Ezetrol®
Preclinical studies have shown that ezetimibe does not induce cytochrome P450 isoenzymes. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs that are metabolized by cytochrome P450 isoenzymes 1A2, 2D6, 2C8, 2C9 and 3A4 or N-acetyltransferase.
Ezetimibe has no effect on 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 the latter.
Concomitant use of antacids reduces the rate of absorption of ezetimibe, but does not affect its bioavailability and, therefore, the decrease in the rate of absorption is not clinically significant.
When used concomitantly with cholestyramine, the AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) is reduced by approximately 55%. The additional reduction in LDL-C due to the addition of ezetimibe to cholestyramine may be reduced by this interaction.
In patients who underwent kidney transplantation with creatinine clearance more than 50 ml/min, constantly receiving cyclosporine, a single dose of Ezetrol at a dose of 10 mg was accompanied by an average 3.4-fold (from 2.3 to 7.9 times) increase in the AUC of ezetimibe. One patient who underwent a kidney transplant and had severe renal failure (creatinine clearance 13.2 ml/min/1.73 m2) who received complex therapy including cyclosporine had a 12-fold increase in ezetimibe concentrations compared with the control group. In 12 healthy volunteers who received ezetimibe at a dose of 20 mg/day for 8 days simultaneously with cyclosporine at a daily dose of 100 mg, on the 7th day an increase in the AUC of cyclosporine by an average of 15% was detected (from a decrease of 10% to an increase of 50%) compared with patients in whom cyclosporine was used as monotherapy at a dose of 100 mg/day.
Concomitant use of fenofibrate or gemfibrozil increases the total concentration of ezetimibe by approximately 1.5 and 1.7 times, respectively. However, this increase is not considered clinically significant.
The safety and effectiveness of ezetimibe when used with fibrates has not been established. Fibrates can increase the release of cholesterol into bile, which can lead to gallstones. In preclinical studies in dogs, ezetimibe increased cholesterol levels in the gallbladder. Although the significance of these data in humans is unknown, coadministration of Ezetrol with fibrates is not recommended prior to clinical trials.
When Ezetrol was taken concomitantly with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin and rosuvastatin, no clinically significant pharmacokinetic interaction was observed.
Ezetrol, 10 mg, tablets, 28 pcs.
Absorption Following oral administration, ezetimibe is rapidly absorbed and extensively conjugated in the small intestine and liver into the pharmacologically active phenolic glucuronide (ezetimibe glucuronide). Absorption of ezetimibe glucuronide is observed after 1-2 hours, ezetimibe - after 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined, since this compound is practically insoluble in water. Concomitant meals (both high-fat and low-fat) do not affect the bioavailability of ezetimibe when administered orally at a dose of 10 mg. Ezetrol® can be taken both during and between meals. Distribution Ezetimibe and ezetimibe glucuronide are 99.7 and 88-92% bound to human plasma proteins, respectively. Metabolism Ezetimibe is metabolized primarily in the small intestine and liver by conjugation with a glucuronide (phase II reaction) followed by excretion in the bile. Minimal oxidative metabolism (phase I reaction) was observed in all species studied. Ezetimibe and ezetimibe glucuronide are the main substances detected in blood plasma. They make up approximately 10-20 and 80-90% of the total drug content in the blood plasma, respectively. Ezetimibe and ezetimibe glucuronide are slowly cleared from the blood plasma under conditions of intensive enterohepatic recirculation. T1/2 of ezetimibe and ezetimibe glucuronide is about 22 hours. Elimination After oral administration of 20 mg of labeled 14C-ezetimibe, the level of total ezetimibe in the blood plasma was 93% of the total radioactivity of the blood plasma. After 48 hours, no radioactive traces of the drug were detected in the blood plasma. Approximately 78 and 11% of the total dose taken were excreted within 10 days in feces and urine, respectively. Pharmacokinetics in special patient populations Children Absorption and metabolism of ezetimibe are similar in children, adolescents (10-18 years) and adults. According to the measurement of the concentration of total ezetimibe, pharmacokinetic parameters in adolescents and adults do not differ. Pharmacokinetic data for children under 10 years of age are not available. Clinical experience with ezetimibe in children and adolescents (9–17 years) is limited to patients with homozygous familial hypercholesterolemia and sitosterolemia. Elderly patients In elderly patients (over 65 years of age), the concentration of total ezetimibe in the blood plasma is approximately 2 times higher than in young patients (from 18 to 45 years of age). The degree of reduction in LDL cholesterol levels and the safety profile are comparable in elderly and young patients receiving Ezetrol®. Patients with Hepatic Impairment Following a single dose of 10 mg ezetimibe, the mean AUC for total ezetimibe in patients with mild hepatic impairment (Child-Pugh score 5-6) increases approximately 1.7-fold compared to healthy subjects. . In a 14-day study of 10 mg ezetimibe per day in patients with moderate hepatic impairment (Child-Pugh score 7-9), the AUC for total ezetimibe was approximately 4 times greater compared with healthy volunteers on both day 1 and and on the 14th day of the study. No dose adjustment is required for patients with mild hepatic impairment. Due to the lack of data on the use of ezetimibe doses exceeding 10 mg, ezetimibe is not recommended for patients with moderate to severe hepatic impairment (Child-Pugh score greater than 9) (see “Contraindications”). Patients with Renal Impairment Following a single 10 mg dose of ezetimibe in patients with severe renal disease (n=8; creatinine Cl less than or equal to 30 mL/min/1.73 m2), the AUC for total ezetimibe increased approximately 1.5-fold. compared with healthy volunteers (n=9). This result is not clinically significant. No dose adjustment is required for patients with impaired renal function. Gender Plasma concentrations of ezetimibe are slightly higher (less than 20%) in women than in men. The LDL-C reduction in low-density lipoprotein cholesterol and safety profile are comparable in men and women treated with ezetimibe. Therefore, no dose adjustment is required due to male or female gender.
Ezetrol®
In clinical studies of up to 112 weeks in which patients received Ezetrol 10 mg daily as monotherapy (n = 2396), concurrently with a statin (n = 11,308), or concomitantly with fenofibrate (n = 185), Ezetrol ® showed good tolerability. Adverse reactions were usually mild and transient; The overall incidence of adverse effects and the incidence of treatment discontinuation due to adverse effects when taking Ezetrol® were comparable to those when taking placebo.
The following common (≥ 1/100 and < 1/10) or infrequent (≥ 1/1000 and < 1/100) adverse reactions were observed when taking Ezetrol® in monotherapy (n = 2396) with a frequency exceeding the same frequency when taking placebo (n = 1159), or while taking Ezetrol® with a statin (n = 11,308) with a frequency exceeding the same frequency when taking a statin in monotherapy (n = 9361).
When taking Ezetrol® in monotherapy
Metabolic and nutritional disorders
Uncommon: decreased appetite.
Vascular disorders
Infrequent: “flushes” of blood to the skin of the face, increased blood pressure.
Respiratory, thoracic and mediastinal disorders Uncommon: cough.
Gastrointestinal disorders
Frequent: abdominal pain, diarrhea, flatulence.
Uncommon: dyspepsia, gastroesophageal reflux, nausea.
Musculoskeletal and connective tissue disorders
Uncommon: arthralgia, muscle spasms, neck pain.
General disorders
Common: fatigue.
Uncommon: chest pain, pain.
Laboratory and instrumental data
Uncommon: increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) activity, increased serum creatinine phosphokinase (CPK) activity, increased gamma-glutamyl transferase activity, impaired liver function tests.
When taking Ezetrol® simultaneously with a statin
Nervous system disorders
Frequent: headache.
Uncommon: paresthesia.
Gastrointestinal disorders
Uncommon: dry mouth, gastritis. Skin and subcutaneous tissue disorders Uncommon: itching, skin rash, urticaria.
Musculoskeletal and connective tissue disorders
Common: myalgia.
Uncommon: back pain, muscle weakness, limb pain.
General disorders
Uncommon: asthenia, peripheral edema.
Laboratory and instrumental data
Frequent: increased activity of ALT and/or AST.
When taking Ezetrol® simultaneously with fenofibrate
Gastrointestinal disorders
Common: abdominal pain.
In a multicenter, double-blind clinical study lasting up to 1 year in patients with mixed hyperlipidemia, the incidence of consistent clinically significant increases (more than 3 times the upper limit of normal (ULN)) in the activity of hepatic serum transaminases was 4.5% in the patient group , taking fenofibrate in monotherapy, and 2.7% in the group of patients taking Ezetrol® simultaneously with fenofibrate. The incidence of cholecystectomy was 0.6% in the group of patients taking fenofibrate alone, and 1.7% in the group of patients taking Ezetrol® simultaneously with fenofibrate (see SPECIAL INSTRUCTIONS). There was no increase in CPK activity (more than 10 times the ULN) in any of the treatment groups in this study.
Patients with coronary heart disease
In the IMPROVE-IT clinical trial (Cardiovascular Risk Reduction Study), 18,144 patients with coronary artery disease received simvastatin + ezetimibe at a dose of 40 mg + 10 mg (n = 9067; of which 6% of patients were titrated to 80 mg + 10 mg) or simvastatin 40 mg (n=9077; 27% of whom were titrated to 80 mg). The safety profile of the drugs in the two groups was similar throughout the entire observation period (median follow-up duration was 6 years). The discontinuation rate due to adverse events was 10.6% in the simvastatin + ezetimibe group and 10.1% in the simvastatin group. The incidence of myopathy was 0.2% in the group of patients taking simvastatin + ezetimibe, and 0.1% in the group of patients taking simvastatin, where myopathy was defined as unexplained muscle weakness or muscle pain, accompanied by an increase in CPK activity by at least 10 times above ULN or two successive increases in CPK activity from 5 to 10 times above ULN. The incidence of rhabdomyolysis was 0.1% in the group of patients taking simvastatin + ezetimibe, and 0.2% in the group of patients taking simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or muscle pain, accompanied by an increase in CPK activity by at least 10 times above ULN with signs of impaired renal function, two consecutive increases in CPK activity from 5 to 10 times higher than ULN with signs of impaired renal function, or CPK activity of at least 10,000 IU/ml without signs of impaired renal function. The incidence of sequential increases in hepatic transaminase activity (at least 3 times the ULN) was 2.5% in the group of patients taking simvastatin + ezetimibe, and 2.3% in the group of patients taking simvastatin (see SPECIAL INSTRUCTIONS). Adverse events from the gallbladder were observed in 3.1% of patients taking simvastatin + ezetimibe and 3.5% of patients taking simvastatin. The rate of hospitalization for cholecystectomy was 1.5% in both groups. Cancer (defined as any new malignancy) was diagnosed in 9.4% of patients treated with simvastatin+ezetimibe and 9.5% of patients treated with simvastatin during the study.
Patients with chronic kidney disease
In the SHARP clinical trial (Study of Cardio- and Nephroprotection) involving 4650 patients taking a fixed-dose combination lipid-lowering drug Ezetrol® (10 mg) and simvastatin (20 mg) once daily, and 4620 patients taking placebo, Safety profiles were comparable throughout the follow-up period (median follow-up duration was 4.9 years). In this clinical study, only serious adverse events and discontinuation due to adverse events were recorded. Discontinuation rates were comparable in both groups (10.4% in the fixed-dose combination group of Ezetrol® and simvastatin and 9.8% in the placebo group). The incidence of m.iopathy and/rhabdomyolysis was 0.2% in the group of patients 10 taking the fixed-dose combination drug of ezetimibe and simvastatin, and 0.1% in the group of patients taking placebo. Sequential increases in hepatic transaminase activity (more than 3 times the ULN) were observed in 0.7% of patients taking the fixed-dose combination drug of ezetimibe and simvastatin and in 0.6% of patients taking placebo. In this clinical study, there was no statistically significant increase in the incidence of adverse events such as malignancy (9.4% in the group of patients taking the fixed-dose combination drug Ezetrol® and simvastatin, and 9.5% in the group of patients taking placebo) , hepatitis, cholecystectomy or complications of gallstone disease or pancreatitis.
Children and teenagers from 6 to 17 years old
In a 12-week controlled clinical trial involving children aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia (n=138), the safety and tolerability profile of Ezetrol® was comparable to that of adult patients receiving Ezetrol®.
In a controlled clinical trial involving children aged 10 to 17 years with heterozygous familial hypercholesterolemia (n=248) receiving combination therapy with Ezetrol® and simvastatin, the safety and tolerability profile was comparable to that of adult patients receiving combination treatment the drug Ezetrol® and simvastatin.
Laboratory indicators
In controlled clinical studies, the frequency of consecutive clinically significant increases in the activity of “liver” transaminases in the blood serum (ALT and/or AST activity 3 or more times higher than ULN) was comparable when using the drug Ezetrol® in monotherapy (0.5%) and when taking placebo (0.3%). When studying the safety of combination therapy, the frequency of clinically significant increases in the activity of hepatic transaminases in the blood serum was 1.3% in patients taking Ezetrol® simultaneously with a statin, and 0.4% in patients taking a statin in monotherapy. The increase in transaminase activity in the blood serum was usually asymptomatic, was not accompanied by the development of cholestasis and returned to the initial level both with continued treatment and after discontinuation of the drug.
The incidence of clinically significant increases in CPK activity (10 or more times higher than ULN) in patients taking Ezetrol® in monotherapy was similar to this indicator in patients taking placebo or statin in monotherapy.
Post-registration observations
When using the drug Ezetrol® in the post-registration period, the following adverse reactions were reported without indicating a cause-and-effect relationship.
Blood and lymphatic system disorders: thrombocytopenia.
Immune system disorders: hypersensitivity reactions including anaphylaxis, angioedema, skin rash and urticaria.
Mental disorders: depression.
Nervous system disorders: dizziness, paresthesia.
Digestive system disorders: pancreatitis, constipation.
Disorders of the liver and biliary tract: hepatitis, cholelithiasis, cholecystitis.
Skin and subcutaneous tissue disorders: erythema multiforme.
Musculoskeletal and connective tissue disorders: myalgia, myopathy/rhabdomyolysis (see: SPECIAL INSTRUCTIONS).
General disorders: asthenia.
