How Safe Is a Combination of Simvastatin and Fenofibrate?

Ezetimibe simvastatin tablets, prescription drugs, were developed and produced by Merck (known as Merck in the United States and Canada). Approved by the State Food and Drug Administration, it was officially listed in China on May 12, 2012.

Ezetimibe simvastatin tablets, prescription drugs, were developed and produced by Merck (known as Merck in the United States and Canada). Approved by the State Food and Drug Administration, it was officially listed in China on May 12, 2012.

Ezetimibe Simvastatin Tablets is currently the only domestic lipid-lowering drug compound preparation. The tablet contains two widely used lipid-lowering drugs--simvastatin and ezetimibe, which are suitable for high cholesterol blood. Patients. ^[1]

Ezetimibe simvastatin tablets have a dual mechanism of action. While inhibiting the synthesis of cholesterol in the liver, it inhibits the absorption of cholesterol in the small intestine, which can effectively reduce LDL-C by more than 50% ^[1] . Among all lipid-lowering drugs Monolithic LDL-C (low-density lipoprotein) has the strongest effect; its safety and tolerability are comparable to conventional statin monotherapy. Clinical studies have shown that Zanzhineng® can effectively help patients with LDL-C failure to meet the standard. At the same time, because its single slice has the strongest lipid-lowering effect, it is possible to replace two other lipid-lowering drugs by using one Zanionn®. Long-term use by patients greatly increases medication compliance. ^[2]

The International Trial of Further Efficacy Reduction in Endpoint Events: Ezine® (Ezetimibe Simvastatin Tablets) (IMPROVE), led by the TIMI Research Group at Brigham and Women's Hospital, Duke University Clinical Institute, and sponsored by Merck -IT study), for the first time, the non-statin drug ezetimibe has been shown to bring cardiovascular benefits on the basis of statins, and once again demonstrate the effectiveness and safety of combined use of statin and ezetimibe, strengthening "cholesterol "Theory" proves that lowering cholesterol levels is the root cause of patients' benefits, and also provides a clinical research basis for the combined application of statins and cholesterol absorption inhibitors. ^[3]

Drug Name

Ezetimibe Simvastatin

Foreign name

zetimibe and SimvastatinTablets

Whether prescription drugs

prescription

Dosage form

tablet

Use classification

Lipid-lowering drugs

Ezetimibe Simvastatin Tablets Drug Information

Ezetimibe Simvastatin Tablets Ingredients

This product is a compound preparation, and its components are:

VYTORIN 10/10 Ezetimibe 10mg and Simvastatin 10mg

VYTORIN 10/20 Ezetimibe 10mg and Simvastatin 20mg

Ezetimibe Simvastatin Tablets Properties:

This product is white or off-white film.

Ezetimibe Simvastatin Tablets Specifications

VYTORIN (10/10), each tablet contains 10mg ezetimibe and 10mg simvastatin

VYTORIN (10/20), each tablet contains 10mg ezetimibe and 20mg simvastatin

Ezetimibe simvastatin tablet manufacturer

Company Name: MSD PHARMA (SINGAPORE) PTE. LTD.

Address: 150 BEACH ROAD # 31-00 GATEWAY WEST SINGAPORE189720

Factory Name: MSD INTERNATIONAL GMBH (SINGAPORE BRANCH)

Factory Address: 21 TUAS SOUTH AVENUE 6 SINGAPORE 637766

Name of Imported Pharmaceutical Sub-packaging Company: Hangzhou Mercadon Pharmaceutical Co., Ltd.

Enter

Outer packing of ezetimibe simvastatin tablets (2 photos)

Oral medicine sub-packaging enterprise address: No. 199 Wenhai North Road, Hangzhou Economic and Technological Development Zone, Hangzhou

Ezetimibe Simvastatin Tablets Indications

Primary hypercholesterolemia

This product is suitable for adjuvant therapy other than dietary control in patients with primary (heterozygous familial or nonfamilial) hypercholesterolemia or mixed hyperlipidemia. This product can reduce total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG) and non-high density lipoprotein cholesterol (non-HDL-C) Levels and can raise high-density lipoprotein cholesterol (HDL-C) levels.

Homozygous familial hypercholesterolemia ( HoFH )

This product is suitable for reducing TC and LDL-C levels in HoFH patients. This product can be used as an adjuvant therapy for other lipid-lowering treatments (such as LDL plasmapheresis); or used to reduce TC and LDL-C levels in HoFH patients when other lipid-lowering treatments are ineffective.

Ezetimibe Simvastatin Tablets Usage and Dosage

Dosage and usage

Patients should maintain a standard low-cholesterol diet before and during treatment with this product. The dose should be individualized according to the patient's baseline LDL-C levels, recommended treatment goals, and patient response. This product is taken once daily, at night, and can be taken on an empty stomach or with food.

The dosage range of this product is 10 / 10mg daily to 10 / 40mg daily. A generally recommended starting dose is 10/20 mg daily. For patients who do not require active LDL-C reduction, the starting dose may be 10/10 mg daily. For patients who need to significantly reduce LDL-C (greater than 55%), the starting dose can be 10 / 40mg daily. Generally, blood lipid levels need to be measured 2 weeks after the initial treatment or dose adjustment, and the dose should be adjusted if necessary.

Dose of homozygous familial hypercholesterolemia

The recommended dosage for patients with homozygous familial hypercholesterolemia is 10/40 mg daily, taken at night. For this type of patients, this product can be used as an adjuvant therapy for other lipid-lowering treatments (such as low-density lipoprotein plasma separation and replacement). When these methods cannot be used, this product can be used alone.

The recommended doses for patients receiving other concomitant treatments or impaired renal function are as follows.

Application of drugs in patients with liver dysfunction

Patients with mild liver dysfunction do not need to adjust the dose (see [Precautions] liver dysfunction )

Drugs for patients with renal insufficiency

No dose adjustment is required in patients with mild renal insufficiency (estimated glomerular filtration rate 60 ml / min / 1.73 m). In patients with chronic kidney disease and glomerular filtration rate estimated to be less than 60 ml / min / 1.73 m, the dose of this product is 10/20 mg, once daily, and in the evening. In these patients, close monitoring should be used if larger doses are used. (See [Precautions] and [Clinical Trials])

Application of drugs in elderly patients

Elderly patients do not need to adjust the dose (see [Pharmacokinetics] special population)

Used in combination with a bile acid chelator

This product should be taken more than 2 hours before or 4 hours after taking the bile acid chelator. (See [Drug Interactions]).

Patients taking verapamil, diltiazem, dronedarone

For patients taking verapamil, diltiazem, dronedarone, the daily dose of this product should not exceed 10/10 mg (see [Precautions] myopathy / striated muscle lysis and [Caution] drug interactions, other medicine interactions).

Patients taking Amiodarone , Amlodipine, Ranolazine

For patients who are taking amiodarone, amlodipine, ranolazine, the daily dose of this product cannot exceed 10 / 20mg (see [Precautions] Myopathy / Rhabdomyolysis and [Drug Interactions]).

Patients in combination with other lipid-lowering therapies

The safety and effectiveness of this product in combination with fibrates have not been established, so the combined use of this product and fibrates should be avoided. (See [Precautions] Myopathy / Striated Myolysis and [Precautions] Drug Interactions, Other Drug Interactions).

Ezetimibe Simvastatin Tablets Adverse Reactions

In foreign clinical studies of this product, safety evaluation was performed on approximately 12,000 patients who used VYTORIN (or a combination of ezetimibe and simvastatin equivalent to VYTORIN). Patients are generally well tolerated by this product.

The following are common (incidence rates 1/100, <1/10) or infrequent (incidence rates 1/1000, <1/100) reported by patients taking this product (n = 2404) and higher rates than placebo Group (N = 1340) drug-related adverse events:

Various inspections

Common: elevated ALT and / or AST; elevated blood CK.

Uncommon: increased blood bilirubin; increased blood uric acid; increased -glutamyl transpeptidase; increased international standardized ratio; proteinuria; weight loss.

Nervous system abnormalities

Uncommon: dizziness; headache.

Digestive disorders

Uncommon: abdominal pain; abdominal discomfort; upper abdominal pain; indigestion; flatulence; nausea; vomiting.

Abnormal skin and subcutaneous tissue

Uncommon: itching; rash.

Musculoskeletal and connective tissue abnormalities

Uncommon: joint pain; muscle spasms; muscle weakness; muscle and bone discomfort; neck pain; limb pain.

Systemic disorders and abnormalities

Uncommon: weakness; fatigue; general malaise; peripheral edema.

Mental disorder

Uncommon: abnormal sleep.

The following common (incidence 1/100, <1/10) or uncommon (incidence 1/1000, <1/100) drug-related adverse events described below occurred in patients taking this product (n = 9595) Patients with a higher incidence than those taking statins alone (n = 8883):

Various inspections

Common: Elevated ALT and / or AST.

Uncommon: elevated blood bilirubin; elevated blood CK; elevated gamma-glutamyl transpeptidase.

Nervous system abnormalities

Uncommon: headache, paresthesia.

Digestive disorders

Uncommon: bloating; diarrhea; dry mouth; indigestion; flatulence; gastroesophageal reflux; vomiting.

Abnormal skin and subcutaneous tissue

Uncommon: itching; rash; rubella.

Musculoskeletal and connective tissue abnormalities

Common: Myalgia

Uncommon: joint pain; back pain; muscle spasms; muscle weakness; muscle and bone pain; limb pain.

Systemic disorders and abnormalities

Uncommon: weakness; chest pain; fatigue; peripheral edema.

Mental disorder

Uncommon: insomnia.

Juvenile patients (10-17 years )

In the study of adolescents with heterozygous familial hypercholesterolemia (n = 248) aged 10-17 years, the safety and tolerability of the treatment group using this product is roughly similar to that of adults (see [Pharmacokinetics] Crowd and [children's medication]).

Patients with chronic kidney disease

In the Heart and Kidney Protection Study (SHARP) (see [Clinical Trials], Prevention of Major Vascular Events in Patients with Chronic Nephropathy (CKD)), a total of 9,270 patients were included in the study and randomized to receive 10/20 mg daily n = 4650) or placebo (n = 4620), with a median follow-up of 4.9 years. In this product and in the placebo group, the proportion of permanent discontinuation of study medication due to adverse events or abnormal blood test results was 10.4% and 9.8%, respectively. The incidence of myopathy (defined as unexplained muscle weakness or pain with serum creatine kinase levels greater than 10 times the normal upper limit) in this product and the placebo group was 0.2% and 0.1%, respectively. Rhabdomyolysis (defined as muscle The incidence of disease-associated creatine kinase levels greater than 40 times the normal upper limit) was 0.09% and 0.02%, respectively. The rate of continuous transaminase elevation (more than 3 times the upper limit of normal) was 0.7% and 0.6%, respectively. At each study visit, patients were asked if they had unexplained muscle pain or weakness: In this product and in the placebo group, 21.5% and 20.9% of patients reported muscle symptoms, respectively. During this clinical trial, the proportion of patients diagnosed with cancer in this product and in the placebo group was 9.4% and 9.5%, respectively.

Post-marketing adverse reactions

The following are other adverse reactions reported after marketing or during clinical trials using this product or any of the ingredients contained in this product. The adverse reactions reported by this product are consistent with the previously reported adverse reactions of ezetimibe and / or simvastatin.

Various tests: abnormal liver function tests.

Blood and lymphatic abnormalities: thrombocytopenia; anemia.

Neurological disorders: peripheral neuropathy; memory disorders.

Respiratory, chest, and mediastinal abnormalities: cough; interstitial lung disease.

Gastrointestinal system: constipation; pancreatitis; gastritis.

Abnormal skin and subcutaneous tissue: hair loss; hypersensitivity syndrome, including rash, rubella, allergic reactions, angioedema; erythema polymorpha.

Muscle, bone and connective tissue abnormalities: muscle spasms; myopathy / striated muscle lysis. (See [Precautions])

Rarely, there have been reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy when used in combination with statins. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which continue to appear after stopping statin treatment; muscle tissue sections show necrotizing myopathy without meaningful inflammation; can be improved by immunosuppressants (see [ Note] Myopathy / rhabdomyolysis).

Metabolic and nutritional disorders: decreased appetite.

Vascular abnormalities: flushing; hypertension.

Systemic disorders and abnormalities at the medication site: pain.

Hepatobiliary disorders: hepatitis / jaundice; liver failure; gallstones; cholecystitis.

Reproductive and breast diseases: erectile dysfunction.

Mental disorders: depression.

A distinct hypersensitivity symptom is reported to occur rarely, and it includes the following characteristics: angioedema, lupus-like syndrome, rheumatic polymyalgia, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia Increased ESR, arthritis and joint pain, rubella, light sensitivity, fever, flushing, difficulty breathing and discomfort.

Post-marketing experience: There are reports of rare cognitive impairments in overseas post-marketing monitoring of statins, manifested as memory loss, decreased memory, confusion, etc., most of which are non-serious, reversible reactions, which can usually be recovered after drug withdrawal .

Laboratory inspection

In a controlled clinical trial using a combination of drugs, the proportion of patients with this product who had clinically significant elevations in serum transaminase levels (three times the upper limit of normal ALT and / or AST) was 1.7%. Patients are generally asymptomatic and have nothing to do with cholestasis. After discontinuing treatment or continuing treatment, serum aminotransferase levels can return to baseline levels (see [Cautions]).

Among patients taking this product, 0.2% of patients with clinically significant increase in creatine kinase (CK) levels (10 times the upper limit of normal value).

Post-marketing monitoring of statins has reported reports of hyperglycemia, impaired glucose tolerance, elevated glycated hemoglobin levels, new-onset diabetes, and worsened glycemic control. Some statins have also reported hypoglycemic reactions.

For simvastatin, there have been reports of elevated glycated hemoglobin and fasting blood glucose.

Concomitant use with other lipid-lowering treatments

In controlled clinical trials with concomitant use of simvastatin and cholestyramine, no special adverse effects during concomitant treatment were observed. Adverse events were limited to those previously reported with simvastatin and cholestyramine.

Juvenile patients (10-17 years )

In a 48-week controlled study of adolescent boys and girls (at least 1 year after menarche) in heterozygous familial hypercholesterolemia (n = 175) aged 10-17 years, simvastatin (10-40mg / The safety and tolerability of the treatment group was roughly similar to that of the placebo group. The most common adverse events in the two groups were upper respiratory infections, headaches, abdominal pain, and nausea (see [Pharmacokinetics] for specific populations and [ Medication for children].

Ezetimibe Simvastatin Taboo

Patients who are allergic to the active ingredients or any of the ingredients in this product.

Patients with active liver disease, or persistently elevated serum aminotransferases of unknown origin. (See [Notes] Liver enzymes)

Patients during pregnancy and lactation. Atherosclerosis is a chronic process, and the temporary discontinuation of lipid-lowering medications during pregnancy has little effect on the long-term risk of primary hypercholesterolemia. In addition, cholesterol and its biosynthetic precursors are important raw materials for embryonic development, including steroid synthesis and cell membrane formation. Because HMG-CoA reductase inhibitors such as simvastatin can reduce the synthesis of cholesterol and its precursors, this product is contraindicated in pregnant and lactating women. Women of childbearing age can use this product only when it is impossible to conceive. If the patient becomes pregnant while taking this product, the use of this product should be stopped immediately, and the potential harm of this product to the fetus should be informed (see [Medication for pregnant and lactating women]).

Used in combination with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boprevir, tilarivir, erythromycin, clarithromycin, taley (Mycin and nefazodone) (see notes, myopathy / striated muscle lysis, and drug interactions).

Combined with gemfibrozil, cyclosporin, or danazol (see notes, myopathy / striated muscle lysis and drug interactions)

Precautions for ezetimibe simvastatin tablets

Myopathy / rhabdomyolysis

Like other HMG-CoA reductase inhibitors, simvastatin can cause myopathy, manifested as myalgia, tenderness, or fatigue, with creatine kinase (CK) levels exceeding 10 times the upper limit of normal (10 × ULN) ; Sometimes myopathy can manifest as rhabdomyolysis, with or without acute renal failure secondary to myoglobinuria; rare deaths occur. The risk of myopathy increases with the concentration of HMG-CoA reductase inhibitor in plasma. Predictable causes of myopathy include age (65 years), women, uncontrolled hypothyroidism, and renal insufficiency.

As with other HMG CoA reductase inhibitors, the risk of myopathy / striated muscle lysis is related to the dose of simvastatin. In a clinical trial database, 41,413 patients were treated with simvastatin, and 24,747 (approximately 60%) of these studies had a median follow-up period of at least 4 years, and 20, 40, and 80 mg / day myopathy The incidence rates were approximately 0.03%, 0.08%, and 0.61%. In these trials, patients were carefully monitored and certain interacting drugs were excluded.

In a clinical trial, patients with a history of myocardial infarction received simvastatin 80 mg / day (mean follow-up 6.7 years), and the incidence of myopathy was approximately 1.0%, compared with 0.02% of patients receiving 20 mg / day . About half of cases of myopathy occur during the first year of treatment. In each subsequent year of treatment, the incidence of myopathy is approximately 0.1%.

All patients who are beginning treatment with this product, or those who are increasing the dose of this product, should be reminded of the risk of myopathy and informed that they should promptly report any unexplained muscle pain, tenderness or weakness. If myopathy is diagnosed or suspected, this product should be discontinued immediately. The onset of these symptoms, and CK levels exceeding 10 times the normal upper limit, indicate the occurrence of myopathy. In most cases, muscle symptoms and elevated CK can be alleviated when patients stop treatment in time (see [Adverse Reactions]). In patients who are beginning treatment with this product or are increasing the dose, consider periodically measuring CK. This monitoring does not necessarily prevent myopathy.

Most patients with rhabdomyolysis during simvastatin treatment have a complex medical history, including renal insufficiency, usually caused by long-term diabetes. Such patients should be monitored more closely. Treatment with this product can be suspended for several days before major elective surgery and in the event of any serious medical or surgical illness.

medicine interactions

Because this product contains simvastatin, it increases the risk of myopathy / striated myolysis when used concurrently with :

Contraindications

CYP3A4 strong inhibitors : Do not list drugs listed in the combined application instructions that have a strong inhibitory effect on CYP3A4 at the therapeutic dose (for example, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin , Telithromycin, HIV protease inhibitor, boprevir, tilarivvir, or nefazodone) . If the use of CYP3A4 strong inhibitors is unavoidable in the short term, treatment with this product should be suspended during this drug treatment. (See contraindications; drug interactions)

Gefitizil, cyclosporin or danazol: This product is contraindicated in combination with these drugs. (See contraindications; drug interactions).

Other drugs :

Fusidic acid: Patients treated with fusidic acid may also increase the risk of developing myopathy / striated muscle when they are treated with simvastatin. (See Drug Interactions, Other Drug Interactions). Fusidic acid is not recommended. For those patients who need systemic use of fusidic acid, consideration should be given to discontinuing this product throughout the fusidic acid administration. In special circumstances, prolonged systemic use of fusidic acid is required. For example, in order to treat severe infections, the condition of each patient should be analyzed specifically, and whether this product is combined with fusidic acid should be considered under strict medical monitoring.

Amiodarone: In an ongoing clinical trial, 6% of patients taking simvastatin 80 mg and amiodarone have reported myopathy. In patients in combination with amiodarone, the dose of this product should not exceed 10/20 mg per day. (See [Drug Interactions].)

Calcium channel blocker

Verapamil or diltiazem: In a clinical trial, the simultaneous use of diltiazem and simvastatin 80mg led to an increased risk of myopathy. The dose of this product should not exceed 10/10 mg per day in patients taking verapamil or diltiazem in combination . (See [Drug Interactions], other drug interactions.).

Amlodipine: In a clinical trial, taking amlodipine and simvastatin 80mg at the same time caused a slight increase in the risk of developing myopathy. In patients taking amlodipine concurrently, the dose of this product should not exceed 10/20 mg per day .

CYP3A4 medium-acting inhibitors: Patients applying the drugs listed in the instruction manual that have moderate inhibitory effects on CYP3A4, the combined use of this product, especially the higher dose of this product, increases the risk of myopathy. When this product is used in combination with a CYP3A4 intermediate inhibitor, it is necessary to adjust the dose of this product.

Other fibrates: The safety and effectiveness of this product in combination with fibrates have not been determined, so the combined application of this product and fibrates should be avoided. Taboo is associated with Gefibet (see Taboo).

Nicotinic acid ( 1g / day) was observed when simvastatin was combined with a lipid-lowering dose (1g / day) of niacin, and cases of myopathy / striated muscle were observed. In a clinical trial (median follow-up period of 3.9 years), patients at high risk of cardiovascular disease and well-controlled LDL-C levels received 40 mg / day sim with or without 10 mg ezetimibe The results of vastatin treatment showed that increasing the lipid-lowering dose (1 g / day) of niacin did not increase the benefit of cardiovascular outcomes. Therefore, when using simvastatin in combination with niacin, the benefits of combined use should be carefully weighed against their potential risks. In addition, in this trial, the incidence of myopathy among Chinese patients receiving simvastatin 40mg or ezetimibe simvastatin 10 / 40mg was approximately 0.24%, compared with simvastatin 40mg or The incidence of myopathy in Chinese patients treated with ezetimibe simvastatin 10 / 40mg and slow-release laropiram 2g / 40mg was 1.24%. However, this clinical trial only evaluated Chinese patients in Asian populations. Since the incidence of myopathy among Chinese patients is higher than that of non-Chinese patients, this product and lipid-lowering dose ( 1g / day) are not recommended. The use of acid in the Asian population. (See Drug Interactions)

Anticoagulants: If this product is used in combination with warfarin, another coumarin anticoagulant, or fluorindione, the internationally standardized ratio (INR) should be appropriately monitored (see Drug Interactions).

Liver enzymes

In the clinical controlled trial of combined use of ezetimibe and simvastatin, a continuous increase in transaminases (3 times the upper limit of normal) has been observed (see [Adverse Reactions]).

It is recommended that a liver function test be performed before application of this product and rechecked as needed. Patients with elevated serum transaminase levels should be given high attention, and liver enzymes should be checked immediately, and frequent follow-up checks are still needed. If the level of transaminase continues to increase, especially when it increases to three times the upper limit of normal value, the use of this product should be terminated. It should be noted that alanine aminotransferase may come from muscle, so alanine aminotransferase is accompanied by an increase in creatine kinase, which may indicate myopathy (see Precautions, Myopathy / Rhabdomyolysis).

There are very few post-market reports on the use of statins, including simvastatin, in patients with fatal and non-fatal liver failure. If severe liver injury with clinical symptoms and / or hyperbilirubinemia or jaundice occurs during the treatment with this product, stop using this product immediately. If no cause is found, do not reapply this product.

Patients who drink heavily and / or have a history of liver disease should use this product with caution. This product is contraindicated in patients with active liver disease or persistently elevated aminotransferases of unknown origin.

Liver dysfunction

As the effect of increased ezetimibe exposure on patients with moderate to severe liver dysfunction is unclear, this product is not recommended for these patients (see [Pharmacokinetics] Patient Characteristics [Special Population])

Ezetimibe simvastatin tablets for pregnant women

This product

The safety of pregnant women has not been proven, and treatment should be discontinued as soon as pregnancy is established. Women of childbearing age can use this product only when it is impossible to conceive and inform them of the possible damage.

Ezetimibe

Ezetimibe was administered orally to rats or white rabbits during embryonic organ formation, and no embryonic lethality was observed at the test doses (250, 500, 1000 mg / kg / day). At a dose of 1000 mg / kg / day of ezetimibe (based on the total AUC _{0-24hr of} ezetimibe, approximately 10 times the human 10 mg daily dose exposure), abnormal fetal skeletal development in rats (paired increase in _sternum ) , Cervical cone pyramidal ossification, ribs shortened) incidence increased. In large white rabbits treated with ezetimibe, _{polythoracic ribopathy was observed} when the dose reached 1000 mg / kg / day (based on the total AUC _{0-24hr of} ezetimibe, approximately 150 times the human 10 mg daily dose exposure). Rate increases. When multiple doses of ezetimibe were administered orally to pregnant rats and large white rabbits, ezetimibe was able to pass through the placenta.

In the study of organ formation in rats and rabbits, multiple doses of ezetimibe and HMG-CoA reductase inhibitor (statin) combined resulted in higher ezetimibe and statin exposure. Compared with the medication alone, reproductive abnormalities occur in combination with low doses.

Simvastatin

Simvastatin rats had a daily dose of 25 mg / kg or rabbits 10 mg / kg, and no teratogenicity was seen. Both doses were three times the human exposed body surface area (mg / m ² ). However, in another study of structurally related HMG-CoA reductase inhibitors, bone abnormalities in rats and mice were found.

Congenital anomalies are rarely reported after intrauterine exposure to HMG-CoA reductase inhibitors. In a retrospective review of approximately 100 pregnant women, the incidence of congenital anomalies, spontaneous abortions, and stillbirths was less than the average after exposure to simvastatin or another structurally related HMG-CoA reductase inhibitor. Expected incidence in the population. The number of cases is only sufficient to rule out a 3- to 4-fold increase in the incidence of congenital anomalies beyond normal. In a prospective study of pregnancy in 89% of women, treatment began before pregnancy and stopped during the first three months of pregnancy after the pregnancy was established.

childbirth

The impact on childbirth of pregnant women is unknown.

Lactation medication

In studies in rats, ezetimibe exposure in lactating mice reached half of the amount observed in maternal plasma. It is unclear whether ezetimibe and simvastatin are passed into human breast milk. Because other drugs similar to simvastatin are excreted into human breast milk in small amounts, and due to the possibility of serious adverse reactions to infants, lactating women should not take this product. (See [taboo])

Ezetimibe simvastatin tablets for children

This product

The safety and effectiveness of pediatric medications have not been established (see ezetimibe and simvastatin below).

Ezetimibe

This product has similar pharmacokinetics to adolescents (10-18 years) as adults. This product's experience with puberty is limited to the study of 4 (9 to 17 years old) homozygous sitosterolemia patients and 5 (11 to 17 years old) homozygous familial hypercholesterolemia patients. This product is not recommended for children (<10 years).

Simvastatin

The safety and effectiveness of simvastatin were evaluated in a controlled study of adolescent boys and girls (at least 1 year after menarche) of heterozygous familial hypercholesterolemia aged 10-17 years. Adverse events in patients receiving simvastatin were approximately similar to those in the placebo group. No studies of doses greater than 40 mg have been performed on this population. In this limited controlled study, there were no detectable effects on growth and sexual maturity in adolescent men and women, nor did they have any effect on the length of menstrual cycles in women. Adolescent women should be informed of proper contraception during treatment with simvastatin (see [Contraindications]). There are no studies of simvastatin in patients younger than 10 years of age or women in the premenstrual period.

Ezetimibe simvastatin tablets for elderly patients

In clinical trials, 792 patients who received this product were over 65 years old (including 176 patients over 75 years old). The efficacy and safety of this product for these patients is similar to that of young patients. Some more sensitive older patients are not included here. ([Pharmacokinetics] Patient Characteristics [Special Population])

Ezetimibe Simvastatin Tablets Drug Interactions

Ezetimibe was used in combination with simvastatin and no clinically significant pharmacokinetic interactions were found. No special pharmacokinetic drug interaction studies have been performed on this product.

This product is bioequivalent when used in combination with ezetimibe and simvastatin.

Banned drugs

The following drugs are prohibited in combination:

Strong inhibitor of CYP3A4

A potent inhibitor of CYP3A4 can reduce the clearance of simvastatin in this product, thereby increasing the risk of myopathy. Therefore, when this product is used in combination with a CYP3A4 inhibitor (such as listed below), elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, especially at higher doses. Do not use drugs with strong inhibitory effects on CYP3A4 (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, popperide Wei, Tilariver, Nefazodone). (See Contraindications, Precautions, Myopathy / Rhabdomyolysis, Pharmacokinetics.)

Cyclosporin or danazol

Coadministration of cyclosporine A or danazol can lead to an increased risk of myopathy, including rhabdomyolysis. Therefore, the combined use of these drugs is prohibited. (See Contraindications and Precautions, Myopathy / Rhabdomyolysis)

Gefibezi: The use with this product is prohibited. (See Contraindications and Precautions, Myopathy / Rhabdomyolysis)

Other drug interactions

Fibrates: The safety and effectiveness of this product in combination with fibrates other than Norbet has not been studied. Because it is known that the combined use of HMG-CoA reductase inhibitors and fibrates increases the risk of myopathy during the treatment period, caution must be exercised when using this product in combination with fibrates (except for banned gemfibrozil). Fibrates increase cholesterol excretion in bile, which can lead to gallstones. In a preclinical study in dogs, ezetimibe increased cholesterol concentrations in bile.

Fusidic acid: Combining this product with fusidic acid may increase the risk of myopathy / rhabdomyolysis (see [Precautions] Myopathy / rhabdomyolysis). Fusidic acid is not recommended.

Amiodarone, dronedarone, ranolazine, or a calcium channel blocker: a combination of amiodarone, dronedarone, ranolazine, or a calcium channel blocker such as verapamil, diltiazem, or ammonia chloride Dipine can cause increased risk of myopathy, including rhabdomyolysis, and the combined use of amiodarone and high doses of this product can increase the risk of myopathy / rhabdomyolysis. Dissolve).

Cholestyramine: The combination of cholestyramine can reduce the average AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) by about 55%. The increase in LDL-C decrease caused by the combination of this product and cholestyramine may be weakened by this interaction.

Moderate inhibitor of CYP3A4: Take this product in combination with other drugs that have a moderate inhibitory effect on CYP3A4 listed in the instructions, especially when the dose of this product is large, the risk of myopathy may increase (see [Precautions] Myopathy / rhabdomyolysis). It is necessary to adjust the dose of this product when used in combination.

Niacin: Myopathy / rhabdomyolysis can be observed during the combined treatment of simvastatin with a lipid-lowering dose ( 1 g of nicotinic acid per day). When using this product in combination with niacin, the benefits must be carefully weighed against the potential risks of myopathy / rhabdomyolysis. Since the incidence of myopathy is higher in Chinese patients than in non-Chinese patients, the combination of this product with a lipid-lowering dose (1 g / day) of niacin in Asian populations is not recommended. (See [Precautions] Myopathy / Rhabdomyolysis).

Colchicine: There are reports of myopathy and rhabdomyolysis after taking colchicine and this product in combination. Therefore, caution should be used when using this product in combination with colchicine.

Other interactions

Grapefruit juice contains one or more ingredients that inhibit CYP3A4 and can lead to elevated plasma levels of drugs metabolized by CYP3A4. Routine intake (1 cup of 250 mL per day) had minimal impact (based on the area under the concentration-time curve, the active plasma HMG-CoA reductase inhibitory activity increased by 13%) and had no clinical relevance. However, since a large amount of grapefruit juice can significantly increase the plasma level of HMG-CoA reductase inhibitory activity, grapefruit juice should be avoided during the treatment of this product (see [Precautions] Myopathy / Rhabdomyolysis).

Anticoagulant

Simvastatin 20-40 mg daily moderately promotes the effect of coumarin anticoagulants: Thrombin reported by International Normalized Ratios (INR) in studies involving healthy volunteers and hypercholesterolemia patients The original time rose from 1.7 to 1.8 seconds and from 2.6 to 3.4 seconds in the baseline period, respectively. Similar to other statins, clinically significant bleeding and / or prolonged prothrombin time have been reported in a few patients taking a combination of coumarin anticoagulants. In these patients, the prothrombin time must be measured before starting this product, and it should be measured at a sufficient frequency early in the treatment to ensure that there is no significant change in the prothrombin time. Once the prothrombin time is confirmed to be stable, this can be monitored at routinely recommended intervals in patients taking coumarin anticoagulants. If the dose of this product changes or is discontinued, the same procedure must be repeated. In patients not taking anticoagulants, simvastatin treatment did not cause bleeding or changes in prothrombin time.

In a study of 12 healthy adult men, the combination of ezetimibe (10 mg once daily) did not significantly affect warfarin's bioavailability and prothrombin time. Patients who have added ezetimibe to warfarin or fluorindione have received post-market reports of increased international standardized ratios. Most patients also receive other medications (see [Precautions]).

The effect of this product on prothrombin time has not been studied.

Digoxin

In one study, the combination of digoxin and simvastatin caused a slight increase in plasma digoxin concentrations. In patients taking digoxin, appropriate monitoring should be performed when starting this product.

Ezetimibe Simvastatin Overdose

This product

There is no special method to deal with this drug overdose. In case of overdose, symptomatic and supportive treatment should be used.

Ezetimibe

The following two clinical trials (15 healthy volunteers taking ezetimibe 50 mg daily for 14 days; 18 patients with primary hypercholesterolemia orally taking 40 mg daily for 56 days) showed good tolerability.

Several overdose cases have been reported, most of which have nothing to do with adverse events. No serious adverse events have been reported.

Simvastatin

Several overdose cases have been reported, with a maximum dose of 3.6 g. All patients recovered without any sequelae.

Simvastatin's dialysate and its metabolites in the human body are currently unknown.

Ezetimibe Simvastatin Tablets Pharmacology and Toxicology

Animal pharmacology

Ezetimibe

Studies of cholesterol-lowering effects of ezetimibe have been evaluated in mouse models of rhesus, dog, rat, and human cholesterol metabolism. Rhesus monkeys are fed cholesterol-containing foods that mimic Western diets. Studies have found that ED ₅₀ (half effective amount) of ezetimibe inhibits rhesus plasma cholesterol levels is 0.5 µg / kg / day, dog ED ₅₀ is 7 µg / kg / day, rat ED50 is 30 µg / kg / day The mouse ED ₅₀ was 700 µg / kg / day. The results show that ezetimibe is an effective cholesterol absorption inhibitor.

In the rat model, the ezetimibe glucuronide metabolite (ezetimibe-glucuronide) was administered intraduodenally, and the metabolite was as effective as ezetimibe in inhibiting cholesterol absorption, suggesting that Glucuronide metabolite activity is similar to patented drugs.

Dogs given ezetimibe (0.03 to 300 mg / kg / day) for one month can increase cholesterol levels in bile by 2-4 times. When dogs were given ezetimibe (300 mg / kg / day) for one year, no gallstones were formed and no adverse effects on the hepatobiliary system were observed. After mice were given ezetimibe (0.3 to 5 mg / kg / day) and gastric orally fed a normal or cholesterol-rich diet for 14 days, the cholesterol concentration in the bile was not affected or decreased to normal levels.

A series of preclinical studies have shown that ezetimibe can selectively inhibit cholesterol absorption. Ezetimibe inhibits the absorption of [C] -cholesterol, but does not affect the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinylestradiol, or fat-soluble vitamins A and D in the small intestine.

In a 4 to 12-week toxicity study in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, pharmacokinetic interactions between ezetimibe and HMG-CoA reductase inhibitors (parent drugs or their active hydroxyl metabolites) have been seen in rats, dogs and rabbits.

Animal Toxicology

CNS toxicity

Normal dogs have clinically experienced optic nerve degeneration after simvastatin 180mg / kg / day (the average plasma drug concentration level produced by this dose is 12 times or higher than the average plasma drug concentration produced by humans taking 80mg / day). .

Normal dogs taking drugs with similar chemical properties to this product at 60 mg / kg / day Activity measurement) produces optic nerve degeneration (Waller's degeneration of retinal-knee body (nerve) fibers). In dogs 180 mg / kg / day (the average plasma drug concentration produced at this dose is 60 mg / kg / day The levels seen were similar at the dose.) 14-week treatment also produced Wallerian-like deterioration of the vestibular (cochlear) cochlea and chromatin dissolution of the retinal ganglion cells: the mean plasma drug concentration at this dose was 60 mg / kg / day. Similar.

CNS vascular damage (characterized by perivascular bleeding and edema, pericyte mononuclear cell infiltration, perivascular fibrin deposition, and small vessel necrosis) is seen in simvastatin 360 mg / kg / day (this dose The resulting average plasma drug concentration level is 14 times or higher than the average plasma drug concentration produced by a human taking 80 mg / day). Similar CNS vascular lesions have been observed with other drugs in this drug classification.

50 and 100 mg / kg / day (22 and 25 times the human 80 mg / day AUC, respectively) to female rats 2 years later, and 90 mg / kg / day (19 times) to dogs three months later and 50 mg / kg / day (5 times) cataract symptoms occurred 2 years after administration.

Carcinogenic , Mutagenicity, reproductive toxicity

This product

No animal carcinogenicity or fertility studies have been performed with ezetimibe and simvastatin. Ezetimibe and simvastatin combined with in vitro Salmonella typhimurium and E. coli (with or without metabolic activation) showed no evidence of mutagenicity.

In vitro analysis of chromosomal aberrations in human peripheral blood lymphocytes with ezetimibe and simvastatin (with or without metabolic activation) was not observed for (chromosomal) fission. In the micronucleus test of mice, ezetimibe and simvastatin (1: 1) doses of 600 mg / kg did not appear to be genotoxic.

Ezetimibe

Ezetimibe was administered to rats in an admixture method. Male rats were given 1500 mg / kg / day, and female rats were given 500 mg / kg / day (based on total _Aiezemeb AUC _0-24hr , approximately human). 20 times the dose of 10 mg per day), a carcinogenicity test was conducted for a period of 104 weeks. At the same time, a 104-week dietary carcinogenicity study was performed on mice at a dose of 500 mg / kg / day (based on total ezetimibe AUC _0-24hr , approximately 150 times the human 10 mg daily dose exposure). There was no statistically significant increase in tumor incidence in drug-treated rats and mice.

No mutations were observed in the bacterial mutagenicity test (Ames) with Salmonella and E. coli (with or without metabolic activation). In human peripheral blood lymphocyte tests (with or without metabolic activation), chromosomal aberrations were negative. In addition, in vitro mouse micronucleus test results were negative.

In the study of oral ezetimibe (gavage) fertility in rats, the dose was 1000 mg / kg / day for male or female rats (based on the total ezetimibe AUC _0-24hr , about human No reproductive toxicity was observed at 10 times the daily 10 mg dose exposure).

Simvastatin

Mice were given simvastatin at 25, 100, and 400 mg / kg / day for 72 weeks. Carcinogenicity experiments showed that the average blood drug concentration was about 1, 4, and 8 times higher than the average blood drug concentration of human 80 mg orally, respectively. (Total inhibitory activity AUC). In the high-dose female group and the middle and high-dose male groups, the incidence of liver cancer increased significantly, with the highest incidence in the male group being 90%. The incidence of hepatic adenomas in the low and high dose female groups increased significantly. The incidence of lung adenomas was also significantly increased in the female and male medium and high dose groups. In the high-dose male group, compared with the control group, para-lacrimal glands (glands of rodent eyes) had significantly more adenomas. The 25 mg / kg / day group had no effect on carcinogenicity. In a 92-week study in which mice were given a dose of 25 mg / kg / day, no carcinogenic effect was seen (calculated by AUC, the average plasma drug concentration was higher than twice the blood concentration of human 80 mg simvastatin).

In a study in which rats were given simvastatin 25 mg / kg / day for two consecutive years, the incidence of thyroid follicular adenoma in female rats increased significantly statistically. According to AUC calculations, their exposure levels were higher than those in humans. Vastatin 80 mg is 11 times higher.

Carcinogenicity studies in rats at doses of 50 and 100 mg / kg / day for 2 consecutive years found hepatocellular adenomas and carcinomas (in the two dose groups in females and in the male 100 mg / kg / day group). Thyroid follicular cell adenomas increased in both the male and female dose groups, and increased in the female 100 mg / kg / day group. Other HMG-CoA reductase inhibitors have increased incidence of thyroid tumors. Its blood drug concentration (AUC) is equivalent to 7 and 15 times (male) and 22 and 25 times (female) the average plasma drug exposure level of a human daily dose of 80 mg.

No evidence of mutagenicity was observed in microbial mutagenicity experiments (Ames) with or without liver metabolism in rats or mice. In addition, in vitro rat liver cell alkaline elution analysis, mammalian V-79 cells No mutagenic effects were found in forward mutagenesis studies, in vitro CHO cell chromosome mutation studies, or in vivo mouse bone marrow cell chromosome mutation analysis experiments.

Simvastatin was given 25 mg / kg (four times the maximum human exposure level of 80 mg / day based on the AUC of the patient's dose) for 34 weeks, and male rats' fertility was reduced. However, in a subsequent fertility test of a male rat taking the same dose of simvastatin for 11 weeks (the complete cycle of sperm development, including epididymal maturation), no effect on fertility was observed. No changes in rat testicles were observed under these two experimental microscopes. At 180 mg / kg / day (this dose is based on body surface area, 22 times higher than the maximum human exposure of 80 mg / kg / day), degeneration of the vas deferens (necrosis and damage to the seminiferous epithelium) was observed. Dogs taking 10 mg / kg / day (approximately twice the human exposure dose of 80 mg / day in AUC) showed drug-related testicular atrophy, reduced sperm production, spermatocyte degeneration, and giant cell formation. The clinical significance of the above findings is unknown.

Clinical pharmacology

Mechanism

This product

Plasma cholesterol comes from absorption in the small intestine and endogenous cholesterol synthesis. This product is a lipid-lowering drug with two complementary mechanisms of action: ezetimibe and simvastatin. This product reduces the levels of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, triglyceride and non-high density lipoprotein cholesterol by inhibiting the absorption and synthesis of cholesterol, and can increase the level of high density lipoprotein cholesterol.

This product has not been shown to benefit cardiovascular morbidity and mortality more than simvastatin.

Ezetimibe

Ezetimibe reduces blood cholesterol levels by inhibiting cholesterol absorption in the small intestine. It has been shown that the molecular target of ezetimibe is the sterol carrier Niemann-Pick C1-like 1 (NPC1L1), which is related to the intestinal absorption of cholesterol and phytosterols. In a two-week clinical study of 18 patients with hypercholesterolemia, compared with placebo, this product inhibited the absorption of cholesterol in the small intestine by 54%. This product has no clinically significant effect on the plasma concentrations of fat-soluble vitamins A, D, and E, and does not reduce the production of adrenal corticosteroids.

HMG-CoA

HMGCoAVLDLTGHDL-C

absorb

Ezetimibe

-

Ezetimibe

10mg(C _max )38%

HMG-CoA

distributed

Ezetimibe

-(>90%)

ß95%

Ezetimibe

--1020%8090%-22

C(20mg)+-93%48

1078% 11% 69%-9%

-HMG-CoAHMG-CoA--6-6-6-

C13%60%+C41210%(<5%)

Special population

Ezetimibe

Multi-dose studies of ezetimibe 10 mg daily for 10 consecutive days showed that the total ezetimibe concentration in plasma of elderly patients (greater than 65 years) was twice that of young patients.

Simvastatin

In a study of 16 patients aged 70 to 78 years receiving simvastatin 40 mg / day, the average plasma level of HMG-CoA reductase inhibitor potency increased by about 45% compared to 18 patients aged 18-30 years.

Child patient

Ezetimibe

Ezetimibe 10 mg daily for 7 consecutive days has shown that the absorption and metabolism of this product in children and adolescents (10-18 years) are similar to those in adult patients. There was no difference in adolescent and adult pharmacokinetics based on total ezetimibe plasma concentrations. No pharmacokinetic data are available for children younger than 10 years of age.

gender

Ezetimibe

Multi-dose studies of ezetimibe 10 mg daily for 10 consecutive days showed that total ezetimibe concentrations in women's plasma were slightly higher than men's (increased value <20%).

race

Ezetimibe

According to a multi-dose pharmacokinetic meta-analysis, there was no difference in pharmacokinetics between blacks and whites. Studies in Asian subjects have shown that ezetimibe's pharmacokinetics are similar to those of Caucasians.

Liver dysfunction

Ezetimibe

Patients with mild hepatic insufficiency (Child-Pugh score 5 or 6) after taking a single dose of ezetimibe 10 mg, the area under the total ezetimibe curve (AUC) increased about 1.7 times compared with the normal population. Patients with moderate liver impairment (Child-Pugh scores 7 to 9) and patients with severe liver impairment (Child-Pugh scores 10 to 15), the total area under the curve (AUC) of ezetimibe and ezetimibe increased, respectively. About 3-4 times and 5-6 times. In a multiple-dose trial of 14 days for patients with moderate liver dysfunction (Child-Pugh scores 7-9), patients took 10 mg of this product daily, under the curve of total ezetimibe and ezetimibe The area is 4 times higher than the normal population.

Renal insufficiency

Ezetimibe

Patients with severe renal insufficiency (n = 8; average CrCl 30mL / min / 1.73m2) after taking a single dose of 10 mg ezetimibe, the area under the mean curve of total ezetimibe and ezetimibe was higher than that of a normal population (n = 9) Increase by 1.5 times.

Simvastatin

Pharmacokinetic studies of another statin similar to the main pathway of simvastatin clearance demonstrated that for a given dose, higher systemic exposures may occur in patients with severe renal impairment (measured by creatinine clearance).

Study on clinical data of ezetimibe simvastatin tablets

Primary hypercholesterolemia

This product

This product reduces TC, LDL-C, Apo B, TG, and non-HDL-C levels and increases HDL-C levels in patients with hypercholesterolemia. During long-term treatment, the maximum to near-maximum efficacy is usually reached and maintained within 2 weeks.

This product is effective for both male and female patients with hypercholesterolemia. The lack of experience in non-Caucasians makes it difficult to accurately estimate the effect of this product.

In five multi-center, double-blind studies, this product was reported to patients with hypercholesterolemia or equivalent amounts of ezetimibe and simvastatin: two compared with simvastatin and two with Atorvastatin comparison, 1 compared with rosuvastatin.

In a 12-week, double-blind, placebo-controlled, multicenter trial, 1,528 patients with hypercholesterolemia were randomly assigned to 10 groups: placebo, ezetimibe 10 mg, and simvastatin 4 Dose groups (10mg, 20mg, 40mg, or 80mg), and 4 ezetimibe and simvastatin in the same amount as this product (10/10, 10/20, 10/40, and 10/80) group.

Compared with each dose group of simvastatin, this product can significantly reduce plasma TC, LDL-C, ApoB, TG, non-HDL-C and C-reactive protein levels. The effect of this product on HDL-C is similar to that of simvastatin. Further analysis showed that compared with placebo, this product can significantly increase HDL-C (see Table 1). The lipid-lowering effect of this product is similar in patients with TG levels above or below 200 mg / dL. ^[4]

In a 23-week, double-blind, controlled, multicenter trial, 710 patients were diagnosed with a risk of coronary heart disease or coronary heart disease (as specified in the NCEP ATP III guidelines), and plasma LDL-C 130 mg / dL Patients were randomly assigned to the following 4 treatment groups: 3 dose groups of ezetimibe combined with simvastatin and simvastatin 20 equivalent to VYTORIN (10/10, 10/20, and 10/40) mg group. For patients whose plasma LDL-C levels do not reach <100 mg / dL, the simvastatin dose is adjusted every 6 weeks until the highest dose of 80 mg is reached.

At week 5, the decrease of LDL-C in each treatment group (10/10, 10/20 and 10/40) was significantly greater than that in the simvastatin 20 mg group (see Table 2). ^[4]

In a 6-week, multicenter, double-blind trial, 1902 patients with primary hypercholesterolemia who did not meet the LDLC treatment goals of NCEP ATP III were randomly assigned to the following 8 treatment groups: Vytorin (10 / 20, 10/40, 10/80) or atorvastatin (10mg, 20mg, 40mg or 80mg).

Within the dose range, this product significantly reduces TC, LDL-C, Apo B, and non-HDL- compared to atorvastatin in patients taking VYTORIN compared to patients taking atorvastatin in equal amounts. C. However, only 10/40 mg and 10/80 mg of this product can significantly reduce HDL-C compared with taking atorvastatin with the same amount of statin. The effect of this product on TG is similar to atorvastatin. ^[4]

In a 24-week, mandatory escalation, double-blind, multicenter trial, 788 patients with primary hypercholesterolemia who did not meet the NCEP ATP III LDL-C treatment goals were randomly assigned to the following 3 groups: Ezetimibe combined with simvastatin administration group and atorvastatin 10 mg group were equivalent to this product (10/10 and 10/20). Patients in these three groups adjusted their statin doses every 6 weeks until they reached 80 mg. In the comparison of each pre-set dose group, the decrease in LDL-C was greater in the two dose groups of VYTORIN than in the atorvastatin group (see Table 4). ^[4]

In a 6-week, multicenter, double-blind trial, 2959 patients with primary hypercholesterolemia who did not meet the LDLC treatment goals of NCEP ATP III were randomly assigned to the following 6 treatment groups: Vytorin (10 / 20, 10/40, 10/80) or rosuvastatin (10mg, 20mg, or 40mg). The effects of this product and rosuvastatin on TC, LDL-C, Apo B, TG, non-HDL-C and HDL-C are shown in Table 5 ^[4]

In a 24-week, double-blind, multicenter trial, 214 patients with type 2 diabetes received at least 3 months of thiazolidinediones (rosiglitazone or pioglitazone) and at least 3 months With the treatment of vastatin 20mg, the average LDL-C level was 89 mg / dL and the average HbA1c level was 7.1%. Patients were randomly assigned to the simvastatin 40 mg group or the combination of active ingredients and VYTORIN 10/20.

VYTORIN 10 / 20mg, compared with simvastatin 40 mg, the effect is more significant. Median change from baseline (VYTORIN vs simvastatin) was LDL-C (-25% vs. -5%), TC (-16% vs. -5%), Apo B (-19% vs. -5) %), And non-HDL-C (-23% vs. -5%). There was no significant difference in the effects of HDL-C and TG between the two groups.

Ezetimibe

In two 12-week, double-blind, placebo-controlled, multicenter studies involving 1,719 patients with primary hypercholesterolemia, ezetimibe significantly reduced TC (-13 %), LDLC (-19%), ApoB (-14%), and TG (-8%), and increased HDLC (+ 3%). LDLC reduction was not affected by age, gender, race, and baseline LDLC values.

Simvastatin

VYTORIN contains simvastatin. Two large-scale, placebo-controlled clinical studies, the Scandinavian Simvastatin Survival Study (N = 4,444) and the Cardioprotection Study (N = 20,536), evaluated Simvastatin in patients at high risk for coronary events ( Presence of clinical effects of coronary heart disease, diabetes, peripheral vascular disease, and stroke or other cerebrovascular diseases). The results demonstrate that simvastatin can reduce coronary heart disease mortality and the risk of non-fatal myocardial infarction and stroke, while reducing patients' need for coronary and non-coronary angioplasty.

There is no data on whether VYTORIN is superior to simvastatin in reducing the incidence and mortality of cardiovascular events.

Homozygous familial hypercholesterolemia (HoFH)

A 12-week, double-blind, randomized trial was performed in HoFH patients with clinical and / or genotypic diagnosis. The study analyzed data from a group of 14 patients who were receiving simvastatin 40 mg at baseline. Compared with the baseline level of simvastatin 40 mg treatment, five patients with a dose of simvastatin increased from 40 mg to 80 mg showed a 13% decrease in LDL-C levels; another nine patients received VYTORIN (10 / 40 and 10/80) patients treated with ezetimibe combined with simvastatin reduced their LDLC levels by 23%, and 5 of them received ezetimibe combined with simvastatin at the same amount as VYTORIN In statin-treated patients, LDL-C decreased by 29%. ^[4]

Major vascular events of chronic kidney disease ( CKD )

The Heart and Kidney Protection Study (SHARP) is a multinational, randomized, placebo-controlled, double-blind clinical trial of 9,438 patients with moderate to severe chronic kidney disease without a history of myocardial infarction or coronary revascularization (approximately three One-quarter of the patients received dialysis at baseline) to study the effect of this product on the timing of the first major vascular event (MVE). Major vascular events were defined as non-fatal myocardial infarction, cardiogenic death, stroke, or any revascularization procedure. The study used a specific method that took into account the distribution of eight important baseline characteristics of the selected patients to assign treatment groups to minimize the imbalance of these characteristics between the two groups.

In the first year, 9438 patients were randomized to receive 10/20 mg of this product, placebo or simvastatin 20 mg daily in a 4: 4: 1 ratio. The 1-year simvastatin treatment group was included in the study to compare the safety and lipid-lowering effects of this product with simvastatin monotherapy. In the first year, the simvastatin monotherapy group was re-randomized to receive 10 / 20mg of this product or placebo at a ratio of 1: 1. During the study period, a total of 9,270 patients received this product 10/20 (n = 4650) or placebo (n = 4620). The median follow-up period was 4.9 years. The average age of patients was 61 years; 63% were male, 72% were Caucasian, and 23% were diabetic; among patients who did not receive dialysis at baseline, the median serum creatinine level was 2.5 mg / dL, and the median kidney was small The estimated value of bulb filtration rate (eGFR) is 25.6 ml / min / 1.73 m2, and the estimated glomerular filtration rate of 94% of patients is less than 45 mL / min / 1.73 m2. Inclusion criteria for blood lipids were not set. The baseline mean LDL cholesterol level was 108 mg / dL. At the time of the 1-year measurement, compared with placebo, the average low-density lipoprotein cholesterol level in the simvastatin group decreased by 26%, compared with a 38% decrease in this product group. At the midpoint of the study (2.5 years), the average LDL cholesterol level in the treatment group was 32% lower than in the placebo treatment group. All blood lipid measurements included patients who were no longer taking study medication.

In the intention-to-treat analysis of the primary endpoint, 639 (15.2%) of the 4,193 patients who initially received this product had major vascular events, while 749 (17.9%) of the 4191 patients who initially received the placebo were equivalent The risk was reduced by 16% (p = 0.001) (see Figure 1). Similarly, 526 (11.3%) of a total of 4,650 patients receiving this product experienced major atherosclerotic events (MAE; a subset of the composite endpoints of major vascular events, excluding non-coronary cardiogenic death and bleeding Sexual stroke), and 619 (13.4%) of the 4,620 patients receiving placebo, which corresponds to a 17% reduction in relative risk (p = 0.002). This study demonstrates that 10/20 mg of this product reduces the risk of MVE and MAE in patients with chronic kidney disease compared to placebo. The study design failed to draw any conclusions about the independent contribution of ezetimibe or simvastatin to efficacy.

Compared with patients who did not receive dialysis at baseline, patients who received dialysis at baseline had less benefit in the treatment of major vascular events with this product. This product reduced the risk of major vascular events by 6% in 3023 patients receiving baseline dialysis (relative risk 0.94: 95% confidence interval 0.80-1.09), and by 22% in 6247 patients not receiving baseline dialysis ( Relative risk 0.78: 95% confidence interval 0.69-0.89) (interaction P = 0.08).

Figure 1: The effect of this product on the primary endpoint, the risk of major vascular events

The effect of this product on the main endpoint, the risk of major vascular events

The occurrence of each component of MVE in all patients receiving randomization can be seen in Table 6.

Table 6

Number of first events of each component of the composite endpoint of major vascular events in the SHARP study

ending	This product (N = 4650)	Placebo (N = 4620)	Risk ratio (95% confidence interval)	P value
Major vascular event	701 (15.1%)	814 (17.6%)	0.85 (0.77-0.94)	0.001
Nonfatal myocardial infarction	134 (2.9%)	159 (3.4%)	0.84 (0.66-1.05)	0.12
Cardiogenic 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

Intention-to-treat analyses were performed in all SHARP study patients randomized to this product or placebo.

Compared with placebo, this product does not reduce the risk of progression to end-stage renal disease in patients not receiving dialysis at baseline (relative risk 0.97: 95% confidence interval 0.89-1.05).

Recommended guidelines for ezetimibe simvastatin tablets

1. The clinical application recommendations of the 2015 Chinese Expert Consensus on Selective Cholesterol Absorption Inhibitors mentioned,

On the basis of reasonable diet control, ezetimibe can be applied to the following conditions:

(1) If the cholesterol level still cannot reach the standard after conventional dose of statin treatment, ezetimibe can be used in combination.

(2) Patients who are not suitable or can not tolerate statin treatment can be treated with ezetimibe monotherapy.

(3) Patients with mixed dyslipidemia whose main manifestation is elevated TG can be combined with fenofibrate and ezetimibe

cloth.

(4) Patients with homozygous familial hypercholesterolemia whose lipids have not reached the standard after receiving special treatment (such as plasma exchange therapy) can be treated with ezetimibe and statin.

(5) For the treatment of patients with homozygous sitosterolemia (or phytosterolemia).

2. "2014 CCEP Expert Recommendations for the Prevention and Treatment of Dyslipidemia" ^[5]

3. "2015 Expert Recommendations on the Combined Application of Cholesterol-lowering Drugs" ^[6]

4. 2015 European Society of Cardiology Annual Meeting Guide

5. 2015 National Lipid Association Guidelines for Management of Dyslipidemia

6. American Heart Association / American Heart Association Guide 2015

7. American Diabetes Association Guide 2015