Ineji, 10 mg+20 mg tablets, 28 pcs.

Pharmacodynamics

A combined hypolipidemic drug that reduces the absorption of cholesterol and related plant sterols in the intestine and also inhibits endogenous cholesterol synthesis.

The drug contains ezetimibe and simvastatin, two hypolipidemic components that complement each other by their mechanism of action.

Cholesterol enters the blood plasma by intestinal absorption and endogenous synthesis. Inegy reduces elevated levels of total chs, LDL, apolipoprotein B (Aro B), TG and low-density lipoproteins (non-HDL), and increases levels by dual inhibition: absorption and cholesterol synthesis.

Ezetimibe

The mechanism of action of ezetimibe differs from other classes of hypolipidemic drugs (e.g., statins, bile acid sequestrants, fibrates).

Ezetimibe, when taken in the small intestine, slows down the absorption of cholesterol, which leads to a decrease in cholesterol flow from the intestine to the liver.

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

A number of preclinical studies of ezetimibe confirm its selectivity in reducing cholesterol absorption. Ezetimibe slows the absorption of ¹⁴C-cholesterol, and has no effect on the absorption of TGs, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat-soluble vitamins A and D.

Simvastatin

After oral administration as an inactive lactone, simvastatin undergoes hydrolysis to form the corresponding P-hydroxy acid derivative with high inhibitory activity against HMG-CoA reductase. This enzyme triggers the initial and most important stage of cholesterol biosynthesis – conversion of HMG-CoA to mevalonate.

Simvastatin reduces both elevated and normal LDL levels. LDL is formed from LDL and undergoes cleavage mainly by the high-affinity LDL-receptor. Reduction of LDL after simvastatin administration leads to a decrease in LDL and activation of LDL receptor, which leads to a decrease in LDL formation and increased catabolism of LDL. During simvastatin therapy, the level of AROB also decreases. In addition, simvastatin moderately increases HDL level and decreases plasma TG. As a result of these changes, total cholesterol and LDL levels decrease.

Pharmacokinetics

Assimilation

Ezetimibe

. After oral administration, ezetimibe is rapidly absorbed and intensely conjugates to the pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).

The C_max of ezetemibe in blood plasma after oral administration is reached after 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined as it is insoluble in none of the aqueous solvents used for injection.

Eating food (low- or high-fat) does not affect the bioavailability of ezetimibe when taken orally, particularly in the form of 10 mg tablets.

Simvastatin

The bioavailability of P-hydroxy acid after oral administration of simvastatin is less than 5% of the dose. In addition to P-hydroxy acid, 4 other active metabolites are detected in plasma.

Eating has no effect on plasma concentrations of active and total metabolites of simvastatin.

Distribution

Ezetimibe

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

Simvastatin

Simvastatin and P-hydroxy acid bind to plasma proteins by 95%.

Pharmacokinetic studies have shown that simvastatin does not accumulate in tissues after repeated doses. The maximum level of metabolites in blood plasma is observed 1.3-2.4 h after taking the drug.

Metabolism

Ezetimibe

The primary metabolism of ezetimibe occurs in the small intestine and liver by conjugation with glucuronide (phase II reaction), followed by excretion with bile. Minimal oxidative metabolism (phase I reaction) was observed at all stages of ezetimibe transformation. Ezetimibe and ezetimibe-glucuronide, the main derivatives of the drug, account for 10-20% and 80-90% of the total drug in plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from the blood plasma by intestinal-hepatic recirculation.

T_1/2 for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Simvastatin

It is an inactive lactone that is rapidly hydrolyzed in vivo to the corresponding P-hydroxy acid, a potent HMG-CoA reductase inhibitor. Hydrolysis mainly occurs in the liver; the rate of hydrolysis in plasma is very low. Simvastatin is well absorbed and almost completely metabolized already during the “first passage” through the liver. The hepatic uptake of simvastatin is determined by the rate of hepatic blood flow. The main metabolism occurs in the liver, metabolites of the drug are excreted with bile. Therefore, the amount of active substance in the systemic bloodstream is very small.

Ejection

Ezetimibe

After oral administration of 20 mg of ezetimibe, labeled ¹⁴C, 93% of total ezetimibe was detected in plasma of total radioactive product levels. Approximately 73% and 11%, respectively, of the ingested radioactive products were excreted through the intestine and kidneys within 10 days. No radioactive products were detected in plasma after 48 hours.

Simvastatin

In 96 h after oral administration of radioactive simvastatin, 13% of the radioactive products were excreted by the kidneys and 60% through the intestine. After intravenous administration of the P-hydroxy acid metabolite, only 0.3% was excreted by the kidneys as metabolites.

Pharmacokinetics in special clinical cases

Children

Pharmacokinetic data, absorption, and metabolism of ezetimibe are similar in children/adolescents (10-18 years) and adults. There are no data on the pharmacokinetics of the drug in children younger than 10 years of age. Clinical use of the drug in pediatric practice (in children and adolescents 9-17 years old) is limited to data on patients with homozygous familial hypercholesterolemia (HFH) or homozygous sitosterolemia (hyper-apo-beta-lipoproteinemia).

Elderly patients

In elderly patients (older than 65 years), the plasma concentration of total ezetimibe is approximately 2 times higher than in younger patients (18-45 years). LDL-lowering levels and safety profiles in older and younger patients taking ezetimibe are about the same.

Patients with hepatic impairment

. After a single dose of ezetimibe 10 mg, the mean AUC for total ezetimibe was 1.7 higher in patients with mild hepatic impairment (Child-Pugh score 5-6) than in patients with preserved liver function. In a 14-day study of ezetimibe at a dose of 10 mg/day involving patients with moderate hepatic impairment (Child-Pugh scores 7-9), the mean AUC for total ezetimibe was 4-fold higher on days 1 and 14 compared with patients with preserved liver function.

Dose adjustment is not required for patients with mild hepatic impairment. Because the effects of increased total ezetimibe concentrations are unknown, ezetimibe is not recommended in patients with moderate to severe (greater than 9 points on the Child-Pugh scale) hepatic impairment.

Patients with renal impairment

Ezetimibe. After a single oral dose of ezetimibe 10 mg, the mean AUC in patients with severe renal impairment (mean CK less than 30 ml/min/1.73 m²) increased 1.5-fold compared to healthy patients.

Simvastatin. In a study of patients with severe renal impairment ( IQ less than 30 ml/min) after taking HMG-CoA reductase inhibitors, the total concentration of simvastatin metabolites was 2 times higher than in healthy volunteers.

Gender

The total concentration of ezetimibe was slightly higher (20%) in women than in men. LDL reduction levels and safety profiles are about the same in men and women taking ezetimibe.

Indications

– Primary hypercholesterolemia: heterozygous (familial and non-familial) hypercholesterolemia or mixed hyperlipidemia (as an adjunct to diet to reduce total cholesterol, LDL, apolipoprotein B, TG, low-density lipoproteins, to increase HDL levels).

– Homozygous familial hypercholesterolemia: to reduce elevated levels of total cholesterol and LDL (both as an additional treatment to other hypolipidemic therapy, such as LDL-apheresis, and in its absence).

Composition

Active substances:

Ezetimibe 10 mg,

Simvastatin 20 mg.

Associates:

Lactose monohydrate,

Microcrystalline cellulose,

Hypromellose 2910 6 cps,

croscarmellose sodium,

citric acid monohydrate,

butyl hydroxyanisole,

propyl gallate,

magnesium stearate.

How to take, the dosage

Patients should switch to a hypocholesterolemic diet before starting therapy with Ineji and follow it for the duration of treatment.

The drug is given orally once daily, in the evening, regardless of meals.

The dose depends on the initial LDL level, the goal of treatment and the therapeutic effect and may vary from 10/10 mg (10 mg ezetimibe + 10 mg simvastatin) to 10/80 mg (10 mg ezetimibe + 80 mg simvastatin) per day. A starting dose of 10/20 mg (10 mg ezetimibe + 20 mg simvastatin) per day is usually recommended.

In order to gradually lower LDL levels, a dose of 10/10 mg (10 mg ezetimibe + 10 mg simvastatin) may be recommended. For a significant reduction of LDL (more than 55%), patients may be recommended an initial dose of 10/40 mg (10 mg ezetimibe + 40 mg simvastatin) per day.

Lipid levels should be monitored 2 weeks after the start of treatment, and throughout the course of treatment, and the dose of the drug should be adjusted if necessary.

Primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia, mixed dyslipidemia)

is recommended to be taken daily at a dose of 10/40 mg (10 mg ezetimibe + 40 mg simvastatin) or 10/80 mg (10 mg ezetimibe + 80 mg simvastatin) in the evening.

The therapy should always be carried out against a background of a hypocholesterolemic diet.

To further decrease TG and non-LDL levels and increase HDL in patients with mixed dyslipidemia, treatment with Ineji may be supplemented with fenofibrate.

Homozygous familial hypercholesterolemia

Ineji is recommended at a dose of 10/40 mg or 10/80 mg once daily in the evening. The drug should be used in combination with other hypolipidemic therapy (e.g., LDL-apheresis). If there is no possibility of additional treatment Inegy can be prescribed as monotherapy.

Dose adjustment is not required in elderly patients.

Patients with mild hepatic impairment (Child-Pugh score 5-6) do not require dose adjustment. It is not recommended to prescribe the drug in patients with moderate (7-9 Child-Pugh scores) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment.

Patients with mild to moderate renal insufficiency do not require dose adjustment. In severe renal failure (CKR < 30 ml/min), the drug at a dose greater than 10/10 mg/day should be used with caution.

Combination with other drugs

Ineji should be taken at least 2 h before or 4 h after taking bile acid sequestrants.

For patients receiving nicotinic acid at a dose greater than 1 g/day, cyclosporine, or danazol, the maximum dose of Ineji is 10/10 mg/day.

For patients receiving amiodarone or verapamil, the maximum dose of Inegy is 10/20 mg/day.

Interaction

In combination with potent CYP3A4 inhibitors such as itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nephazodone, especially in high doses, the risk of myopathy/rhabdomyolysis increases. If therapy with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is necessary, Ineji should be discontinued.

Powerful CYP3A4 isoenzyme inhibitors increase the risk of myopathy because they interfere with the excretion of simvastatin. Concomitant use of the drug with other drugs containing strong CYP3A4 inhibitors should be avoided unless the expected benefit of combined therapy exceeds the potential risk.

Concomitant use of Ineji and fenofibrate or gemfibrozil increases plasma concentrations of ezetimibe by 1.5 and 1.7-fold, respectively; however, this increase is not clinically significant.

The safety and efficacy of InEGI in combination with fibrates (except fenofibrate) have not been adequately studied. In a study involving 184 patients taking Inegy at a dose of 10/20 mg/day and fenofibrate at a dose of 160 mg for 12 weeks, no adverse gallbladder reactions were noted. It has been suggested that fibrates may increase cholesterol excretion into the bile, which in turn may lead to cholelithiasis.

The simultaneous use of Inegy, especially in high doses, with cyclosporine, danazol or nicotinic acid (more than 1 g/day) increases the risk of myopathy/rhabdomyolysis. Inegy in combination with nicotinic acid (more than 1 g/day) should be prescribed with caution because nicotinic acid as monotherapy may cause myopathy.

For patients taking cyclosporine or danazol at doses greater than 1 g/day, the dose of Ineji should not exceed 10/10 mg/day. The potential benefit and possible risk should be evaluated if Inegy should be administered to patients receiving cyclosporine or danazol. When Inegy is prescribed in combination with cyclosporine, continuous monitoring of cyclosporine blood concentrations is necessary.

The risk of myopathy/rhabdomyolysis increases with Inegy, especially at high doses, with amiodarone or verapamil. There are data on the development of myopathy in 6% of patients who participated in relevant clinical trials and received simvastatin at a dose of 80 mg and amiodarone. For patients taking amiodarone or verapamil, the dose of Inegy should not exceed 10/20 mg/day. Co-administration of Inegy at doses greater than 10/20 mg/day with amiodarone or verapamil should be avoided unless the benefits of combined therapy exceed the potential risk of myopathy.

Patients receiving fusidic acid concomitantly with Ineji may have an increased risk of myopathy, so clinical monitoring is necessary in these patients.

In patients receiving diltiazem and Ineji at a dose of 10/80 mg, the risk of myopathy increases slightly. Clinical studies have shown that the risk of myopathy is the same in patients taking simvastatin at a dose of 40 mg, with or without concomitant therapy with diltiazem.

Preclinical studies have shown that ezetimibe does not induce the CYP3A4 isoenzyme. No clinically significant pharmacokinetic interaction between ezetimibe and other drugs that are substrates of metabolism involving cytochrome P450 1A2, 2D6, 2C8, 2C9, and 3A4 or N-acetyltransferase system isoenzymes was found. Simvastatin is metabolized by CYP3A4 isoenzyme, but has no CYP3A4-inhibitory activity, so its effect on plasma concentrations of other drugs metabolized by CYP3A4 is unlikely.

When combined with colestiramine, the average AUC of total ezetimibe (ezetimibe and ezetimibe glucuronide) was reduced by approximately 55%. When Ineji and colestiramine are used in combination, the incremental decrease in LDL may become less pronounced.

. In 2 clinical studies (one in healthy volunteers and the other in patients with hypercholesterolemia), simvastatin at a dose of 20-40 mg/day moderately potentiated the effect of coumarin anticoagulants by prolonging prothrombin time, when the baseline MHO value (ratio of patient’s prothrombin time to normal blood plasma prothrombin time) of 1.7 in healthy volunteers increased to 1.8, and in patients with hypercholesterolemia the baseline value of 2.6 increased to 3.4.

Patients taking coumarin anticoagulants should have their clotting parameters (prothrombin time) carefully monitored before the first administration of Ineji. Subsequent measurements should be regular until stable MHO values are achieved, then measurements are performed at the usual intervals recommended for control with coumarin anticoagulants. If the drug is withdrawn and the dose is changed, an unscheduled determination of clotting parameters is performed. In patients not taking anticoagulants, therapy with simvastatin has not caused bleeding or changes in blood clotting parameters.

The concomitant use of Ineji and antacids slightly decreases the absorption of ezetimibe, while its bioavailability does not change.

Grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme and may increase plasma levels of substances metabolized by this isoenzyme. The effect of drinking juice in small amounts (250 ml per day) is minimal (the activity inhibiting HMG-CoA reductase is increased in plasma by 13%, as indicated by the AUC value) and has no clinical significance. However, drinking large amounts of juice (more than 1 liter per day) while taking simvastatin significantly increases the level of HMG-CoA reductase inhibitory activity in plasma. Therefore, large amounts of grapefruit juice and concomitant administration of the drug should be avoided.

Special Instructions

If it is necessary to prescribe Ineji in patients with severe renal insufficiency (CK < 30 ml/min), the drug at a dose greater than 10/10 mg/day should be used with caution.

Inegy should be used with caution in patients who take alcohol in large quantities and/or have a history of liver disease. Acute liver disease or unexplained sustained high levels of liver enzyme activity are contraindications to the drug. It is not recommended for patients with moderate to severe hepatic impairment to be prescribedIneji. Patients with a severe medical history require close monitoring during treatment with Inejand in a few days before major surgical procedures and in the early postoperative period it is recommended to temporarily discontinue the drug.

Simvastatin, like other HMG-CoA reductase inhibitors, may cause myopathy manifested by muscle pain, weakness, fatigue, and an increase in CPK levels more than 10-fold relative to IGN. Sometimes myopathy takes the form of rhabdomyolysis and may be accompanied by myoglobinuria, acute renal failure, in rare cases with fatal outcome. The risk of myopathy is increased due to increased plasma inhibitory activity against HMG-CoA reductase. The decision about therapy with Inegy in combination with other drugs should be made individually, taking into account the possible risk of myopathy.

The majority of cases of rhabdomyolysis during treatment with simvastatin were combined with a history of poor health, including renal failure, predominantly of diabetic origin.

Patients with a history of aggravated myeloma require close monitoring during treatment with Inegy.

The risk of myopathy/rhabdomyolysis depends on the dose of simvastatin. In clinical trials, when patients were closely monitored, myopathy/rhabdomyolysis was observed: when taking simvastatin at a dose of 20 mg in about 0.03% of cases, at a dose of 40 mg in 0.08%, and at a dose of 80 mg in 0.4% of cases.

When starting or increasing the dose of Ineji, patients should be warned of the risk of myopathy and the need to immediately inform their physician of the occurrence of unexplained muscle pain, weakness, or malaise. If myopathy is diagnosed or suspected, therapy with Inegy should be stopped immediately. The presence of these symptoms and/or an increase in CPK levels of more than 10 times the IGN indicates the development of myopathy. In most cases, upon discontinuation of simvastatin, myopathy symptoms and elevated CPK levels disappeared.

When starting or increasing the dose of Inegy, periodic monitoring of CPK levels may be necessary, but this measure does not guarantee prevention of the development of myopathy.

Influence on ability to drive vehicles and other mechanisms requiring increased concentration

There have been no studies to evaluate the effect of the drug on the ability to drive vehicles and other potentially hazardous activities. However, there is no evidence to suggest that Ineji may have any effect on these processes.

With caution:The drug should be used in severe renal failure (CK < 30 ml/min), alcohol abuse, history of liver disease, muscle soreness or changes in skeletal muscle tone of unclear etiology, gallbladder disease when Inegi is concomitantly administered with fibrates.

Side effects

The safety of Inegi has been studied in clinical studies involving more than 3,800 patients and in post-marketing surveillance in various countries. Inegi is generally well tolerated by patients.

The side effects with Inegi are comparable to those previously reported with ezetimibe and/or simvastatin.

The following characteristic side effects with a frequency of > 1/100 and < 1/10 have been reported in patients while taking Inegi, both related to the drug and without a clearly established relationship, according to placebo-controlled studies and in the post-marketing follow-up period:

Digestive system side effects: meteorism, abdominal pain, constipation, diarrhea, dyspepsia, vomiting, cholelithiasis, cholecystitis, jaundice, hepatitis; rarely ( > 1/10,000, < 1/1000) – nausea; very rarely ( < 1/1,000) – pancreatitis; in rare cases – liver failure. According to data of controlled combined clinical trials a clinically significant increase of transaminases in serum (ALT and/or ACT 3 times or more) was noted in 1.7% of patients treated with Inegi (these changes were asymptomatic, did not lead to cholestasis and passed on their own at discontinuation or continuation of treatment).

Hematopoietic system:thrombocytopenia, anemia.

Muscular system disorders: myalgia, arthralgia; very rare – myopathy/rhabdomyolysis.

CNS side:dizziness, headache.

Allergic reactions: rare ( > 1/10 000, < 1/1000) – skin rash and urticaria; very rare ( < 1/10 000) – anaphylactic reactions and angioedema.

Others: increased fatigue, asthenia. In 0.2% of patients receiving Inegy, there was a clinically significant increase in CPK (10 times or more of VGN).

Overdose

A few cases of simvastatin overdose have been reported without clinically significant effects on patients; the maximum dose taken was 3.6 g.

In clinical trials, 15 healthy patients who took ezetimibe at a dose of 50 mg/day for 14 days and 18 patients with primary hypercholesterolemia who took ezetimibe at a dose of 40 mg/day for 56 days had good tolerance to therapy. Several cases of overdose were reported in which adverse effects were either not observed or were not serious.

Treatment:There are no antidotes to ezetimibe and simvastatin. In case of overdose of Inegi, symptomatic and supportive treatment is recommended.

Pregnancy use

The drug is contraindicated in pregnancy and during lactation (breastfeeding).

In children under 18 years of age.