Ineji

Ineji is a lipid-lowering drug.

Indications Ineji

Used to treat hypercholesterolemia.

Primary form of the disease.

As an adjuvant in combination with diet in people with primary hypercholesterolemia (hereditary or non-familial heterozygous) or mixed hyperlipidemia, when a combination drug is needed. It is prescribed to people who have not achieved the desired effect when using statins alone, and in addition to this, to people who have previously used ezetimibe and statins.

To reduce the incidence of complications associated with the functioning of the cardiovascular system in people with coronary artery disease and an increased likelihood of such consequences.

Homozygous hereditary hypercholesterolemia.

As an adjunct to diet. In addition, additional therapy (eg, LDL apheresis) may be administered.

Release form

The drug is released in tablet form, 14 pieces inside a cell plate. There are 2 plates in a pack.

Pharmacodynamics

Inedzhi is a hypolipidemic substance that inhibits intestinal absorption of cholesterol with related plant sterols, as well as the processes of endogenous cholesterol binding.

The composition of the drug contains simvastatin with ezetimibe (these are hypolipidemic elements with a complementary principle of therapeutic effect). The drug reduces increased levels of cholesterol, LDL cholesterol, and in addition, apo-B, triglycerides and IDL cholesterol. At the same time, it increases the values of HDL cholesterol, providing a double effect - suppression of absorption and binding of cholesterol.

Ezetimibe.

The component inhibits intestinal absorption of cholesterol. The mechanism of its medicinal effect differs from other groups of drugs that reduce cholesterol levels (for example, fibrates with statins, resins, and plant stanols). The molecular effect of ezetimibe is aimed at the sterol transporter NPC1L1, whose function is the intestinal absorption of phytosterols with cholesterol.

The element is located in the area of brush strips of the small intestine and inhibits the absorption of cholesterol, reducing the volume of intestinal cholesterol delivered into the liver. Statins reduce the hepatic binding of cholesterol. Both of these mechanisms contribute to an additional decrease in cholesterol levels. Ezetimibe has no effect on the absorption of bile and fatty acids, triglycerides with ethinyl estradiol and progesterone, or fat-soluble calciferol with retinol.

Simvastatin.

After oral administration, simvastatin, which is an inactive lactone, undergoes a process of hepatic hydrolysis with subsequent formation of the active β-hydroxy acid form (has a powerful inhibitory effect on the activity of HMG-CoA reductase). This enzyme acts as a catalyst for the early and most important phase of cholesterol biosynthesis - the process of transformation of HMG-CoA into the component mevalonate.

The element reduces both elevated and standard LDL-C levels. LDL substances are formed from VLDL and are largely catabolized by high-affinity LDL-endings. Along with reducing LDL levels, simvastatin can also reduce VLDL-C values and induce the activity of LDL-endings, which reduces production and increases catabolism of LDL-C.

Simvastatin therapy significantly reduces apo-B values. At the same time, the component moderately increases HDL-C and plasma TG levels. All these changes lead to a decrease in the total cholesterol/HDL and LDL/HDL ratios.

Pharmacokinetics

Suction.

Ezetimibe.

When administered orally, the component is absorbed at high speed and conjugated to form a therapeutically active phenolic glucuronide (ezetimibe-glucuronide). Plasma Cmax is observed after 1-2 hours (ezetimibe-glucuronide) and 4-12 hours (ezetimibe).

Eating food (either high or low in fat) does not affect the bioavailability of the substance.

Simvastatin.

After administration of simvastatin, the level of active β-hydroxy acid in the bloodstream is less than 5% of the used portion (after 1st hepatic passage). In addition to β-hydroxy acid, 4 more active metabolic products are excreted into human plasma. If the substance is taken before meals (on an empty stomach), the plasma values of total and active inhibitors remain the same.

Distribution processes.

Ezetimibe.

The active element with ezetimibe-glucuronide undergoes plasma protein synthesis, respectively, by 99.7% and 88-92%.

Simvastatin.

Intraplasmic protein synthesis of simvastatin with β-hydroxy acid is 95%. Pharmacokinetic tests have demonstrated that simvastatin is not subject to tissue accumulation. The Cmax values of inhibitors are recorded after 1.3-2.4 hours from the moment of drug administration.

Exchange processes.

Ezetimibe.

Initial metabolism processes of ezetimibe develop in the liver and small intestine via conjugation with glucuronide (reaction occurring at stage 2), and then it is excreted with bile. Minimal metabolic oxidative processes (reaction occurring at stage 1) are noted in all phases of substance transformation.

Ezetimibe together with ezetimibe glucuronide are the main components observed in blood plasma. They constitute about 10-20%, and also 80-90% of the total plasma parameters of the drug. These elements are excreted from blood plasma at a low rate during the recirculation that occurs in the liver with the intestine.

The half-life of the components is approximately 22 hours.

Simvastatin.

Simvastatin is an inactive lactone that undergoes rapid hydrolysis in vivo, converting it to a β-hydroxy acid. The hydrolysis processes occur mainly within the liver, and its plasma rate is extremely low.

The substance is well absorbed and participates in active extraction during the first intrahepatic passage. Hepatic extraction is determined by the rate of blood circulation within the liver.

The medicinal effect of drugs is initially directed at the liver, after which metabolic products are excreted with bile. Active decay products penetrate poorly into the systemic bloodstream.

The half-life of β-hydroxy acid after intravenous injection is 1.9 hours.

Excretion.

Ezetimibe.

In volunteers who took 14C-ezetimibe orally (20 mg), 93% of the total ezetimibe (from the total plasma radioactivity) was detected in the blood plasma. About 78%, as well as 11% of the used radioactive portion, was excreted in feces and urine over 10 days. After 48 hours, no radioactive indicators were observed in the blood plasma.

Simvastatin.

Simvastatin acid moves with hepatocytes with the participation of the transporter OATP1B1.

Simvastatin is a substrate of the efflux transporter breast cancer resistance protein (BCRP).

Within 96 hours of oral administration of radioactive simvastatin, it was excreted in urine (13%) and feces (60%). The amount of drug excreted in feces includes absorbed drug, biliary excretion, and unabsorbed drug.

Following administration of a β-hydroxy acid metabolic product, only 0.3% of the administered dose was excreted in the urine in the form of inhibitory substances.

Dosing and administration

Primary form of hypercholesterolemia.

Before the start of the treatment cycle, the patient must be transferred to a standard cholesterol-lowering diet, which he must adhere to for the entire period of therapy.

The dose of Inegy is determined individually, taking into account the initial values of LDL-C, the purpose of therapy and the clinical response to its implementation. The medication is taken once a day, in the evening, without reference to food intake.

The dosage range is 10/10-10/40 mg per day. Basically, the drug is initially taken in a dosage of 10/20 or 10/40 mg per day.

During dose titration or from the start of therapy, blood lipid levels should be monitored (at minimum 4-week intervals) and the dosage adjusted if necessary.

Homozygous hereditary hypercholesterolemia.

Initially, the drug should be taken in a dose of 10/40 mg per day (evening dose). The drug is used as an auxiliary therapeutic element in other cholesterol-lowering treatment (for example, LDL-apheresis) or if such therapy is not available.

Use in combination with other medications.

Inegy should be administered at least 2 hours before or at most 4 hours after administration of bile acid sequestrants.

Individuals taking amlodipine, diltiazem, amiodarone with verapamil, or niacin in lipid-lowering doses should take no more than 10/20 mg of the drug per day.

Children.

The initial stage of therapy should be carried out under the supervision of a medical specialist.

For children aged 10-17 years, information on the use of the drug is limited (puberty period: boys - 2nd or higher stage of the Tanner scale; girls - at least 1 year after the onset of menarche). At first, you need to take the drug in a dose of 10/10 mg, 1 time per day. The recommended dosage range is 10/10-10/40 mg of the drug per day.

Persons with liver failure.

The drug should not be prescribed to people with moderate (7-9 points in the Child-Pugh classification) or severe (over 9 points) impairment.

People with problems with kidney function.

People with CRF and SCF values <60 ml/minute/1.73 m2 ^are required to take 10/20 mg of the drug once a day in the evenings. Larger doses are used with extreme caution.

[ 2 ]

Use Ineji during pregnancy

Inedzhi is prohibited for use in pregnant women. There is no clinical data regarding the use of the drug in pregnant women.

There is no information on whether the active ingredients of the drug are excreted in breast milk. For this reason, it is not used during breastfeeding.

Contraindications

Main contraindications:

• the presence of strong sensitivity to medicinal elements;
• aggravated liver diseases;
• prolonged elevation of serum transaminase levels of unknown origin;
• combination with potent substances that inhibit the activity of the CYP3A4 enzyme (for example, ketoconazole, voriconazole and itraconazole with posaconazole, as well as telithromycin, clarithromycin with erythromycin, telaprevir with boceprevir and nefazodone with HIV protease inhibitors (for example, nelfinavir));
• combination with cyclosporine, gemfibrozil or danazol.

Side effects Ineji

The use of the drug may lead to the development of side effects:

• disorders in the functioning of the lymph and hematopoietic system: anemia or thrombocytopenia;
• disorders of the nervous system function: memory impairment or polyneuropathy;
• lesions of the respiratory system, mediastinum and sternum: dyspnea, cough or interstitial lung disease;
• manifestations in the gastrointestinal tract: gastritis, constipation or pancreatitis;
• signs associated with the subcutaneous layer and epidermis: MEE or alopecia, as well as intolerance symptoms, including urticaria, rashes, angioedema and anaphylaxis;
• disorders of the connective and musculoskeletal tissues: muscle spasms, myopathy (including myositis), as well as rhabdomyolysis (whether accompanied by acute renal failure or not) and tendinopathy, which is sometimes complicated by a fracture;
• disorders of nutritional and metabolic processes: loss of appetite;
• vascular lesions: increased blood pressure and hot flashes;
• systemic symptoms: pain;
• problems with the functioning of the biliary tract and liver: liver failure, jaundice, hepatitis or cholecystitis;
• genital lesions: impotence;
• mental disorders: insomnia or depression.

Rarely, a pronounced intolerance syndrome may be observed, manifested by the following symptoms: dermatomyositis, Quincke's edema, drug-induced lupus, rheumatic polymyalgia and vasculitis. In addition, this list includes eosiophilia, arthralgia, thrombocytopenia, arthritis, dyspnea, increased ESR, hot flashes, urticaria, fever, photosensitivity and a feeling of malaise.

Laboratory test results may change: the alkaline phosphatase level increases or liver function values change.

Statins, including simvastatin, increase HbA1c levels and also blood sugar levels.

Rarely, cognitive impairment (a state of forgetfulness, memory loss or impairment, amnesia, and confusion) has been reported with statin use. These impairments are often mild and treatable after discontinuation of the drug.

The use of statins can also cause additional negative effects: sleep disorders (may include nightmares), sexual dysfunction, diabetes mellitus (the frequency of its development is determined by the presence of risk factors (fasting blood sugar levels are ≥5.6 mmol/l, and the body weight index is ≥30 kg/m2 ^; in addition, increased blood pressure and increased triglyceride levels)).

[ 1 ]

Overdose

In case of drug poisoning, supportive and symptomatic measures are taken.

Interactions with other drugs

The use of the drug (especially in large doses) together with strong substances that slow down the action of CYP3A4 (for example, ketoconazole, itraconazole, as well as telithromycin, erythromycin with nefazodone, clarithromycin and HIV protease inhibitors) leads to an increased risk of rhabdomyolysis or myopathy. If the administration of erythromycin, itraconazole, clarithromycin, ketoconazole or telithromycin is required, the use of INEGY should be discontinued. Drugs that have a strong inhibitory effect on the CYP3A4 isoenzyme increase the likelihood of myopathy, because they interfere with the excretion of simvastatin. It is necessary to refuse to combine the drug with other drugs that contain strong components that slow down the activity of CYP3A4; the only exception may be a situation when the probable benefit of such treatment is more expected than the risk of complications.

The combination of the drug with fenofibrate or gemfibrozil increases plasma levels of ezetimibe by 1.5 and 1.7 times, respectively; however, this increase is not clinically significant.

Combining the drug (especially in large doses) with danazol, cyclosporine, or niacin (over 1000 mg per day) also increases the risk of rhabdomyolysis or myopathy.

Concomitant use with niacin (above 1000 mg per day) should be very careful, because monotherapy with niacin can lead to myopathy.

For people using danazol or cyclosporine in doses exceeding 1000 mg per day, the dosage of the drug should be a maximum of 10/10 mg per day. It is also necessary to evaluate the possible benefits and risks of administering these drugs simultaneously. When combining the drug with cyclosporine, blood values of this component should be regularly monitored.

An increased risk of rhabdomyolysis or myopathy is also observed when the drug is combined with verapamil or amiodarone. There is information about the occurrence of myopathy in 6% of individuals participating in clinical trials using 80 mg of simvastatin together with amiodarone.

For people using verapamil or amiodarone, the daily dose of the medication may be a maximum of 10/20 mg. Exceptions are possible only in situations where the benefit of therapy is more likely than the risk of myopathy.

People using fusidic acid together with the drug may have an increased risk of myopathy, so the condition of such patients should be monitored.

Combined use with cholestyramine resulted in a decrease in the mean AUC values of total ezetimibe by approximately 55%. Combination of the drug with this component may reduce the severity of the progressive decrease in LDL levels.

During 2 clinical tests (with healthy volunteers and with individuals with hypercholesterolemia), the simvastatin component in a dose of 20-40 mg per day moderately increased the effect of anticoagulants from the coumarin group, prolonging the PT indices. In this case, the initial INR level, which was 1.7 in volunteers, increased to 1.8, and in individuals with hypercholesterolemia - from 2.6 to 3.4.

People using coumarin anticoagulants should closely monitor their blood coagulation values (PT) before first using INEGY. These measurements should then be taken regularly until a stable level of INR values is achieved. After this, measurements are taken at standard intervals that are required for monitoring during therapy with coumarin anticoagulants. After discontinuing INEGY or changing its dosage, blood coagulation values should be measured without a scheduled interval.

The combination of the drug with antacids leads to an insignificant decrease in the absorption rates of ezetimibe (the level of bioavailability of the substance remains unchanged).

Grapefruit juice contains 1 or more elements that inhibit the activity of the CYP3A4 isoenzyme and are capable of increasing the plasma values of components whose metabolic processes occur with the participation of this isoenzyme. When using juice in small quantities (0.25 l per day), its effect will be minimal (the activity that inhibits the action of HMG-CoA reductase increases in the blood plasma by 13%, according to AUC readings), which does not have clinical significance. But using juice in large volumes (over 1 l per day) when using simvastatin significantly increases the intraplasmic indicators of the activity that inhibits the action of HMG-CoA reductase. Because of this, during the administration of the drug, you should stop taking such juice in large volumes.

[ 3 ], [ 4 ]

Storage conditions

Inedzhi should be stored in a place out of reach of small children. Temperature range – no higher than 30°C.

[ 5 ]

Shelf life

Inedzhi can be used within a 2-year period from the date of manufacture of the medicinal substance.

[ 6 ]

Application for children

The medication should not be used before the age of 10, because there is no information regarding its effectiveness and drug safety for this group.

Analogues

The following medications are analogs of the drug: Garlic oil, Peponen, Pumpkin seed oil, Omacor with Sikod, as well as Ravisol with Epadol, Revital with Eikonol and Fish oil.

Reviews

Inedzhi is a very effective medication, but it should be taken into account that it is quite expensive.