Inedzhi

General characteristics. Structure:

Active ingredients: 10 mg of an ezetimib, 10 mg, 20 mg, 40 mg or 80 mg of a simvastatin.

Excipients: lactoses monohydrate, cellulose microcrystallic, gipromelloza of 2910 6 cps, croscarmellose sodium, citric acid monohydrate, butylhydroxyanisole, propyl gallate, magnesium stearate.

Pharmacological properties:

Pharmacodynamics. The combined hypolipidemic drug which reduces absorption of cholesterol and related vegetable sterol in intestines and also suppresses endogenous synthesis of cholesterol.

Drug contains эзетимиб and симвастатин, two hypolipidemic components supplementing each other with the mechanism of action.

Cholesterol comes to a blood plasma as a result of intestinal absorption and endogenous synthesis. Inedzhi reduces the increased level of general Hs, LPNP, apolipoproteins B (Aro In), TG and lipoproteins of low density (ne-LPVP), and increases level by double inhibition: absorption and synthesis of cholesterol.

Эзетимиб. The mechanism of action of an ezetimib differs from other classes of hypolipidemic means (for example, statines, sekvestrant of bile acids, fibrat).

Эзетимиб at receipt in a small intestine slows down cholesterol absorption that leads to reduction of intake of cholesterol from intestines in a liver.

After 2-week use эзетимиб reduces absorption of cholesterol in intestines by 54% in comparison with placebo.

A number of preclinical trials of an ezetimib confirms its selectivity in decrease in absorption of cholesterol. Эзетимиб slows down 14C-cholesterol absorption, and does not affect absorption of TG, fatty acids, bile acids, progesterone, ethinylestradiol, or fat-soluble vitamins A and D in any way.

Simvastatin. After intake in the form of an inactive lactone, симвастатин is exposed to hydrolysis with education corresponding R-hydroxyacid derivative, having the high inhibiting activity concerning GMG-KOA-reduktazy. This enzyme starts an initial and most significant stage of biosynthesis of cholesterol - conversion GMG-KOA in мевалонат.

Simvastatin reduces as raised, and the LPNP normal levels. LPNP are formed of LPONP and are exposed to splitting preferential by means of a high-affine LPNP-receptor. Decrease in LPNP after reception of a simvastatin leads to reduction of maintenance of LPONP and activation of LPNP-receptors that leads to reduction of education and strengthening of a catabolism of LPNP. At therapy simvastatiny the level of Ares also decreases. Besides, симвастатин moderately increases the LPVP level and reduces blood plasma TG. As a result of these changes the level of the general cholesterol and LPNP decrease.

Pharmacokinetics. Эзетимиб. Absorption. After intake эзетимиб it is quickly soaked up and intensively conjugates in pharmacological active phenolic glucuronide (ezetimib-glucuronide).

Cmax of an ezetemib in a blood plasma after administration of drug is inside reached in 4-12 h. Absolute bioavailability of an ezetimib cannot be defined since it is insoluble in one of the water solvents used for injections.

Meal (with the low or high content of fat) does not influence bioavailability of an ezetimib at intake, in particular in the form of tablets of 10 mg.

Simvastatin. Bioavailability of R-hydroxyacid after reception of a simvastatin inside makes less than 5% of a dose. In addition to R-hydroxyacid in a blood plasma 4 more active metabolites are found.

Meal does not exert impact on plasma concentration of active and general metabolites of a simvastatin.

Distribution. Эзетимиб. Эзетимиб and an ezetimib-glucuronide contact proteins of a blood plasma for 99.7% and 88-92% respectively.

Simvastatin. Simvastatin and R-hydroxyacid contact proteins of a blood plasma for 95%.

Pharmacokinetic researches showed what симвастатин does not collect in fabrics after reception of repeated doses. The maximum level of metabolites in a blood plasma is observed in 1.3-2.4 h after administration of drug.

Metabolism. Эзетимиб. Primary metabolism of an ezetimib happens in a small intestine and a liver by conjugation to a glucuronide (reaction of the II phase), to the subsequent allocation with bile. The minimum oxidizing metabolism (reaction of Ifazy) was observed at all stages of transformation of an ezetimib. Эзетимиб and the ezetimib-glucuronide, the main derivatives of drug, make 10-20% and 80-90% of the general content of drug in a blood plasma respectively. Эзетимиб and an ezetimib-glucuronide are slowly brought out of a blood plasma in the course of enterohepatic recirculation.

T1/2 for an ezetimib and an ezetimib-glucuronide makes about 22 hours.

Simvastatin. Is an inactive lactone which is quickly hydrolyzed by in vivo in the corresponding R-hydroxyacid, powerful inhibitor of HMG-CoA reductase. Hydrolysis generally happens in a liver; hydrolysis speed in a blood plasma very low. Simvastatin is well soaked up and almost completely metabolized already at "the first passing" through a liver. Capture of a simvastatin a liver is defined by the speed of a hepatic blood-groove. The main metabolism happens in a liver, metabolites of drug are removed with bile. Therefore amount of active agent in a system blood-groove very insignificant.

Removal. Эзетимиб. After intake of 20 mg of an ezetimib, marked 14C, in a blood plasma 93% of a total ezetimib of the general level of radioactive products were revealed. About 73% and 11% according to the accepted radioactive products are removed through intestines and kidneys within 10 days. In 48 h radioactive products in a blood plasma it was revealed not.

Simvastatin. During 96 h after intake of a radioactive simvastatin, 13% of radioactive products 60% - through intestines were removed by kidneys, and. Later in/in introductions of a metabolite of R-hydroxyacid only 0.3% were removed by kidneys in the form of metabolites.

Pharmacokinetics in special clinical cases. Children. Pharmacokinetic data, absorption and metabolism of an ezetimib are identical at children / teenagers (10-18 years) and adults. At children 10 years are younger than data on drug pharmacokinetics is not present. The clinical use of drug in pediatric practice (children and teenagers have 9-17 years) is limited to data on patients with a homozygous family hypercholesterolemia (GOSG) or a homozygous sitosterinemiya (hyper - апо - beta lipoproteinemiyey).

Patients of advanced age. At elderly patients (65 years are more senior) concentration of the general ezetimib in a blood plasma approximately twice higher, than at younger patients (18-45 years). Level of decrease in LPNP and profiles of safety at the elderly and younger patients accepting эзетимиб are approximately identical.

Patients with a liver failure. After a single dose of an ezetimib of 10 mg average AUC value for the general ezetimib in 1.7 was higher at patients with a slight liver failure (5-6 points on a scale of Chayld-Pyyu), than at patients with the kept function of a liver. In a 14-day research of an ezetimib in a dose of 10 mg/days with participation of patients with a moderate liver failure (I Drink 7-9 points on a scale of Chayld-) average AUC value for the general ezetimib increased by 4 times for the 1st and 14th day in comparison with patients with the kept function of a liver.

For patients with a slight liver failure of dose adjustment it is not required. As effects of the increased concentration of a total ezetimib are unknown, эзетимиб is not recommended to patients with moderate and heavy (more than 9 points on a scale of Chayld-Pyyu) a liver failure.

Patients with a renal failure. Эзетимиб. After a single dose in an ezetimib of 10 mg average AUC at patients with a heavy renal failure (average KK less than 30 ml/min. / 1.73 sq.m) increased by 1.5 times in comparison with healthy patients.

Simvastatin. In a research of patients with a heavy renal failure (KK less than 30 ml/min.) after reception of inhibitors of HMG-CoA reductase the general concentration of metabolites of a simvastatin was twice higher, than at healthy volunteers.

Floor. The general concentration of an ezetimib is a little higher (20%) at women, than at men. Level of decrease in LPNP and profiles of safety are approximately identical at the men and women accepting эзетимиб.

Indications to use:

— primary hypercholesterolemia: heterozygous (family and single) a hypercholesterolemia or the mixed lipidemia (as addition to a diet for the purpose of decrease in level of the general cholesterol, LPNP, apolipoprotein V, TG, lipoproteins of low density, for increase in the LPVP level);

— homozygous family hypercholesterolemia: for decrease in the increased level of the general cholesterol and LPNP (as as additional treatment to other hypolipidemic therapy, for example, to LPNP-aferez, and at its absence).

Route of administration and doses:

Prior to therapy by Inedzhi's drug patients have to pass to a gipokholesterinemichesky diet and observe it throughout all course of treatment.

Drug is appointed in 1 times/days, in the evening, irrespective of meal.

The dose depends on the LPNP initial level, the purpose of treatment and therapeutic effect and can vary from 10/10 mg (10 mg of an ezetimib + 10 mg of a simvastatin) to 10/80 mg (10 mg of an ezetimib + 80 mg of a simvastatin) in days. The initial dose - 10/20 mg (10 mg of an ezetimib + 20 mg of a simvastatin) in days is usually recommended.

For gradual decrease in the LPNP level the mg drug 10/10 dose can be recommended (10 mg of an ezetimib + 10 mg of a simvastatin).

For considerable decrease in LPNP (more than for 55%), the initial dose of 10/40 mg (10 mg of an ezetimib + 40 mg of a simvastatin) in days can be recommended to patients.

In 2 weeks after an initiation of treatment, and also throughout all course of treatment, it is necessary to control the level of lipids, and if necessary to adjust a drug dose.

Primary hypercholesterolemia (heterozygous family and single hypercholesterolemia, the mixed dislipidemiya). Inedzhi is recommended to be accepted daily in a dose of 10/40 mg (10 mg of an ezetimib + 40 mg of a simvastatin) or 10/80 mg (10 mg of an ezetimib + 80 mg of a simvastatin) in the evening.

Therapy always should be carried out against the background of a gipokholesterinemichesky diet.

For further decrease in the TG levels and ne-LPVP and increases in LPVP at patients with the mixed dislipidemiya treatment by Inedzhi's drug it can be added with purpose of a fenofibrat.

Homozygous family hypercholesterolemia. Inedzhi is recommended to accept in a dose 10/40 mg or 10/80 mg of 1 times/days in the evening. Drug should be used in combination with other hypolipidemic therapy (for example, LPNP-aferez). In the absence of a possibility of performing additional treatment of Inedzhi it is possible to appoint as monotherapy.

Dose adjustment is not required to patients of advanced age.

Dose adjustment is not required to patients with a slight liver failure (5-6 points on a scale of Chayld-Pyyu). It is not recommended to appoint drug to patients with moderated (7-9 points on a scale of Chayld-Pyyu) or heavy (more than 9 points on a scale of Chayld-Pyyu) a liver failure.

Easy and moderate severity dose adjustment is not required to patients with a renal failure. At a renal failure of heavy degree (KK <30 ml/min.) drug in a dose more than 10/10 mg/days should be applied with care.

Use in a combination with other medicines. Inedzhi should be taken at least for 2 h to or in 4 h after reception of sekvestrant of bile acids.

For the patients receiving niacin in a dose more than 1 g/days, cyclosporine or даназол the maximum dose of Inedzhi makes 10/10 mg/days.

For the patients receiving Amiodaronum or verapamil, the maximum dose of Inedzhi makes 10/20 mg/days.

Features of use:

Use at pregnancy and feeding by a breast. Drug is contraindicated at pregnancy and in the period of a lactation (breastfeeding).

Special instructions. In need of Inedzhi's appointment to patients with the expressed renal failure (KK <30 ml/min.) drug in a dose more than 10/10 mg/days has to be applied with care.

Inedzhi has to be applied with care at the patients who are accepting alcohol in large numbers, and/or having liver diseases in the anamnesis. Acute diseases of a liver or it is inexplicable the steady high level of activity of enzymes of a liver are contraindications to administration of drug. Inedzhi's appointment is not recommended to patients with a moderate or heavy liver failure.

With the burdened anamnesis it is required to patients careful observations during treatment by Inedzhi's drug. Some days before performing big surgeries and in the early postoperative period administration of drug is recommended to be stopped temporarily.

Simvastatin, as well as other inhibitors of GMG-KOA-reduktazy, can cause the myopathy which is shown muscular pains, weakness, exhaustion, and also increase in the KFK level more than by 10 times VGN is relative. Sometimes the myopathy takes the form of a rabdomioliz and can be followed by a myoglobinuria, an acute renal failure, in rare instances with a lethal outcome. The risk of a myopathy increases due to increase in a blood plasma of the inhibiting activity concerning GMG-KOA-reduktazy. The decision on performing therapy by Inedzhi's drug in a combination with other medicines should be made individually, taking into account possible risk of development of a myopathy.

The majority of cases of a rabdomioliz against the background of treatment simvastatiny was combined with the burdened anamnesis, including a renal failure, preferential diabetic genesis. With the burdened anamnesis it is required to patients careful observations during treatment by Inedzhi's drug.

The risk of development of a myopathy / рабдомиолиза depends on a dose of a simvastatin. In clinical trials when careful control of a condition of patients was carried out, a myopathy / рабдомиолиз were observed: at reception of a simvastatin in a dose of 20 mg approximately in 0.03% of cases, in a dose of 40 mg - in 0.08%, in a dose of 80 mg - in 0.4% of cases.

At the beginning of reception or at increase in a dose of drug of Inedzhi patients have to be warned about risk of a myopathy and need to immediately report to the doctor about developing of inexplicable muscular pains, weaknesses or indispositions. During the diagnosing or suspicion on a myopathy therapy by Inedzhi's drug should be stopped immediately. Existence of the specified symptoms and/or increase of the KFK level is more than 10 times higher than VGN, means development of a myopathy. In most cases, at the termination of reception of a simvastatin symptoms of a myopathy and the increased KFK level disappeared.

At the beginning of reception or increase in a dose of Inedzhi periodic control of the KFK level can be required, however this measure does not guarantee prevention of development of a myopathy.

Influence on ability to driving of motor transport and to control of mechanisms. Researches for drug impact assessment on ability to control of motor transport and to other potentially dangerous types of activity were not conducted. However there are no bases to assume that Inedzhi can influence these processes somehow.

Side effects:

Safety of drug of Inedzhi is studied in clinical trials with participation more than 3800 patients and during post-marketing observation in the different countries. In the whole Inedzhi it is well transferred by patients.

Side effects at Inedzhi's reception are comparable to side effects about which it was reported earlier at reception of an ezetimib and/or simvastatin.

According to placebo of controlled researches and during postmarkentingovy observation at patients at Inedzhi's reception the following characteristic side effects with a frequency> 1/100 and <1/10 as connected with administration of drug, and without accurately established connection were noted:

From the alimentary system: meteorism, abdominal pain, lock, diarrhea, dyspepsia, vomiting, cholelithiasis, cholecystitis, jaundice, hepatitis; seldom (> 1/10 000, <1/1000) – nausea; very seldom (<1/1 000) – pancreatitis; in some cases – a liver failure. According to the controlled combined clinical trials clinically significant increase in transaminases in serum (ALT and/or ACT by 3 times and more) was noted at 1.7% of the patients receiving Inedzhi (these changes were asymptomatic, did not lead to a cholestasia and passed independently at the termination or continuation of treatment).

From system of a hemopoiesis: thrombocytopenia, anemia.

From a musculoskeletal system: mialgiya, arthralgia; very seldom - a myopathy / рабдомиолиз.

From TsNS: dizziness, headache.

Allergic reactions: seldom (> 1/10 000, <1/1000) - skin rash and a small tortoiseshell; very seldom (<1/10 000) - anaphylactic reactions and a Quincke's disease.

Others: increased fatigue, adynamy. At 0.2% of the patients receiving Inedzhi clinically significant increase in KFK was observed (by 10 times and more VGN).

Interaction with other medicines:

At Inedzhi's use, especially in high doses, in a combination with powerful CYP3A4 inhibitors for example, with itrakonazoly, ketokonazoly, erythromycin, klaritromitsiny, telitromitsiny, HIV protease inhibitors, nefazodony, the risk of development of a myopathy / рабдомиолиза increases. In need of performing therapy itrakonazoly, ketokonazaly, erythromycin, klaritromitsiny or telitromitsiny Inedzhi's reception should be stopped. Strong inhibitors of an isoenzyme CYP3A4 increase risk of development of a myopathy since interfere with removal of a simvastatin. It is necessary to avoid a concomitant use of drug with other medicines containing strong CYP3A4 inhibitors if only the expected advantage of a combination therapy does not exceed potential risk.

At simultaneous use of Inedzhi and a fenofibrat or gemfibrozil concentration of an ezetimib in a blood plasma increases in 1.5 and 1.7 times respectively; however such increase is not clinically significant. Safety and Inedzhi's efficiency in a combination from fibrata (except for a fenofibrat) are insufficiently studied. In a research in which 184 patients accepting Inedzhi in a dose of 10/20 mg/days and фенофибрат in a dose of 160 mg within 12 weeks participated undesirable reactions from a gall bladder were not noted. It is supposed that fibrata can increase release of cholesterol in bile that in turn can lead to cholelithiasis.

At simultaneous use of drug of Inedzhi, especially the risk of development of a myopathy / рабдомиолиза increases in high doses, with cyclosporine, danazoly or niacin (more than 1 g/days). Inedzhi in combination with niacin (more than 1 g/days) should appoint with care since niacin as monotherapy can cause a myopathy. For the patients accepting cyclosporine or даназол in a dose more than 1 g/days, Inedzhi's dose should not exceed 10/10 mg/days. It is necessary to estimate potential advantage and possible risk in need of Inedzhi's appointment to the patients receiving cyclosporine or даназол. At Inedzhi's appointment in combination with cyclosporine constant control of concentration of cyclosporine in blood is necessary.

At simultaneous use with Inedzhi, especially in high doses, with Amiodaronum or verapamil the risk of development of a myopathy / рабдомиолиза increases. There are data on development of a myopathy in 6% of the patients who were taking part in the corresponding clinical trials and receiving симвастатин in a dose of 80 mg and Amiodaronum. For the patients accepting Amiodaronum or verapamil, Inedzhi's dose should not exceed 10/20 mg/days. It is necessary to avoid the combined use of Inedzhi in the doses exceeding 10/20 mg/days with Amiodaronum or verapamil if only advantages of the combined therapy do not exceed potential risk of a myopathy.

At the patients receiving fuzidovy acid along with Inedzhi the risk of development of a myopathy therefore clinical control is necessary for such patients can increase.

At the patients receiving diltiazem and Inedzhi in a dose of 10/80 mg, the risk of development of a myopathy increases slightly. Clinical trials showed that the risk of a myopathy is identical at the patients accepting симвастатин in a dose of 40 mg with the accompanying therapy by diltiazem or without it.

Preclinical trials showed what эзетимиб does not induce CYP3A4 isoenzyme. Clinically significant pharmacokinetic interaction between ezetimiby and other drugs which are metabolism substrates with participation of isoenzymes of system of P450 1A2, 2D6, 2C8, 2C9 cytochrome, and 3A4 or N-acetyltransferases was not revealed. Simvastatin is metabolized by CYP3A4 isoenzyme, but CYP3A4 - the inhibiting activity therefore its influence on plasma concentration of other drugs which are metabolized CYP3A4 is improbable does not possess.

At the combined use with Colestyraminum average AUC value of a total ezetimib (an ezetimib and an ezetimib of a glucuronide) decreased approximately by 55%. At the combined Inedzhi's use and Colestyraminum the accruing decrease in LPNP can become less expressed.

In 2 clinical trials (one - at healthy volunteers, another – at patients with a hypercholesterolemia) симвастатин in a dose of 20-40 mg/days the effect of coumarinic anticoagulants moderately potentiated, extending a prothrombin time when the reference value of MHO (the relation of a prothrombin time of the patient to a prothrombin time of a normal blood plasma) equal 1.7 at healthy volunteers increased to 1.8, and patients with a hypercholesterolemia have a reference value 2.6 increased to 3.4. To the patients accepting coumarinic anticoagulants carry out careful control of indicators of coagulant system of blood (prothrombin time) to the first reception of Inedzhi. The subsequent measurements have to be regular before achievement of stable indicators of MHO, then take measurements with the usual frequency recommended for control at treatment by coumarinic anticoagulants. At drug withdrawal and change of a dose of Inedzhi carry out extraordinary determination of parameters of coagulability of blood. Therapy simvastatiny did not cause in the patients who are not accepting anticoagulants bleedings or changes of parameters of coagulability of blood.

At a concomitant use of Inedzhi and antacids the level of absorption of an ezetimib slightly decreases, at the same time its bioavailability does not change.

Grapefruit juice contains one or more components inhibiting CYP3A4 isoenzyme and can increase the level of the substances which are metabolized this isoenzyme in a blood plasma. The effect of the use of juice in small amounts (250 ml a day) is minimum (the activity inhibiting HMG-CoA reductase increases in a blood plasma for 13% as shows AUC value) and has no clinical importance. However the use of a large amount of juice (more than 1 l a day) during reception of a simvastatin considerably increases the level of the activity inhibiting HMG-CoA reductase in a blood plasma. Therefore it is necessary to avoid the use of a large number of grapefruit juice and a concomitant use of drug.

Contraindications:

— liver diseases in an active phase or permanent increase in activity of hepatic transaminases of not clear etiology;

— moderate and heavy degree of a liver failure (7 and more points on a scale of Chayld-Pyyu);

— pregnancy;

— period of a lactation (breastfeeding);

— age up to 18 years;

— hypersensitivity to drug components.

With care it is necessary to use drug at a renal failure of heavy degree (KK <30 ml/min.), an alcohol abuse, liver diseases in the anamnesis, painful feelings in muscles or change of a tone of skeletal muscles of not clear etiology, diseases of a gall bladder at co-administration of Inedzhi from fibrata.

Overdose:

It was reported about several cases of overdose simvastatiny without clinically significant effects for patients; the maximum accepted dose made 3.6 g.

In clinical trials at 15 healthy patients accepting эзетимиб in a dose of 50 mg/days within 14 days and at 18 patients with primary hypercholesterolemia accepting эзетимиб in a dose of 40 mg/days within 56 days good tolerance of therapy was observed. It was reported about several cases of overdose at which undesirable effects either were not observed, or were not serious.

Treatment: antidotes to an ezetimib and a simvastatin are not available. In case of overdose of drug of Inedzhi it is recommended to carry out the symptomatic and supporting treatment.

Storage conditions:

List B. Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

7 pieces - blisters (1) - packs cardboard.
10 pieces - blisters (1) - packs cardboard.
14 pieces - blisters (1) - packs cardboard.
100 pieces - bottles from polyethylene of high density (1) - packs cardboard.