Product Overview
[Drug Name]
Generic Name: Ezetimibe Tablets
Trade Name: EZETROL
English Name: Ezetimibe Tablets
Chinese Pinyin: YiShiChun (YiZheMaiBuPian)*1HeWeiShengSuCPian (TangChenBeiJian)*1Ping
[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-azetidine (azetidin)one. Chemical Structure: Molecular Formula: C₂₄H₂₁F₂NO₃. Molecular Weight: 409.4
[Properties]
This product is a white or off-white tablet.
[Indications]
Primary Hypercholesterolemia: This drug is indicated as an adjunct to dietary control, either alone or in combination with an HMG-CoA reductase inhibitor (statin), for the treatment of primary (heterozygous familial or non-familial) hypercholesterolemia. It can lower total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B). Homozygous Familial Hypercholesterolemia (HoFH): This drug is indicated in combination with a statin as an adjunct to other lipid-lowering therapies (such as LDL-C apheresis), or for lowering TC and LDL-C levels in HoFH patients when other lipid-lowering therapies are ineffective. Homozygous Sitosterolemia (or Phytosterolemia): This drug is indicated as an adjunct to dietary control, for lowering sitosterol and phytosterol levels in patients with homozygous familial sitosterolemia.
[Dosage and Administration]
Patients should maintain an appropriate low-fat diet during treatment with this drug. The recommended dose of this drug is 10 mg once daily. It can be taken alone, in combination with a statin, or in combination with fenofibrate. This drug can be taken at any time of the day, on an empty stomach or with food. Use in Elderly Patients: No dose adjustment is required for elderly patients. Use in Pediatric Patients: Children and adolescents 10 years of age and older: No dose adjustment is required. Children under 10 years of age: This drug is not recommended. Use in Patients with Impaired Hepatic Function: No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh score of 5 or 6) (see [Pharmacokinetics]). Use in Patients with Impaired Renal Function: No dose adjustment is required for patients with impaired renal function. When used with bile acid sequestrants, this drug should be taken at least 2 hours before or 4 hours after the bile acid sequestrant.
[Adverse Reactions]
In a 112-week clinical study, patients received 10 mg of fenofibrate daily, either alone (n=2396) or in combination with a statin (n=11,308) or fenofibrate (n=185). Results showed that fenofibrate was generally well tolerated, with mild and transient adverse reactions. The overall incidence of side effects was similar to that of placebo, and the rate of trial discontinuation due to adverse reactions was comparable to that of the placebo group. The incidence of common (≥1/100, 1/10) and uncommon (≥1/1000, 1/100) drug-related adverse reactions was higher in patients receiving fenofibrate alone (n=2396) compared with the placebo group (n=1159). The incidence of adverse reactions in patients receiving fenofibrate in combination with a statin (n=11,308) was higher than in patients receiving a statin alone (n=9361). When used alone: Tests: Uncommon: Elevated ALT and/or AST; elevated blood CPK; elevated gamma-glutamyl transferase; abnormal liver function tests. Respiratory, chest, and mediastinal disorders; Uncommon: cough. Digestive Disorders: Common: abdominal pain; diarrhea; flatulence. Uncommon: dyspepsia; gastroesophageal reflux; nausea. Musculoskeletal and Connective Tissue Disorders: Uncommon: joint pain; muscle cramps; neck pain. Metabolic and Nutritional Disorders: Uncommon: loss of appetite. Vascular Disorders: Uncommon: hot flashes; hypertension. Systemic and Administration Site Disorders: Common: fatigue. Uncommon: chest pain; generalized pain. When used in combination with statins: Tests: Common: elevated ALT and AST. Neurological Disorders: Common: headache. Uncommon: paresthesia. Digestive Disorders: Uncommon: dry mouth; gastritis. Skin and Subcutaneous Tissue Disorders: Uncommon: pruritus; rash; urticaria. Musculoskeletal and Connective Tissue Disorders: Common: Myalgia. Uncommon: Back pain; Myasthenia; Limb pain. General and Administration Site Disorders: Common: Fatigue; Peripheral edema. Combination use of ezetimibe with fenofibrate: Digestive Disorders: Common: Abdominal pain. In a multicenter, double-blind, placebo-controlled clinical study in patients with mixed hyperlipidemia, 625 patients were treated for 12 weeks and 576 patients were treated for an additional 48 weeks. The combination of ezetimibe and 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 aminotransferases (sustained 3 times the upper limit of normal) was 4.5% (1.9, 8.8) with fenofibrate alone and 2.7% (1.2, 5.4) with ezetimibe and fenofibrate, respectively (adjusted for treatment). The corresponding cholecystectomy rates were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0), respectively (see Precautions). The study was insufficient to assess the risk of gallbladder disease in patients treated with ezetimibe or fenofibrate alone or in combination. In this study, no CPK elevations exceeding 10 times the upper limit of normal (ULN) occurred in either treatment group. Laboratory Indexes: In controlled clinical studies of ezetimibe alone, the incidence of transaminase elevations (ALT and/or AST ≥ 3 times ULN) was similar in ezetimibe (0.5%) and placebo (0.3%). In studies of ezetimibe in combination with statins, the incidence of transaminase elevations was 1.3% in patients receiving ezetimibe and statins and 0.4% in patients receiving statins alone. However, these transaminase elevations were clinically insignificant, unrelated to cholestasis, and resolved to normal values after treatment interruption or continuation. Elevations in CPK (≥10 times the upper limit of normal) caused by this drug alone or in combination with a statin were similar to those observed with placebo or a statin alone, respectively. Adverse reactions reported postmarketing for this drug (ignoring causality assessment): Hematologic and lymphatic system disorders: thrombocytopenia. Nervous system disorders: dizziness; paresthesia. Digestive system disorders: pancreatitis; constipation. Skin and subcutaneous system disorders: erythema multiforme. Musculoskeletal and connective tissue disorders: myalgia; myopathy/rhabdomyolysis (see Precautions). Systemic and application site disorders: asthenia. Immune system disorders: hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Hepatic system disorders: hepatitis; gallstones; cholecystitis. Psychiatric disorders: depression.
[Contraindications]
Hypersensitivity to any component of this drug. Active liver disease or persistently elevated serum transaminases of unknown cause. All HMG-CoA reductase inhibitors restrict their use in pregnant and lactating women. When this product is used in combination with other drugs of this type in women of childbearing potential, the HMG-CoA reductase inhibitor product package insert should be consulted (see Use in Pregnant and Lactating Women).
[Precautions]
When this product is used in combination with statins or fenofibrate, please refer to the product package insert for that statin or fenofibrate. Liver Enzyme Effects: In controlled studies of this product used in combination with statins, persistent elevations in serum transaminases (≥3 times the upper limit of normal) have been observed. Therefore, when this product is used in combination with statins, liver function tests should be performed before treatment, and the statin product package insert should be consulted. Skeletal Muscle: In clinical studies, this product did not cause an increase in myopathy or rhabdomyolysis compared with the control group (placebo or statin alone). Myopathy and rhabdomyolysis are known adverse reactions of statins and other lipid-lowering drugs. The incidence of CPK elevations greater than 10 times the upper limit of normal was 0.2% with this product, 0.1% with placebo, 0.1% with this product used in combination with a statin, and 0.4% with statin alone. Cases of myopathy and rhabdomyolysis have been reported since this product was marketed (whether these cases are drug-related is unclear). Most patients who develop rhabdomyolysis were taking statins before starting ezetimibe. However, rare cases of rhabdomyolysis have been reported when ezetimibe is used alone or in combination with other drugs known to increase the risk of rhabdomyolysis. All patients should be informed of the risk of myopathy when starting ezetimibe and instructed to promptly report any unexplained myalgia, tenderness, or weakness. If myopathy is diagnosed or suspected, ezetimibe and any concomitant statin should be discontinued immediately. The presence of these symptoms and a creatine phosphokinase (CPK) level above 10 ULN indicates myopathy. Hepatic Impairment: Given the unknown effects of long-term ezetimibe use in patients with moderate or severe hepatic impairment, ezetimibe is not recommended for such patients (see Pharmacokinetics). Fibrates: The safety and efficacy of ezetimibe combined with fibrates other than fenofibrate have not been established; therefore, the combined use of these two drugs (except fenofibrate) is not recommended. Cyclosporine: ezetimibe should be used with caution during cyclosporine use. Patients receiving this product in combination with cyclosporine should monitor cyclosporine concentrations. Anticoagulants: If this product is coadministered with warfarin, other coumarin anticoagulants, or fluindione, the international normalized ratio (INR) should be monitored appropriately.
[Special Use in Special Populations]
Precautions for Pediatric Patients:
In children and adolescents (10-18 years), the absorption and metabolism of ezetimibe are similar to those in adults. Based on plasma concentrations of total ezetimibe, there are no differences in pharmacokinetics between adolescents and adults. Pharmacokinetic data are not available in children younger than 10 years of age. Clinical data in children and adolescents (9-17 years of age) are limited to patients with HoFH and sitosterolemia.
Precautions for Pregnancy and Lactation:
No clinical data are available regarding use during pregnancy. Animal studies have shown that ezetimibe has no direct or indirect adverse effects on pregnancy, embryonic and fetal development, delivery, or postnatal neonatal development. However, ezetimibe should be used with caution in pregnant women. In studies of pregnant rodents, no embryonal or fetal teratogenic effects were observed when ezetimibe was used in combination with lovastatin, simvastatin, pravastatin, and atorvastatin. In studies of pregnant rabbits, a small number of skeletal malformations were observed. Studies in rats have shown that ezetimibe is excreted in rat breast milk. It is currently unknown whether ezetimibe is excreted in human breast milk. Therefore, ezetimibe should not be used in lactating women unless the potential benefit can be demonstrated to outweigh the potential risk to the infant.
Precautions for Elderly Patients:
Geriatric patients (over 65 years) had plasma concentrations of total ezetimibe twice as high as those in younger patients (18-45 years). The LDL-C lowering and safety profile of ezetimibe were not significantly different in elderly and younger patients. Therefore, no dose adjustment is required in elderly patients.
[Drug Interactions]
Preclinical studies have shown that ezetimibe does not induce cytochrome P450 drug-metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between this product and drugs known to be metabolized by cytochromes P450, 1A2, 2D6, 2C8, 2C9, 3A4, or N-acetyltransferases. This product has not been shown to affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam when coadministered with this product. Cimetidine did not affect the bioavailability of this product when coadministered with this product. Antacids: Concomitant administration of antacids may decrease the absorption rate of this product but does not affect its bioavailability. Antacids: Concomitant administration of antacids may decrease the absorption rate of this product but does not affect its bioavailability. This decrease in absorption rate is not clinically significant. Cholestyramine: Concomitant administration of cholestyramine may decrease the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) by approximately 55%. When ezetimibe is added to cholestyramine to enhance the LDL-C lowering effect, the enhanced effect may be reduced due to the above-mentioned interaction. Cyclosporine: In one study, eight renal transplant patients with a creatinine clearance of 50 ml/min and stable cyclosporine were treated with a single 10 mg dose of ezetimibe, resulting in a 3.4-fold increase (ranging from 2.3 to 7.9-fold) in the mean AUC of total ezetimibe compared to healthy controls 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) receiving multiple medications, including cyclosporine, experienced a 12-fold increase in total ezetimibe exposure compared to the control group. In a two-period crossover study in 12 healthy subjects, each receiving 20 mg of ezetimibe daily for 8 days, followed by a single 100 mg dose of cyclosporine for 7 days, the mean AUC of cyclosporine increased by 15% (range, -10% to +51%) compared to cyclosporine alone. Fibrates: The combination of this product with fibrates other than fenofibrate has not been studied. Fibrates can increase bile cholesterol concentrations, contributing to the development of cholelithiasis. In preclinical studies in dogs, this product was found to increase bile cholesterol levels. Combination use of this product with fibrates other than fenofibrate is not recommended until such studies are conducted. Fenofibrate: In pharmacokinetic studies, when this product was co-administered with fenofibrate, fenofibrate increased total ezetimibe concentrations by approximately 1.5-fold. If gallstones are suspected in a patient receiving this product in combination with fenofibrate, a gallbladder examination should be performed, and alternative lipid-lowering therapies should be considered. Gemfibrozil: In pharmacokinetic studies, when this product was co-administered with gemfibrozil, gemfibrozil increased total ezetimibe concentrations by approximately 1.7-fold. No clinical data are available. Statins: No clinically significant pharmacokinetic interactions have been observed with this drug when used in combination with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin. Anticoagulants: A study in 12 healthy men demonstrated that coadministration of this drug (10 mg/day) with warfarin or fluindione did not significantly affect warfarin bioavailability or clotting time. Post-marketing, increased international normalized ratios have been reported in patients taking this drug in combination with warfarin. Most of these patients were also receiving other medications.
[Pharmacological Action]
Isoprena is an oral, potent lipid-lowering drug with a mechanism of action that differs from other lipid-lowering drugs (such as statins, bile acid sequestrants (resins), benzoic acid derivatives, and plant sterol esters). Isoprena binds to the brush border of the small intestinal villi, inhibiting cholesterol absorption, thereby reducing cholesterol transport from the small intestine to the liver. This reduces hepatic cholesterol storage and increases cholesterol clearance from the blood. Ezetimibe does not increase bile secretion (like bile acid sequestrants) or inhibit hepatic cholesterol synthesis (like statins). Compared with placebo, Ezetimibe inhibits small intestinal cholesterol absorption by 54%. Statins reduce hepatic cholesterol synthesis. Combining these two drugs can further lower cholesterol levels, surpassing either drug alone. While Ezetimibe selectively inhibits cholesterol absorption, it does not affect small intestinal absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat-soluble vitamins A and D. Combining Ezetimibe with an HMG-CoA reductase inhibitor significantly improves serum TC, LDL-C, ApoB, TG, and HDL-C levels compared to either drug alone. The effects of ezetimibe alone or in combination with an HMG-CoA reductase inhibitor on cardiovascular morbidity and mortality have not been established.
Storage: Store in a dark, airtight container (below 30°C).
Strength: 10 mg
Packaging: Aluminum-plastic packaging, 10 tablets/box
Expiration Date: 36 months
Approval Number: National Medical Products Approval No. HJ20160181/National Medical Products Approval No. HJ20171017
