Ezetimibe Tablets Instructions

Date of approval.
Date of revision.
Ezetimibe Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Ezetimibe Tablets
English name: Ezetimibe Tablets
Hanyu Pinyin: Yizhemaibu Pian
Ingredients
The main ingredient of this product is: Ezetimibe Chemical name: 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-acridine (azetidinyl) ketone.
Chemical structure formula.
Molecular formula: C24H21F2NO3
Molecular weight: 409.4
Properties]: This product is white or off-white tablet.
Indications
Primary hypercholesterolemia
It can be used alone or in combination with HMG-CoA reductase inhibitors (statins) for the treatment of primary (heterozygous familial or non-familial) hypercholesterolemia as an adjunctive therapy to dietary control to reduce total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B).
Pure-hereditary familial hypercholesterolemia (HoFH)
It is used in combination with statins as an adjunct to other lipid-lowering therapies (e.g. LDL-C plasma isolation and replacement method) or to lower TC and LDL-C levels in patients with HoFH when other lipid-lowering therapies are ineffective.
Pure congenital glutathionemia (or phytosterolemia)
This product is used as an adjuvant therapy in addition to dietary control to reduce glutathione and phytosterol levels in patients with pure-hereditary familial glutathioneemia.
Specification】10mg.
【Dosage】.
Patients should adhere to an appropriate low-fat diet during the course of treatment with this product.
The recommended dose of this product is 10mg once a day, either alone, or in combination with a statin, or in combination with fenofibrate. It can be taken at any time of the day, either on an empty stomach or with food.
Drug Use in Elderly Patients
No dose adjustment is required in elderly patients.
Use of the drug in pediatric patients
Children and adolescents older than or equal to 10 years of age: no dose adjustment is required.
Children younger than 10 years of age: the application of this product is not recommended.
Drug use in patients with impaired hepatic function
No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh score of 5 or 6). Ezetimibe therapy is not recommended for patients with moderate (Child-Pugh score 7-9) or severe (Child-Pugh score>9) hepatic function abnormalities. (See [Precautions] and [Pharmacokinetics].)
Drug Use in Patients with Impaired Renal Function
Dose adjustment is not required in patients with impaired renal function.
Combined use with bile acid chelators
This product should be taken more than 2 hours before or more than 4 hours after the administration of bile acid chelator.
Adverse reactions]
In a 112-week clinical study, patients taking 10 mg of this product daily alone (n=2396) or in combination with statins (n=11,308) or fenofibrate (n=185) showed that the product was generally well tolerated by patients, with mild and transient adverse reactions, an overall incidence of side effects similar to placebo, and a discontinuation rate due to adverse reactions comparable to that of the placebo group. The overall incidence of side effects was similar to placebo, and the rate of discontinuation due to adverse reactions was comparable to the placebo group.
The following common (≥1/100, <1/10) or uncommon (≥1/1,000, <1/100) drug-related adverse reactions were reported in patients on this product alone (n=2,396) with a higher incidence than in the placebo group (n=1,159) and in patients in combination with statins (n=11,308) with a higher incidence than in patients on statins alone (n =9,361).
With this product alone.
Laboratory tests.
Uncommon: elevated glutamate aminotransferase (ALT) and/or glutathione aminotransferase (AST), elevated creatine phosphokinase (CPK), elevated gamma-glutamyl transferase, abnormal liver function tests
Respiratory, thoracic and mediastinal system abnormalities.
Uncommon: cough
Abnormalities of the digestive system.
Common: abdominal pain, diarrhea, gastrointestinal gas and bloating
Uncommon: dyspepsia, gastroesophageal reflux, nausea
Musculoskeletal and connective tissue abnormalities.
Uncommon: joint pain, muscle spasms, neck pain
Metabolic and nutritional abnormalities.
Uncommon: loss of appetite
Abnormalities of the vascular system.
Uncommon: hot flashes, elevated blood pressure
Systemic abnormalities and medication site abnormalities.
Common: fatigue
Uncommon: chest pain, generalized pain
In combination with a statin.
Laboratory tests.
Common: elevated ALT, elevated AST
Neurological abnormalities.
Common: headache
Uncommon: sensory abnormalities
Digestive system abnormalities.
Uncommon: dry mouth, gastritis
Skin and subcutaneous tissue abnormalities.
Uncommon: pruritus, rash, rubella
Musculoskeletal and connective tissue abnormalities.
Common: myalgia
Uncommon: back pain, myalgia, limb pain
Systemic abnormalities and medication site abnormalities.
Common: malaise, peripheral edema
Digestive system abnormalities.
Common: abdominal pain
Combination of this product with fenofibrate.
In a multicenter, double-blind, placebo-controlled clinical study in patients with mixed hyperlipidemia, 625 patients were treated for 12 weeks, of whom 576 were extended for 48 weeks. Ezetimibe in combination with fenofibrate was well tolerated. The study was not designed to compare rare events between treatment groups. The incidence (95% confidence interval) of clinically significant elevations in serum transaminases [sustained >3 times the upper limit of normal (ULN)] was 4.5% (1.9,8.8) and 2.7% (1.2,5.4) with fenofibrate alone and in combination with fenofibrate, respectively (adjusted for treatment). The incidence of cholecystectomy was 0.6% (0.0,3.1) and 1.7% (0.6,4.0), respectively (see [Caution]). The number of patients in this study on ezetimibe or fenofibrate alone or in combination with both was not sufficient to evaluate the risk of gallbladder disease. There was no CPK elevation >10-fold ULN in any of the groups in this study.
This product was used in combination with simvastatin in
Patients with coronary artery disease
In the Ezetimibe/Simvastatin International Efficacy Trial (IMPROVE-IT) study, a total of 18,144 patients with coronary artery disease were treated with either ezetimibe/simvastatin 10/40 mg (n=9067, of which 6% were dosed up to ezetimibe/simvastatin 10/80 mg) or simvastatin 40 mg (n=9077, of which 27% were dosed up to simvastatin 80 mg). upregulated to simvastatin 80 mg), with similar safety profiles during a median follow-up period of 6.0 years. The proportion of discontinuations due to adverse effects was 10.6% in the ezetimibe/simvastatin treatment group and 10.1% in the simvastatin treatment group. The incidence of myopathy was 0.2% in the ezetimibe/simvastatin treatment group and 0.1% in the simvastatin group. Myopathy was defined as unexplained muscle weakness or pain with serum CK ≥ 10-fold ULN or two consecutive tests for CK ≥ 5 and<10-fold ULN. the incidence of rhabdomyolysis was 0.1% in the ezetimibe/simvastatin-treated group and 0.2% in the simvastatin group. Rhabdomyolysis was defined as unexplained muscle weakness or pain with serum CK ≥ 10-fold ULN with manifestations of renal injury, or two consecutive CK ≥ 5 and <10-fold ULN with manifestations of renal injury, or CK ≥ 10,000 IU/L without manifestations of renal injury. The incidence of consecutive elevations of transaminases (≥3-fold ULN) was 2.5% in the ezetimibe/simvastatin-treated group and 2.3% in the simvastatin-treated group. (See [Precautions].) Gallbladder-related adverse reactions were 3.1% and 3.5% in the ezetimibe/simvastatin treatment group and the simvastatin treatment group, respectively. The incidence of inpatient cholecystectomy was 1.5% in both groups. The proportion of patients diagnosed with cancer (any new malignancy) during the study period was 9.4% and 9.5% in the ezetimibe/simvastatin treatment group versus the simvastatin treatment group, respectively.
Patients with chronic kidney disease
In the Study of Heart and Renal Protection (SHARP), more than 9,000 patients with chronic kidney disease were treated with ezetimibe 10 mg daily in combination with simvastatin 20 mg (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. Discontinuation rates due to adverse events were similar in the ezetimibe combined with simvastatin and placebo groups, 10.4% versus 9.8%, respectively; the incidence of myopathy/rhabdomyolysis was 0.2% and 0.1%, respectively, and the proportion of patients with persistent transaminase elevations (>3-fold ULN) was 0.7% and 0.6% in the ezetimibe simvastatin combination and placebo treatment groups, respectively. (See [Caution].) In this clinical trial, no statistically significant increase in the incidence of predefined adverse events, including cancer (9.4% and 9.5% in the combination of this product with simvastatin and placebo-treated groups, respectively), hepatitis, gallstones gallbladder removal or complications of gallstones, or pancreatitis was seen.
Pediatric patients (6 to 17 years of age)
In a study enrolling pediatric patients (6 to 10 years of age) with heterozygous familial or nonfamilial hypercholesterolemia (n=138), the safety and tolerability of pediatric patients treated with this product were similar to those of adult patients (see [Pediatric Dosage] and [Clinical Trials], Clinical Studies in Pediatric Patients (6 to 17 Years of Age)). The safety and efficacy of this product in combination with simvastatin was evaluated in a study that included adolescent patients (10 to 17 years of age, n=248) with heterozygous familial hypercholesterolemia. Adolescent patients receiving this product in combination with simvastatin had an adverse effect profile similar to that of adult patients.
Laboratory indicators.
In controlled clinical studies of this product alone, the incidence of transaminase elevations (ALT and/or AST ≥3 times ULN) following administration of this product (0.5%) was similar to placebo (0.3%). In the combination study of this product with a statin, the incidence of transaminase elevation was 1.3% in patients taking this product in combination with a statin and 0.4% in patients taking a statin alone. This transaminase elevation is not clinically manifest and is not associated with cholestasis and decreases to normal values after interruption or continuation of therapy.
CPK elevations (≥10-fold ULN) occurred at similar rates in patients taking placebo or statins alone or in combination with statins, respectively.
Post-marketing reported adverse reactions (ignoring causality evaluation).
Hematologic and lymphatic abnormalities: thrombocytopenia
Abnormalities of the nervous system: dizziness; sensory abnormalities
Abnormalities of the digestive system: pancreatitis; constipation
Skin and subcutaneous system abnormalities: erythema multiforme
Musculoskeletal and connective tissue abnormalities: myalgia; myopathy/rhabdomyolysis (see [Precautions])
Systemic abnormalities and drug administration site abnormalities: weakness.
Immune system abnormalities: hypersensitivity reactions, including allergic reactions, angioneurotic edema, rash, and urticaria.
Hepatic system abnormalities: hepatitis; gallstones; cholecystitis.
Mental abnormalities: depression.
[Contraindication
Hypersensitivity to any of the ingredients of this product.
This product is contraindicated in combination with HMG-CoA reductase inhibitors in patients with active liver disease, or unexplained persistent elevation of serum transaminases.
All HMG-CoA reductase inhibitors are restricted for use in pregnant and lactating women. When this product is used in combination with such drugs in women with potential childbirth, refer to the HMG-CoA reductase inhibitor product insert (see [Use in Pregnant and Lactating Women]).
Precautions]
When this product is used in combination with a statin or fenofibrate, please refer to the instructions for use of that statin or fenofibrate.
Liver enzymes
Persistent elevation of serum transaminases (≥3 times ULN) has been found in controlled studies of this product in combination with statins. Therefore, when this product is used in combination with a statin, liver function should be measured prior to treatment, and the product insert for the statin should be consulted.
The IMPROVE-IT study included 18,144 patients with coronary artery disease randomized to treatment with ezetimibe/simvastatin 10/40 mg/day (n=9067) or simvastatin 40 mg/day (n=9077). The median follow-up period was 6.0 years, and the incidence of serial elevations of transaminases (≥3 times ULN) was 2.5% in the ezetimibe/simvastatin-treated group and 2.3% in the simvastatin-treated group. (See [Adverse Reactions].)
Skeletal muscle
In clinical studies, application of this product did not increase the incidence of myopathy or rhabdomyolysis compared to the control group (placebo or statin alone). Myopathy and rhabdomyolysis are known adverse effects of statins and other lipid-lowering drugs. In clinical studies, the incidence of CPK > 10-fold ULN was 0.2% in the treatment group with this product and 0.1% in the placebo group, and the incidence was 0.1% with the combination of this product and statins and 0.4% with statins alone. Cases of myopathy and rhabdomyolysis have been reported after the introduction of this product (whether myopathy and rhabdomyolysis are drug-related is unclear). Most patients who developed rhabdomyolysis were taking statins before taking this product. However, very rare cases of rhabdomyolysis have been reported when this product is used alone or in combination with drugs known to increase the risk of rhabdomyolysis. All patients should be informed of the risk of rhabdomyolysis occurring at the time of initiating treatment with this product and be advised to promptly report any unexplained myalgia, tenderness, or weakness. If a patient is diagnosed with or suspected of having myopathy, this product and any statin being combined should be discontinued immediately. The presence of these symptoms and a CPK level >10 times ULN indicates the occurrence of myopathy.
The IMPROVE-IT study included 18,144 patients with coronary artery disease randomized to daily ezetimibe/simvastatin 10/40 mg (n=9067) or simvastatin 40 mg (n=9077), with a median incidence of myopathy of 0.2% in the ezetimibe/simvastatin treatment group and 0.1% in the simvastatin treatment group during a median follow-up of 6.0 years. Myopathy was defined as unexplained muscle weakness or pain with serum CK ≥10 times ULN or two consecutive tests for CK ≥5 and<10 times ULN. the incidence of rhabdomyolysis was 0.1% in the ezetimibe/simvastatin-treated group and 0.2% in the simvastatin group. Rhabdomyolysis was defined as unexplained muscle weakness or pain with serum CK ≥ 10 times ULN with manifestations of renal injury, or two consecutive CK ≥ 5 and<10 times ULN with manifestations of renal injury, or CK ≥ 10,000 IU/L without manifestations of renal injury. (See [Adverse Reactions].)
Hepatic insufficiency
Given that the effects of long-term application of ezetimibe on patients with moderate or severe hepatic insufficiency are not known, it is not recommended for such patients (see [Pharmacokinetics]).
Betablockers
The safety and efficacy of this drug in combination with fibrates other than fenofibrate have not been established, so the combination of these two drugs (except fenofibrate) is not recommended.
Fenofibrate
If gallstones are suspected in patients taking ezetimibe and fenofibrate, examination of the gallbladder is indicated and other drugs should be considered for lipid-lowering therapy (see [Adverse Reactions] and the instructions for fenofibrate).
Cyclosporine
This product should be used with caution during the use of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving this product in combination with cyclosporine.
Anticoagulants
If this product is used in combination with warfarin, other coumarin anticoagulants, or fluoroindandione, the International Normalized Ratio (INR) should be monitored appropriately.
Pregnant women and nursing mothers
There is no clinical data on the use during pregnancy. Animal studies have shown no direct or indirect adverse effects on pregnancy, embryonic and fetal development, delivery, or postnatal neonatal development. However, this product should be used with caution in pregnant women.
In studies on pregnant rats, no embryonic or fetal teratogenic effects were observed in combination with lovastatin, simvastatin, pravastatin and atorvastatin. In studies with pregnant rabbits, a small number of skeletal malformations were seen to occur.
Studies in rats have found that ezetimibe can be excreted from rat breast milk. It is uncertain whether ezetimibe is excreted in human breast milk, therefore, it should not be used in nursing women unless it can be demonstrated that the potential benefits outweigh the potential risks to the infant.
Pediatric Dosage]
The pharmacokinetics of ezetimibe in pediatric patients ≥6 years of age are similar to those in adult patients. No pharmacokinetic data are available for pediatric populations younger than 6 years of age. The safety and efficacy of this product was evaluated in a 12-week controlled clinical trial in patients aged 6 to 10 years with heterozygous familial or nonfamilial hypercholesterolemia. The adverse effect profile in children treated with this product was similar to that in adult patients treated with this product. No effects on growth or sexual maturation were detected overall in boys or girls in this study. However, the effects of ezetimibe on growth and sexual maturation after a treatment period longer than 12 weeks have not been studied. (See [DOSAGE]; [ADVERSE REACTIONS]; and [CLINICAL TRIALS], Clinical Studies in Pediatric Patients (6 to 17 Years of Age).)
In a controlled clinical trial in adolescent boys and girls (at least one year after menarche), the safety and efficacy of combining this product with simvastatin was evaluated in patients aged 10 to 17 years with heterozygous familial hypercholesterolemia. Adolescent patients treated with this product and up to 40 mg/day of simvastatin had an adverse effect profile similar to that of adult patients treated with this product and simvastatin. In this controlled study, no effects on growth or sexual maturation of adolescent boys or girls were detected, nor were there any effects on the length of menstrual cycles in girls. (See [DOSAGE]; [ADVERSE REACTIONS]; and [CLINICAL TRIALS] for clinical studies in pediatric patients (6 to 17 years of age).)
[Geriatric Use].
Plasma concentrations of total ezetimibe (ezetimibe + ezetimibe glucosinolate) were twice as high in elderly patients (>65 years) as in younger patients (18-45 years). The extent and safety of LDL-C reduction after dosing did not differ significantly between older and younger patients. Therefore, no dose adjustment is required in elderly patients.
Drug Interactions]
Preclinical studies have shown no induction of cytochrome P450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions were found with drugs known to be metabolized by cytochrome P450, 1A2, 2D6, 2C8, 2C9, 3A4, or trans-N-acetylases.
When combined with aminophene, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, toluenesulfonylurea or midazolam, this product was not found to affect the pharmacokinetics of these drugs. When cimetidine was combined with this product, cimetidine did not affect the bioavailability of this product.
Antacids: Concomitant administration of antacids may reduce the absorption rate of this product but does not affect its bioavailability. This reduction in absorption rate is not clinically significant.
Desipramine: Concomitant administration of desipramine reduces the mean AUC of total ezetimibe by approximately 55%. When this product is added to bilirubicin to augment the LDL-C lowering effect, the augmentation effect may be reduced by the interactions described above.
Cyclosporine: In one study, the mean AUC of total ezetimibe increased 3.4-fold (range 2.3 to 7.9-fold) in eight renal transplant patients with creatinine clearance >50 ml/min and on stable doses of cyclosporine, after a single dose of 10 mg ezetimibe, compared with a healthy population in another study (n=17). In another study, a renal transplant patient with severe renal insufficiency (creatinine clearance 13.2 ml/min/1.73 m2) treated with multiple drugs including cyclosporine had a 12-fold increase in total ezetimibe exposure compared to controls. In a phase II crossover study of 12 healthy subjects, each receiving 20 mg of this product daily for 8 days and a single dose of 100 mg of cyclosporine for 7 days resulted in a 15% increase in the mean AUC of cyclosporine compared to cyclosporine alone (range -10% to +51%).
Betablockers: Studies of the combination of this product with betablockers other than fenofibrate have not been conducted.
Betablockers can increase the concentration of cholesterol in the bile and contribute to the development of cholelithiasis. In preclinical studies in dogs, this product was found to increase cholesterol levels in the bile. The combination of this product with fenofibrate is not recommended at this time until relevant studies are conducted.
Fenofibrate: In pharmacokinetic studies, fenofibrate increased total ezetimibe concentrations approximately 1.5-fold when co-administered with fenofibrate. If gallstones are suspected while the patient is receiving this product in combination with fenofibrate, gallbladder examination is required and other drug options for lipid-lowering therapy should be considered.
Gemfibrozil: In pharmacokinetic studies, gemfibrozil increased total ezetimibe concentrations approximately 1.7-fold when this product was co-administered with gemfibrozil. No clinical data are available.
Statins: No clinically meaningful pharmacokinetic interactions have been observed in combination with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, and rasulvastatin.
Anticoagulants: Studies in 12 healthy men have shown that co-administration of this product (10 mg/day) with warfarin or fluoxetine did not significantly affect the bioavailability or clotting time of warfarin. An increase in the international normalized ratio has been reported in patients who have received this product in combination with warfarin since its introduction. Most of these patients were also receiving other medications.
[Drug Overdose].
In clinical studies, 15 healthy subjects took 50 mg of this product daily for 14 consecutive days, 18 patients with primary hypercholesterolemia took 40 mg of this product daily for 56 consecutive days, and 27 patients with pure congenital glutathionemia took 40 mg of this product daily for 26 weeks and generally tolerated it well.
A few overdoses of this product have been reported, and the vast majority did not experience adverse reactions, and none of the reported adverse reactions were serious. Symptomatic and supportive treatment should be administered in overdose events.
Clinical trials]
Foreign clinical study data show that
Primary hypercholesterolemia
Individual dosing
In two multicenter, double-blind, placebo-controlled, 12-week studies, 1719 patients with primary hypercholesterolemia were treated with 10 mg of this product daily. It significantly reduced TC, LDL-C, Apo B and TG and increased HDL-C (see Table 1). LDL-C reduction was consistent across patients of different ages, genders, races, and baseline LDL-C levels. It had no effect on plasma concentrations of lipolytic vitamins A, D, and E, no effect on prothrombin time, and no effect on adrenocortical steroid production.
Table 1 Mean values of changes in each index in patients with primary hypercholesterolemia treated with this product
(Mean amount of change from baseline values %)
Treatment group N TC LDL-C Apo B TGa HDL-C
Trial 1 Placebo 205 +1 +1 -1 -1 -1 -1 This product 622 -12 -18 -15 -7 +1 Trial 2 Placebo 226 +1 +1 -1 -1 +1 +2 -2 This product 666 -12 -18 -16 -9 +1 Total data (Trial 1&2) Placebo 431 0 +1 -2 0 -2 This product 1288 -13 -18 -16 -8 +1a vs. TG, as median % change from baseline values compared to the median % change.
Combination of this product with a statin
The starting combination of this product with a statin
In four multicenter, double-blind, placebo-controlled, 12-week studies, 1187 patients with primary hypercholesterolemia were treated with 10 mg of this product alone or in combination with various doses of atorvastatin, simvastatin, pravastatin, and lovastatin daily. The additional LDL-C lowering effect in patients in the combination treatment group was independent of the type and dose of the statin. The LDL-C lowering effect of this product in combination with the smallest dose of statins was superior to that of high-dose statins alone (see Table 2).
Table 2 Mean % change in LDL-C plasma concentrations in patients on the combination compared with baseline values
Atorvastatin Simvastatin Pravastatin Lovastatin
Study Study Study Study Study
Placebo + 4-1-10 Benadryl-20-19-20-1910 mg Statin-37-27-21-20 Benadryl + 10 mg Statin-53-46-34-3420 mg Statin-42-36-23-26 Benadryl + 20 mg Statin-54-46-40-4140 mg Statin-45-38-31-30 Benadryl + 40 mg statin-56-56-42-4680 mg statin-54-45–this product + 80 mg statin-61-58–Total data: all statin doses-44-36-25-25Total data: all this product + statin doses-56-51-39-40In the overall analysis of this product in combination with statins, this product had a lowering effect on TC, Apo B TG, while HDL-C was elevated (Table 3).
Table 3 Mean % change in TC, Apo B, TG, and HDL-C in the pooled analysis compared with baseline values
TC Apo B TGa HDL-C
This product + Atorvastatin -41 -45 -33 +7 Atorvastatin alone -32 -36 -24 +4 This product + Simvastatin -37 -41 -29 +9 Simvastatin alone -26 -30 -20 +7 This product + Pravastatin -27 -30 -21 +8 Pravastatin alone -17 -20 -14 +7 This product + Lovastatin -29 -33 -25 +9 Lovastatin alone with lovastatin -18 -21 -12 +4a on TG, as median % change.
The addition of this product to the application of statin therapy
In a multicenter, double-blind, placebo-controlled 8-week clinical study, 769 patients with primary hypercholesterolemia were receiving statin monotherapy but had not yet reached NCEP-specified LDL-C levels (100 to 160 mg/dl, depending on baseline levels), after which they were randomized to the addition of this product or placebo.
Among patients who did not reach the LDL-C target value with baseline statin therapy (approximately 82%), the proportion of patients who achieved the LDL-C target for the study endpoint was 72% and 19% in the Benadryl and placebo groups, respectively.
This study showed that combining this product with statin therapy significantly reduced plasma TC, LDL-C, Apo B, and TG and increased HDL-C (see Table 4). The effect of combining this product with various statins to lower LDL-C was similar.
Table 4 Mean change in each index after addition of this product in patients with primary hypercholesterolemia undergoing statin therapya (mean % change from baseline values)
Treatment (daily) N TC LDL-C Apo B TGb HDL-C
Taking statin + placebo 390 -2 -4(-6mg/dlc) -3 -3 +1 Taking statin + this product 379 -17 -25(-36mg/dlc) -19 -14 +3a Proportion of patients on various statins: 40% atorvastatin, 31% simvastatin, 29% other (pravastatin, fluvastatin, cerivastatin, lovastatin)
bMedian % change in TG compared to baseline values.
cChange in LDL-C compared to baseline values (138 mg/dl basal LDL-C in the statin + this product group and 139 mg/dl baseline LDL-C in the statin + placebo group)
In a multicenter, double-blind, placebo-controlled, 14-week study, 621 patients with primary hypercholesterolemia who were taking atorvastatin and had LDL-C greater than 130 mg/dl were randomized to two groups, one receiving atorvastatin 20 mg daily and the other receiving atorvastatin 10 mg + 10 mg of this product daily. In LDL-C-naive patients (LDL-C <100 mg/dl), the dose was increased to 80 mg in patients treated with atorvastatin monotherapy and to 40 mg in patients treated with atorvastatin in combination with this product. the mean baseline LDL-C in the combination treatment group was 187 mg/dl, and 60% had heterozygous familial hypercholesterolemia (HeFH). At the end of the study, LDL-C attainment was 7% in the monotherapy group compared to 22% in the combination therapy group, a highly significant difference. LDL-C reduction rates were already significantly different between the two groups at week 4 (24% in the combination group versus 9% in the monotherapy group). LDL-C attainment and reduction rates showed similar results in the subgroup of patients with heterozygous familial hypercholesterolemia.
In a similar study, 100 patients treated with simvastatin 20 mg did not reach the LDL-C standard, with one group receiving simvastatin + 10 mg of this product and the other group doubling the simvastatin dose, with results similar to the study with atorvastatin described above. If there was a significant difference in LDL-C attainment (3% in the simvastatin monotherapy group and 27% in the combination therapy group). The mean LDL-C reduction was 11% in the monotherapy group and 24% in the combination therapy group.
Combination with fenofibrate
In a multicenter, double-blind, placebo-controlled clinical study enrolling patients with mixed hyperlipidemia, 625 patients were treated for 12 weeks, including 576 patients treated for up to 1 year. Patients were randomized to receive placebo, to this product alone, to fenofibrate 160 mg alone, or to receive this product in combination with 160 mg of fenofibrate.
The combination of this product with fenofibrate significantly reduced TC, LDL-C, ApoB, and non-HDL-C compared to fenofibrate alone. the percentage reduction in TG and the percentage increase in HDL-C were comparable to fenofibrate monotherapy, as shown in Table 5.
Table 5 Effect of the combination of this product and fenofibrate in patients with mixed hyperlipidemia
(a Mean percentage change from baseline values after 12 weeks of treatmentb)
Treatment (daily) NTCLDL-CApo BTGaHDL-CNon-HDL-C Placebo 6300-1-9+30 Benadryl 185-12-13-11-11+4-15 Fenofibrate 160mg 188-11-6-15-43+19-16 Benadryl + Fenofibrate 160mg 183-22-20-26-44+19 -30aTriglycerides mean percentage change from baseline
bBaseline – no lipid-lowering drugs
The improvement in lipid levels at 1 year of treatment was consistent with the data presented above at 12 weeks.
Clinical studies in pediatric patients (6 to 17 years of age)
In a multicenter, double-blind, controlled study, 138 [59 boys, (51 Tanner stage I and 6 Tanner stage II) and 79 girls (52 Tanner stage I, 22 Tanner stage II and 1 Tanner stage III)] aged 6 to 10 years (mean age 8.3 years) with heterozygous familial or nonfamilial hyper cholesterolemic patients were randomized to receive either 10 mg of this product or placebo for 12 weeks. Inclusion criteria: 1) LDL-C baseline level >159 but <400 mg/dl; 2) history and clinical presentation consistent with HeFH.
At week 12, this product significantly reduced TC, LDL-C, Apo B, and non-HDL-C compared to the placebo group. results for TG and HDL- C were similar in both groups.
Table 6 Effect of this product in pediatric patients with heterozygous familial hypercholesterolemia
(Mean % change from untreated baseline-a)
Treatment (daily dose) NTotal-CLDL-CApo BHDL-CTGaNon-HDL-C Week 12 This product 85-21-28-22+2-6-26 Placebo 420-1-1+1+1+80a For triglycerides, geometric mean % change from baseline
bBaseline – no lipid-lowering agents applied
In a multicenter, double-blind, controlled study, 142 boys and 106 postmenarcheal girls (10 to 17 years of age (mean age 14.2 years)) with heterozygous familial hypercholesterolemia (HeFH) were randomized to receive either the combination of this product and simvastatin or simvastatin monotherapy. Enrollment requirements: 1) LDL-C between 160 and 400 mg/dl at baseline; 2) history and clinical presentation consistent with HeFH. Patients received 6 weeks of combination therapy with this product and simvastatin ( 10mg, 20mg or 40mg) or simvastatin monotherapy (10mg, 20mg or 40mg), followed by 27 weeks of combination therapy with this product and 40mg simvastatin, or simvastatin 40mg monotherapy, and open access for the following 20 weeks to this product and simvastatin (10mg, 20mg or 40 mg) combination therapy.
At week 6, the ezetimibe simvastatin (all doses) combination treatment group reduced TC, LDL-C, ApoB, and non-HDL-C significantly more than the simvastatin monotherapy group (all doses), with similar results for TG and HDL-C (see Table 7). At week 33, ezetimibe combined with simvastatin had a more significant effect on reducing TC, LDL-C, Apo B, TG, and non-HDL-C compared with simvastatin monotherapy; the effect of increasing HDL-C was similar in both groups. In addition, at week 33, the proportion of patients achieving the ideal LDL-C target recommended by the American Academy of Pediatrics (AAP) (<110 mg/dl) was significantly higher in the ezetimibe combined with simvastatin treatment group (63%) than in the simvastatin 40 mg monotherapy group (27%). At week 53, the mean percent change in lipids compared to baseline levels in the group treated with the combination of this product and simvastatin (all doses) were: -39 % (TC); -49 % (LDL-C), -23 % (Apo B), +3 % (HDL-C), -17 % (TG) and -46 % (non-HDL-C), respectively.
Table 7 Ezetimibe in combination with simvastatin in adolescent patients with heterozygous familial hypercholesterolemia ( a mean % change compared to untreated baseline levelsb)
Treatment (daily dose) N Total-CLDL-CApo BHDL-CTGa Non-HDL-C Week 6 Pooled Data
This product + all doses of simvastatin 126-38-49-39+7-17-47 All doses of simvastatin 120-26-34-27+6-12-33 This product + different doses of simvastatin
This product + simvastatin 10mg43-37-47-37+4-18-44 This product + simvastatin 20mg40-37-50-39+10-17-47 This product + simvastatin 40mg43-40-52-41+6-13-49 Different doses of simvastatin
10mg39-23-30-23+3-4-28 20mg39-26-34-27+10-12-33 40mg42-30-39-29+7-20-37 Week 33 This product + simvastatin 40mg126-42-54-43+5-20-51 Simvastatin 40mg120-29-38-28+4-13- 36aFor triglycerides, median % change in evaluation from baseline
bBaseline – no lipid-lowering drugs applied
The safety and efficacy of the combination of this product with octreotide at doses above 40 mg per day has not been studied in children. This product has not been studied in patients younger than 6 years of age. Long-term studies have not been conducted on the effectiveness of treatment with this product in children to reduce morbidity and mortality in adulthood.
Pure-Homozygous Familial Hypercholesterolemia
In a double-blind, randomized, 12-week study evaluating the efficacy of this product in pure-sibling familial hypercholesterolemia, 50 patients with a clinical or genotypic diagnosis of pure-sibling familial hypercholesterolemia, not all of whom had abnormal LDL-C and were treated with atorvastatin (40 mg) or simvastatin (40 mg), were enrolled. Patients were divided into three groups, one group received atorvastatin (40 mg) or simvastatin (80 mg), one group received this product 10 mg + atorvastatin (40 mg) or simvastatin (40 mg), and the other group received this product 10 mg + atorvastatin (80 mg) or simvastatin (80 mg). The results are shown in Table 8, which indicates that the combination of this product with atorvastatin (40 or 80 mg) or simvastatin (40 or 80 mg) was significantly more effective in lowering LDL-C than monotherapy with simvastatin or atorvastatin (40 mg-80 mg).
Table 8 LDL-C-lowering effect of this product in patients with purex familial hypercholesterolemia
(Mean % change from baseline)
Treatment (daily dose) NLDL-C atorvastatin (80 mg) or simvastatin (80 mg) 17-7 This product + atorvastatin (40,80 mg) or simvastatin (40,80 mg) 33-21 Subgroup analysis: This product + atorvastatin (80 mg) or simvastatin (80 mg) 17-27 Cardiovascular disease prevention
Further Reduction in Outcome: The International Trial of Ezetimibe/Simvastatin Efficacy (IMPROVE-IT) is a multicenter, randomized, double-blind, active drug-controlled study enrolling 18,144 patients who developed acute coronary syndrome (ACS) within 10 days [acute myocardial infarction (MI) or unstable angina (UA)]. Lipid levels were LDL-C ≤ 125 mg/dL ( ≤ 3.2 mmol/L) if patients were not receiving lipid-lowering therapy and LDL-C ≤ 100 mg/dL (≤ 2.6 mmol/L) if they had received lipid-lowering therapy. Patients were randomly assigned in a 1:1 ratio to either the ezetimibe/simvastatin 10/40 mg treatment group ( n = 9067 ) or the simvastatin 40 mg treatment group (n = 9077) with a median follow-up period of 6.0 years.
Patients had a mean age of 63.6 years, 76% were male, 84% were white, and 27% were diabetic. The mean LDL-C at study entry was 80 mg/dL (2.1 mmol/L) in patients receiving lipid-lowering therapy (n=6390) and 101 mg/dL (2.6 mmol/L) in patients who had not received lipid-lowering therapy (n=11594). Prior to hospitalization, 34% of patients with ACS received statins. 1 year later, the mean LDL-C was 53.2 mg/dL (1.4 mmo/L) in the ezetimibe/simvastatin-treated group and 69.9 mg/dL (1.8 mmol/L) in the simvastatin monotherapy group. Lipid parameters were collected from all patients treated in the study.
The primary endpoints were cardiovascular death, major coronary events (MCE: defined as nonfatal infarction, unstable angina requiring hospitalization, or any coronary revascularization after 30 days of randomization), and the composite endpoint of nonfatal stroke. Results showed that adding ezetimibe treatment to simvastatin provided additional benefit compared with simvastatin monotherapy for the primary composite endpoint of cardiovascular death, MCE, and nonfatal stroke (relative risk reduction of 6.4%, p=0.016). 2572 patients in the 9067 ezetimibe/simvastatin treatment group experienced the primary endpoint (7-year Kaplan- Meier (KM) event rate of 32.72%) and 2742 patients in the 9077 simvastatin monotherapy patients (7-year KM event rate of 34.67%). (See Figure 1 and Table 9.) This gain is expected to be similar to that seen with the combination of other statins that are effective in reducing the risk of cardiovascular events.
The effect of ezetimibe/simvastatin treatment was consistent with the overall results in subgroup analyses that included sex, age, race, history of diabetes, baseline lipid levels, prior statin therapy, prior stroke, and hypertension (see Figure 2).
Figure 1: Effect of ezetimibe/simvastatin on the primary composite endpoint of cardiovascular death, major coronary events, and nonfatal stroke
Figure 2: Subgroup analysis of the primary composite endpoint of cardiovascular death, major coronary events and non-fatal stroke
Table 9 Primary cardiovascular events in the treatment arm for all randomized patients in the IMPROVE-IT study
Ending ezetimibe/simvastatin
10/40mg* (N=9067) Simvastatin
40mgœ
(N=9077) Risk ratio (95% Cl) p-value nK-M %╪nK-M %╪ Primary composite endpoint (cardiovascular death, major coronary events, and nonfatal stroke) 257232.72% 274234.67% 0.936(0.887,0.988) 0.016 Secondary composite efficacy endpoint Coronary death, nonfatal infarction, 30 days after randomization Coronary revascularization132217.52%144818.88%0.912(0.847,0.983)0.016 Primary cardiovascular event, nonfatal stroke, death (all causes)308938.65%324640.25%0.948(0.903,0.996)0.035 Cardiovascular death, nonfatal infarction, need for hospitalization for unstable angina, revascularization, nonfatal stroke 271634.49% 286936.20% 0.945 (0.897,0.996) 0.035 Primary composite endpoint composition and selection of efficacy endpoints (first occurrence of the specified event at any time) Cardiovascular death 5376.89% 5386.84% 1.000 (0.887 ,1.127) 0.997 Major coronary events: nonfatal infarction94512.77%108314.41%0.871 (0.798,0.950) 0.002 Unstable heart requiring hospitalization
Angina 1562.06%1481.92%1.059(0.846,1.326)0.618 Coronary revascularization after 30 days169021.84%179323.36%0.947(0.886,1.012)0.107 Non-fatal stroke2453.49%3054.24%0.802(0.678, 0.949) 0.010 All types of myocardial infarction (fatal and nonfatal) 97713.13% 111814.82% 0.872 (0.800,0.950) 0.002 All types of stroke (fatal and nonfatal) 2964.16% 3454.77% 0.857 (0.734,1.001) 0.052 Nonhemorrhagic stroke §2423.48%3054.23%0.793(0.670,0.939)0.007 Hemorrhagic stroke590.77%430.59%1.377(0.930,2.040)0.110 Deaths from any cause121515.36%123115.28%0.989(0.914,1.070) 0.782* 6% dose up-regulation to ezetimibe/simvastatin 10/80 mg
œ 27% dose upregulation to simvastatin 80mg.
╪ Estimated Kaplan-Meier event rate at 7 years.
§ Includes ischemic stroke or stroke of type to be determined.
Prevention of major vascular events in patients with chronic kidney disease (CKD )
The Study of Heart and Renal Protection (SHARP) is a multinational, randomized, placebo-controlled, double-blind study in 9438 patients with chronic kidney disease, 1/3 of whom were on dialysis at baseline. In year 1, patients were randomly assigned in a 4:4:1 ratio to the ezetimibe 10 mg simvastatin 20 mg fixed-combination group, the placebo group, and the simvastatin 20 mg group. the 1-year simvastatin monotherapy group was designed to compare the safety and lipid-lowering effects of ezetimibe combined with simvastatin versus simvastatin monotherapy. At 1 year, the simvastatin monotherapy group was randomly reassigned 1:1 to the ezetimibe 10 mg simvastatin 20 mg fixed-combination treatment group and the placebo group. A total of 4650 patients were assigned to the ezetimibe 10 mg simvastatin 20 mg combination treatment group and 4620 to the placebo group, with a median follow-up time of 4.9 years. Mean age was 62 years, 63% were male, 72% were white, and 23% were diabetic. The estimated mean glomerular filtration rate (eGFR) for patients not on dialysis was 26.5 mL/min/1.73 m2, and no lipid inclusion criteria were set. The mean LDL-C at baseline was 108 mg/dl. After 1 year, the LDL-C reduction compared with placebo was 26% in the simvastatin 20 mg monotherapy group and 38% in the ezetimibe 10 mg simvastatin 20 mg combination treatment group. At mid-study (2.5 years), the mean LDL-C reduction for all patients in the combination group was 32% compared to the placebo group. Lipid testing results included all patients who were no longer taking study medication.
The primary endpoint of the SHARP study was an intention-to-treat analysis comparing “major vascular events” (MVE; defined as non-fatal infarction, sudden cardiac death, stroke, or any revascularization) in patients in the ezetimibe simvastatin combination treatment group (n=4193) or the placebo group (n=4191) at randomization. The secondary endpoint analysis included components of the composite endpoint for all post-randomization (at study baseline or 1 year) patients in the combination therapy group ( n=4650) or placebo group ( n=4620) of this product and simvastatin.
The primary endpoint results showed that the combination of this product and simvastatin significantly reduced the risk of major vascular events (749 major vascular events in the placebo group and 639 in the combination of this product and simvastatin) with a 16% relative risk reduction (p=0.001) (see Figure 3).
The reduction in risk of the composite endpoint of major vascular events was consistent with the results of the predefined subgroups at baseline (better values in the combination of this product and simvastatin than in the placebo group), which included: age, sex, dialysis versus non-dialysis, eGFR, diabetes, preexisting atherosclerotic disease, blood pressure, or trichotomies of baseline LDL-C levels.
Figure 3:Effect of the combination of this product with simvastatin on the risk of major vascular events as the primary endpoint
Major vascular events
At risk Placebo group 419138073495317724191239 Ezetimibe/Simvastatin 419338683567327325011232 The components of MVE for all randomized patients are shown in Table 10.The combination of this product with simvastatin significantly reduced the risk of stroke and any revascularization, and the effect of the combination of this product with simvastatin on non-fatal There was a non-significant numerical advantage for non-fatal heart attack and sudden cardiac death.
Table 10 Significant vascular events in all randomized patients in SHARP in the treatment groupa
Outcome Combination of this product 10 mg with simvastatin 20 mg (N=4650) Placebo
(N=4620) Risk Ratio
(95% Cl) P-value Major vascular events 701 (15.1%) 814 (17.6%) 0.85 (0.77-0.94) 0.001 Non-fatal MI 134 (2.9%) 159 (3.4%) 0.84 (0.66-1.05) 0.12 Cardiac death 253 (5.4%) 272 (5.9%) 0.93 ( 0.78-1.10) 0.38 Any stroke 171 (3.7%) 210 (4.5%) 0.81 (0.66-0.99) 0.038 Non-hemorrhagic stroke 131 (2.8%) 174 (3.8%) 0.75 (0.60-0.94) 0.011 Hemorrhagic stroke 45 (1.0%) 37 (0.8%) 1.21 (0.78 -1.86) 0.40 Any revascularization 284 (6.1%) 352 (7.6%) 0.79 (0.68-0.93) 0.004 Major atherosclerotic event (MAE)b 526 (11.3%) 619 (13.4%) 0.83 (0.74-0.94) 0.002a For all patients randomly assigned at baseline or year 1 to this product in combination with Intent-to-treat analysis of SHARP patients in the simvastatin combination treatment arm or placebo arm.
bMAE was defined as the composite endpoint of nonfatal infarction, coronary death, nonhemorrhagic stroke, or any revascularization.
Pure congenital glutathionemia (phytosteronemia)
One study evaluated the efficacy of this product in the treatment of pure subglutaminemia. In this multicenter, double-blind, placebo-controlled, 8-week study, 37 patients with pure congenital glutathionemia were randomly assigned to the 10 mg group (n=30) and the placebo group (n=7). This product significantly reduced glutathione and rape sterols by 21% and 24%. Patients in the placebo group had a 4% and 3% increase in glutathione and rapesterol, respectively. In the study, this product gradually reduced glutosterol and phytosterol levels.
There was no difference in the degree of reduction of glutosterol and phytosterol in patients who received both bile acid chelator and this product (n=8) compared to those who received only this product (n=21).
Pharmacology and toxicology
Pharmacological effects
Ezetimibe reduces blood cholesterol levels by inhibiting cholesterol absorption in the small intestine. The molecular target of ezetimibe has been shown to be the sterol carrier Niemann-Pick C1-like1 (NPC1L1), which is associated with the intestinal absorption of cholesterol and phytosterols. Ezetimibe attaches to the brush border of the small intestinal villous epithelium and inhibits cholesterol absorption, thereby reducing the transport of cholesterol from the small intestine to the liver, resulting in a decrease in hepatic cholesterol storage and thus an increase in the clearance of pericholesterol from the blood.
Toxicological studies
Genotoxicity.
In vitro Ames test with Salmonella and E. coli, human peripheral blood lymphocyte chromosome aberration test (with or without metabolic activation), and mouse micronucleus test results were negative. Reproductive toxicity:
No significant effects on fertility were seen in rats given ezetimibe orally at doses up to 1000 mg/kg/day in males or females (based on total ezetimibe AUCo-24hr, approximately 7 times the human dose exposure of 10 mg/day). Carcinogenicity.
Ezetimibe was administered orally to rats at doses up to 1500 mg/kg/day in males and 500 mg/kg/day in females (based on total ezetimibe AUCo-24hr, approximately 20 times the human dose exposure of 10 mg/day) for 104 weeks by adulteration; and to mice at doses up to 500 mg/kg/day by adulteration (based on total ezetimibe AUCo-24hr, approximately 150 times the human dose of 10 mg/day) for 104 weeks, and no significant increase in tumor incidence was observed.
[Pharmacokinetics].
Absorption
After oral administration, ezetimibe is rapidly absorbed and extensively bound into pharmacologically active phenolic glucosinolates (ezetimibe-glucosinolates). The ezetimibe-glucosinolate conjugate reaches the mean plasma peak concentration (Cmax) within 1 to 2 hours after dosing, while ezetimibe has a mean plasma peak concentration at 4 to 12 hours. Since ezetimibe is insoluble in aqueous media for injection, its absolute bioavailability cannot be measured.
The oral bioavailability of ezetimibe 10 mg was not affected by its administration with food (high-fat or fat-free diet). This product can be taken with or without food.
Distribution
The plasma protein binding of ezetimibe and ezetimibe-glucosinolate conjugate was 99.7% and 88-92%, respectively.
Metabolism
Ezetimibe is primarily bound to glucosinolates in the small intestine and liver (phase II reaction) and is subsequently excreted by the bile and kidneys. A very small amount of ezetimibe was oxidatively metabolized (phase I reaction) in all studied species. Ezetimibe and ezetimibe-glucosinolate conjugates were the major drug derivatives detected in plasma, accounting for 10-20% and 80-90% of the total drug concentration in plasma, respectively. The clearance of ezetimibe and ezetimibe-glucosinolate conjugates from plasma was slow, suggesting a significant enterohepatic circulation. The half-life of ezetimibe and ezetimibe-glucosinolate conjugates is approximately 22 hours.
Clearance
After oral administration of 14C-ezetimibe (20 mg) to subjects, total ezetimibe accounted for approximately 93% of total plasma radioactivity. Approximately 78% and 11% of the administered radioactivity was recovered from feces and urine, respectively, during the 10-day collection period. after 48 hours, no radioactivity was detectable in plasma.
Hepatic insufficiency
Patients with mild hepatic insufficiency (Child-Pugh score 5 or 6) receiving a single dose of ezetimibe 10 mg had an approximately 1.7-fold increase in total ezetimibe AUC compared to the normal population. In a 14-day multiple-dose study in patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), patients taking 10 mg of ezetimibe daily had a 4-fold higher total ezetimibe AUC on days 1 and 14 compared with the normal population. No dose adjustment was required in patients with mild hepatic insufficiency. The effect of increased ezetimibe exposure in patients with moderate and severe hepatic insufficiency (Child-Pugh score>9) is not known and ezetimibe is not recommended for use in these patients. (See [Contraindications] and [Precautions], Hepatic insufficiency.)
Renal insufficiency
Patients with severe renal insufficiency (n=8; mean CrCl ≤ 30 mL/min/1.73 m²) showed a 1.5-fold increase in total ezetimibe AUC after a single dose of ezetimibe 10 mg compared to normal subjects (n=9). However, the results were not clinically significant. Therefore, no dose adjustment was required in patients with renal insufficiency.
However, one patient in this study (renal transplant multi-drug therapy, including cyclosporine) had a 12-fold higher total ezetimibe exposure than normal.
Gender
Total ezetimibe plasma concentrations were mildly elevated in women compared to men (elevated values<20%). The safety of dosing and the degree of LDL-C reduction after dosing were similar in male and female patients. Therefore, no dose adjustment based on gender is required.
Race
According to the pharmacokinetic meta-analysis, there is no difference in the pharmacokinetics of this product between blacks and whites.
Storage】Store in a sealed place under 30℃, protected from light.
Package】 Aluminum-plastic package, 20 tablets/box.
Expiration date】 18 months.
Standard
Approval number
[Marketing authorization holder
Company name: Hunan Fangsheng Pharmaceutical Co.
Registered Address: No. 789, Lusong Road, Changsha, Hunan Province
Manufacturer
Company name: Hunan Fangsheng Pharmaceutical Co.
Address: No. 789, Lusong Road, Changsha City, Hunan Province
Postal code: 410205
Telephone number: 0731-88997128
Fax number: 0731-88997189
Website: www.fangsheng.com.cn