation of liver function.

In patients who took ezetimibe in combination therapy with statins, the most often observed the following adverse effects: headache, myalgia, increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT).

In patients who took ezetimibe in combination therapy with stati, we rarely met: gastritis, pain in the extremities, asthenia, peripheral edema.

When combining ezetimibe with fibrates, the abdominal pain was most often observed. Laboratory indicators

The frequency of a clinically significant increase in the activity of enzymes in the serum of ALT and / or ACT, 3 or more times higher than the upper limit of the norm (VGN), was similar in the appointment of the ezetimnba in monotherapy (0.5%) and placebo (0.3%). When studying the safety of combination therapy, the rate of clinically significant increase in serum enzymes was 1.3% in patients taking ezetimibe in combination with statin, and 0.4% in patients taking statin in monotherapy. The increase in enzyme activity in serum was usually asymptomatic, but was accompanied by the development of cholestasis and passed both during the continuation of treatment and after the drug was discontinued.

The incidence of a clinically significant increase in creatine phosphokinase (CKF) activity (≥10 × WGH) in patients who received ezetimibe in monotherapy, was similar to this indicator in patients who received placebo or statin in monotherapy.

Post-marketing clinical experience

With the use of ezegimib in clinical practice, the following adverse reactions have been reported: hypersensitivity reactions, including angioedema and skin rash; myalgia; increase in the activity of enzymes CK, ACT, ALT; hepatitis; thrombocytopenia; pancreatitis; nausea; paresthesia; myopathy / rhabdomyolysis.

Causal relationship with the occurrence of depression, cholelithiasis, cholecystitis, erythema multiforme during the post-marketing clinical experience with the use of ezetimibe has not been established.

Overdose:

Several cases of overdose have been reported, most of which have not been associated with the occurrence of adverse events, and in the event of their occurrence, adverse events have not been serious.

In clinical studies, one of which ezetimibe 15 healthy volunteers were given 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 of the drug.

In case of an overdose, symptomatic and supportive therapy should be given.

Interaction:

In preclinical studies it was shown that ezetimibe does not induce cytochrome P450 isofermites involved in the metabolism of drugs (LS). Between ezetimibe and drugs metabolized by isozymes CYP1A2, CYP2D6, CYP2C8 / 9 and CYP3A4 or Nacetyltransferase, clinically significant pharmacokinetic interactions were not observed.

Ezetimibe with simultaneous administration 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 ezetimibe.

Antacids: simultaneous administration of antacids reduces the rate of absorption of ezetimibe, but does not affect its bioavailability. This decrease in the rate of absorption is not considered to be clinically significant.

Kolestyramine: simultaneous reception of colestyramine reduces the average AUC of total ezetimibe (ezetimibe + glucuronide ezetimibe) by approximately 55%. Additional reduction in LDL cholesterol concentration due to the addition of ezetimibe to colestyramine can be reduced by this interaction.

Cyclosporin

In patients who underwent kidney transplantation, with KK> 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 AUC ezetimibe averaged 3.4 times (2.3 to 7.9 times), compared with healthy volunteers in the control group from another study who received ezetimibe as a monotherapy (n= 17). In one patient after kidney transplantation and with severe renal insufficiency (KK 13.2 ml / min / 1.73 m²), who received complex therapy, including ciclosporin, there was a 12-fold increase in the concentration of ezetimibe compared with the control group. 12 healthy volunteers received within 8 days ezetimibe in a dose of 20 mg / day simultaneously with cyclosporine at a dose of 100 mg / day on the 7th day, an increase AUC cyclosporine an average of 15% (from a decrease of 10% to an increase of 51%) compared with patients in whom ciclosporin was used in monotherapy in a dose of 100 mg / day.

Fibrates

Patients receiving fenofibrate along with ezetimibe, should be warned about the possible risk of gallstone disease (CHD) and gallbladder disease. If the doctor assumes the possible development of the aforementioned diseases in the patient, Lipobon® therapy should be discontinued.

Simultaneous reception of fenofibrate or gemfibrozil increases the total concentration of ezetimibe by approximately 1.5 and 1.7 times, respectively.However, these increases are not considered clinically significant.

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 LAD. In preclinical research on dogs ezetimibe increased the concentration of cholesterol in the gallbladder. Although the significance of these data for a person has not yet been established / found, simultaneous administration of ezetimibe with fibrates to obtaining additional data from the results of clinical studies is not recommended.

Statins

With the simultaneous administration of ezetimibe with atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin and rosuvastatin, clinically significant pharmacokinetic interactions were not observed.

Anticoagulants

With the simultaneous administration of ezetimibe with warfarin, with other anticoagulants derived from coumarin or with fluinidone, it is necessary to carefully monitor the international normalized ratio

Special instructions:

Before starting treatment, patients should switch to the appropriate gynocholesterolemic diet and continue to follow this diet during the entire period of therapy with Lipobon®.

If Lipobon® 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 simultaneous prescription of ezetimibe and statin in patients, an increase in activity of "hepatic" enzymes (3 times higher than UGN) was observed. If ezetimibe is prescribed in combination with statin, the control of liver function should be performed at the beginning of treatment and further in accordance with the recommendations for this statin (see section "Side effect").

Skeletal musculature

In clinical postmarketing studies, cases of myopathy and rhabdomyolysis were observed. The incidence of myopathy or rhabdomyolysis associated with the use of ezetimibe did not exceed that in comparison with the corresponding control group (placebo or statin). However, myopathy and rhabdomyolysis are known undesirable reactions of statins and other gynolipidemics. In clinical studies, the frequency of increase in activity of CK, more than 10 times higher than HHV, was 0.2% in the group of ezetimibe compared with 0.1% in the placebo group,and 0.1% in the combination group of ezetimibe with statin versus 0.4% in the statin monotherapy group (see "Side effect").

Before starting treatment with Lipobon®, the doctor should warn the patient about the risk of developing myopathy and rhabdomyolysis and that the patient should inform the doctor of any unexplained muscle pain, tenderness and weakness.

Liver failure

Since the effect of doses of ezetimibe exceeding 10 mg in patients with moderate and severe degree of hepatic insufficiency has not been studied, the appointment of ezetimibe to such patients is not recommended (see the sections "Pharmacokinetics" and "Contraindications").

Fibrates

Patients receiving fenofibrate together with ezetimibe, should be warned about the possible risk of developing CLD and gallbladder disease. If the doctor assumes the possible development of the aforementioned diseases in the patient, Lipobon® therapy 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 is not yet established for the human (it has been clarified that the simultaneous administration of ezetimibe with fibrates to obtaining additional data from the results of clinical trials is not recommended.sections "Interaction with other medicines" and "With care").

Cyclosporin

When prescribing ezetimibe to patients receiving ciclosporin, you should follow the precautionary measures. With the simultaneous administration of ezetimibe and cyclosporine, regular monitoring of the plasma cyclosporine concentration is required (see sections "With caution", "Interaction with other drugs").

Effect on the ability to drive transp. cf. and fur:

Studies to study the effect of the drug on the ability to drive vehicles and mechanisms were not conducted. Care must be taken when driving vehicles and working with machinery (risk of dizziness).

Form release / dosage:

Tablets 10 mg.

Packaging:

For 10 tablets in a blister of the combined film "cold"(polyamide / aluminum foil / PVC) // aluminum foil, 3, 6 or 9 blisters in a cardboard pack together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002929

Date of registration:24.03.2015 / 07.08.2015

Expiration Date:24.03.2020

The owner of the registration certificate:EGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Manufacturer: & nbsp

NOBEL ILAC SANAYII VE TICARET, A.S. Turkey

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp10.04.2018

Illustrated instructions

Instructions

Lipbon® (Lipobon®)