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Simvastatin tablets

Product description

Approval date: 21 June 2006

 

Modification date: September 30, 2010

 

October 16, 2013

 

November 30, 2015

 

Instructions for simvastatin tablets

 

Please read the instructions carefully and use them under the guidance of your physician.

 

[name of drug]

 

Generic name: simvastatin tablets

 

Simvastatin Tablets

 

Mandarin spelling: Xinfatating Pian

 

【 ingredients 】 【 main ingredients of simvastatin and its chemical name is: 2, 2 - dimethyl butyric acid (4 r, 6 r) - 6 - [2 - [(1 s, 2 s, 6 r, 8 s, 8 ar) - 1,2,6,7,8,8 six hydrogen - 8 - hydroxy - a - 2, 6 - dimethyl - 1 - naphthyl] ethyl] four hydrogen - 4 - hydroxy - 2 h - pyran - 2 - keto - 8 - ester.

 

Molecular formula: C25H38O5

 

Molecular weight: 418.57

 

[properties] this product is a thin film coating piece, showing white or similar white after removing the coating.

 

[indications]

 

1. Hypercholesterolemia

 

(1) simvastatin can be given to patients with primary hypercholesterolemia when dietary control and other non-drug treatment are unsatisfactory. Simvastatin can not only reduce total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride, but also increase HDL cholesterol, thereby reducing the ratio of LDL cholesterol/HDL cholesterol and total cholesterol/HDL cholesterol.

 

(2) simvastatin can reduce the cholesterol level in patients with hypercholesterolemia and hypertriglyceridemia, who are mainly hypercholesterolemia.

 

2. Coronary heart disease (CHD)

 

Simvastatin is recommended for patients with coronary heart disease with hypercholesterolemia:

 

(1) reduce the risk of death;

 

(2) reduce the risk of coronary heart disease death and non-fatal myocardial infarction;

 

(3) reduce the probability of requiring myocardial recanalization surgery (coronary artery bypass surgery and percutaneous balloon coronary angioplasty) due to coronary events;

 

(4) delay the progression of coronary atherosclerosis, including reducing the formation of new lesions and total blockages.

 

[specification] 10mg

 

[usage and dosage]

 

Patients should be on a standard cholesterol-lowering diet prior to simvastatin treatment and maintained during treatment.

 

1. Hypercholesterolemia:

 

The general starting dose is 10mg(1 tablet) per day, taken at night. For patients with mild to moderate elevated cholesterol levels, the starting dose is 5mg(1/2 tablet) per day. Adjust the dose more than four weeks apart, with a maximum dose of 40mg(4 tablets) per day, taken at night.

 

Cholesterol levels should be monitored regularly, and if cholesterol levels are significantly below the target range, consider reducing simvastatin doses.

 

2. Coronary heart disease:

 

Patients with coronary heart disease can start with 20mg(2 tablets) per day, and adjust the dose more than four weeks apart. The maximum dose is 40mg(4 tablets) per day, and take it at night.

 

3. Combination of drugs:

 

Simvastatin was effective either alone or in combination with cholic acid chelator. In general, use with betters or niacin should be avoided. For patients taking immunosuppressants such as cyclosporin, the starting dose of simvastatin should be 5mg(1/2 tablet) per day and no more than 10mg(1 tablet) per day.

 

4. Patients with renal insufficiency:

 

Because simvastatin is primarily excreted by bile and is rarely excreted by the kidney, patients with moderate renal insufficiency do not need to adjust the dose. Patients with severe renal insufficiency (creatinine clearance rate less than 30ml/min) should use this product with caution. The starting dose for such patients should be 5mg/day (1/2 tablet), and when the dose exceeds 10mg/day (1 tablet), it should be closely monitored.

 

[adverse reactions]

 

Simvastatin was generally well tolerated and most of the adverse reactions were mild and transient. In controlled clinical studies, less than 2% of patients stopped taking simvastatin because of adverse reactions.

 

In the clinical control study, the adverse reactions related to drugs with the incidence of ≥1% included abdominal pain, constipation and gastrointestinal distension, and the adverse reactions with the incidence of 0.5% ~ 0.9% included fatigue and headache.

 

Reports of myopathy are rare.

 

The following adverse reactions have been reported in clinical observation and post-marketing application: nausea, diarrhea, rash, indigestion, pruritus, hair loss, dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting and anemia, rhabdomyolysis, and hepatitis/jaundice rarely occur.

 

Including one or more of the following symptoms of obvious allergic reaction syndrome rarely reported: sample angioneurotic oedema, lupus syndrome, rheumatoid multiple myalgia, vasculitis, thrombocytopenia, increased eosinophils, elevated ESR, arthritis, joint pain, urticaria, light sensitive, fever, flush, dyspnea and discomfort.

 

Laboratory findings: significant and sustained elevation of serum transaminase is rarely reported. Elevated alkaline phosphatases and gamma-glutamine-transpeptidases have been reported. Abnormal liver function examination is usually mild or transient. Elevated serum creatine kinase (CK) from skeletal muscle has been reported.

 

In the post-marketing monitoring of statins, there were reports of hyperglycemia reaction, abnormal glucose tolerance, increased glycosylated hemoglobin level, new diabetes, and deteriorating blood glucose control, and some statins also reported hypoglycemia reaction.

 

Post-marketing experience: there are rare reports of cognitive impairment in post-marketing monitoring of statins in foreign countries, manifested as memory loss, memory decline, confusion of thinking, etc. Most of them are non-severe and reversible reactions, which can be recovered after withdrawal.

 

【 taboo 】

 

Disable:

 

1. Allergic to any ingredient of this product.

 

2. Patients with active liver disease or unexplained elevated serum transaminase.

 

3. Pregnant and lactating women.

 

4. Do not use with tetrahydrophenolic calcium channel blocker mibedil.

 

[precautions]

 

1. Muscle function

 

Hmg-coa reductase inhibitors occasionally cause myopathy with muscle pain or weakness accompanied by a significant increase in CK (10 times higher than the upper limit of normal). Rhabdomyolysis in acute renal failure with or without secondary myoglobinuria is rarely reported. In the Nordic simvastatin survival study, 1 myopathy occurred in 1399 patients taking 20mg simvastatin per day during the median 5.4 year period, while 822 patients taking 40mg simvastatin per day showed no myopathy. In two controlled clinical studies over six months, 1 myopathy occurred in 436 patients taking simvastatin 40mg and 5 myopathy occurred in 699 patients taking simvastatin 80mg. The study was designed to rule out some of the drugs that combine simvastatin with certain drugs to increase the risk of myopathy.

 

Myopathy caused by drug interactions

 

HMG-CoA reductase inhibitors increase the incidence and severity of myopathy when used in combination with drugs that can cause myopathy alone, including giffebecci and other betters, and niacin at a lipid lowering dose (≥1g/ day).

 

In addition, increased plasma HMG-CoA reductase inhibitor activity also increases the risk of myopathy. Simvastatin and other hmg-coa reductase inhibitors are metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4). Some drugs that significantly inhibit this metabolic pathway at therapeutic doses can increase blood levels of hmg-coa reductase inhibitors, and thus may increase the risk of myopathy. These drugs include cyclosporin, the antifungal azole itraconazole and ketoconazole, macrolidene antibiotics (erythromycin, clarithromycin, talomycin), ferdisic acid, HIV protease inhibitors, and the antidepressant nefazolone.

 

Reduce the risk of myopathy:

 

(1) general measures

 

Patients should be informed of the risks of myopathy and instructed to report unexplained muscle pain, tenderness, or weakness when starting simvastatin treatment. The patient's CK level was 10 times higher than the upper limit of normal value and accompanied by unexplained muscular symptoms, indicating myopathy. Simvastatin therapy should be discontinued if myopathy is diagnosed or suspected. In most cases, muscular symptoms and increased CK will recover after prompt termination of treatment.

 

Many patients with rhabdomyolysis have a history of complications. Some patients have a history of renal insufficiency, which is often a follow-up to long-term diabetes. In such patients, caution should be exercised when increasing the dose. At the same time, simvastatin therapy should be discontinued several days before major surgery and in the event of a more severe acute medical or surgical illness due to an unknown adverse secondary to short-term interruption of treatment.

 

(2) measures to reduce the risk of myopathy caused by drug interactions (see above)

 

The pros and cons of simvastatin in combination with any other drug that interacts with it should be weighed, and signs and symptoms of muscle pain, tenderness, or weakness should be carefully monitored, especially during the first few months of treatment and during increased doses. In this case, regular CK screening may be considered, but this does not guarantee that myopathy will be prevented.

 

Simvastatin should be avoided in combination with betters or niacin unless the benefits of changing lipid levels are likely to outweigh the increased risks associated with the combination. In small, short-term, carefully monitored clinical studies, low doses of simvastatin combined with betters or niacin did not cause myopathy. Hmg-coa reductase inhibitors used in combination with these drugs usually do not lower LDL cholesterol by much, but can further lower triglycerides and raise HDL cholesterol. Clinical practice shows that the risk of myopathy of simvastatin combined with niacin is lower than that of the combination of betters.

 

Simvastatin should not exceed 10mg/ d in patients taking cyclosporin, bette or niacin at large doses because of the increased risk of myopathy (see administration and dosage]. Combination of simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, talomycin, ferdisic acid, HIV protease inhibitor or nefazolone is not recommended. Since there have been no reports of adverse effects on long-term lipid reduction due to short-term discontinuation, simvastatin can be temporarily discontinued when short-term treatment such as itraconazole, ketoconazole, erythromycin or clarithromycin is necessary. Simvastatin should be avoided in combination with other drugs labeled with potential CYP3A4 inhibition unless the benefits of combined treatment outweigh the increased risk.

 

Liver action

 

In clinical studies, a small number of simvastatin treated adults showed a significant increase in sustained serum transaminase (three times higher than the upper limit of normal). In these patients, transaminase levels usually slow down to pre-treatment levels after discontinuance or discontinuation of the medication. This elevation of aminotransferase is not associated with jaundice or other clinical symptoms or signs and is not allergic. Some of these patients had abnormal liver function and/or had consumed large amounts of alcohol before simvastatin treatment.

 

All patients are advised to undergo regular (e.g., semiannually) liver function examinations before and after treatment and during the first year and the first year after dose escalation. For patients with elevated serum transaminase, the liver function should be reviewed in time and the examination frequency should be increased. If transaminase levels show an upward trend, especially if they rise to three times the normal upper limit and remain unchanged, the drug should be discontinued.

 

Caution should be exercised in patients who consume large amounts of alcohol and/or have a history of liver disease. Simvastatin should not be used in patients with active liver disease or unexplained elevation of transaminase.

 

As with other lipid-lowering agents, moderate (3 times below the normal upper limit) elevation of serum transaminase was reported after simvastatin treatment. These changes appear soon after simvastatin treatment begins, but are often transient, with no symptoms and no need to interrupt treatment.

 

3. Eye examination

 

The incidence of lens opacity increases with age, even in the absence of any medication. Long-term clinical data show that simvastatin has no adverse effect on human lens.

 

4. Hypertriglyceridemia

 

Simvastatin only moderate of lowering triglycerides, not suitable for treatment is given priority to with elevated triglycerides anomalies (such as Ⅰ, Ⅳ and Ⅴ type hyperlipidemia).

 

5. This product should be used with caution in patients with heavy alcohol consumption and/or a history of liver disease.

 

[drugs for pregnant and lactating women]

 

Simvastatin has not been used in pregnant women. Because atherosclerosis is a chronic process, discontinuation of lipid-lowering agents during pregnancy has little effect on long-term treatment of primary hypercholesterolemia. Cholesterol and other products of its biosynthesis pathway are essential components of fetal development, including steroid and membrane synthesis. Pregnant women should not use simvastatin because hmg-coa reductase inhibitors, such as simvastatin, reduce the synthesis of cholesterol and other products of the biosynthetic pathway. Simvastatin should only be used in women of childbearing age who are less likely to become pregnant. If a woman is pregnant while taking the drug, she should stop simvastatin and be informed of possible damage to the fetus.

 

It is not known whether simvastatin and its metabolites are secreted by human milk, as many drugs are secreted by human milk and may cause serious adverse reactions, so women taking simvastatin should not breastfeed (see [contraindistions].

 

【 medicines for children 】

 

The safety and efficacy of medication in children has not been determined. Simvastatin is not currently recommended for children.

 

【 geriatric medicine 】

 

In older patients (older than 65 years), simvastatin was used in controlled clinical studies to reduce total and low-density lipoprotein (LDL) cholesterol in a manner similar to other groups, with no significant increase in the incidence of adverse reactions or laboratory abnormalities.

[drug interactions]

 

Gifferbecci and other betters, niacin at a lipid lowering dose (≥1g/ d) : these drugs are associated with an increased risk of myopathy when used in combination with simvastatin, possibly because they both cause myopathy when used alone (see muscular effects). There is no evidence that these drugs affect the pharmacokinetics of simvastatin.

 

Interactions with CYP3A4:

 

Simvastatin has no CYP3A4 inhibitory activity, so it is speculated that it does not affect plasma levels of other drugs metabolized by CYP3A4. However, simvastatin itself is the substrate for CYP3A4. During simvastatin treatment, CYP3A4 may increase the risk of myopathy by increasing the level of plasma hmg-coa reductase inhibitory activity. These potent agents include cyclosporin, mibedil, itraconazole, ketoconazole, erythromycin, clarithromycin, talimycin, ferdisic acid, HIV protease inhibitor, and nefazolone (see muscle action].

 

Grapefruit juice contains one or more compounds that inhibit CYP3A4 and increase plasma levels of drugs metabolized by CYP3A4. The effect of regular consumption (1 cup 250ml per day) was small (13% increase in plasma hmg-coa reductase inhibitory activity by measuring the area under the concentration time curve) and had no clinical significance. However, large amounts of simvastatin (more than l l per day) during simvastatin treatment significantly increase plasma levels of HMG-CoA reductase inhibition, which should be avoided (see [precautions] muscle effects).

 

Coumarin derivatives:

 

In a another hypercholesterolemia patients and healthy volunteers to participate in the clinical research of taking simvastatin 20 to 40 mg/day, can moderate to improve the anticoagulant effect of coumarin anticoagulants: international standardization on prothrombin time ratio (INR), healthy volunteers from the baseline set of 1.7 to 1.8 seconds, a group of patients with hypercholesterolemia risen from 2.6 to 3.4 seconds. For patients using coumarin anticoagulants, prothrombin time should be measured before simvastatin and often at the beginning of treatment to ensure no significant change in prothrombin time. Once a stable prothrombin time has been recorded, patients should be advised to monitor prothrombin time periodically during administration of coumarin anticoagulants. Repeat the above steps when adjusting simvastatin dose or discontinuation. Bleeding or prothrombin time changes were not associated with simvastatin in patients who did not receive coumarin anticoagulants.

 

Amiodarone, verapamil: combination with high doses of simvastatin increases the risk of myopathy/rhabdomyolysis.

 

Diltiazem: combined with simvastatin 80mg increases myopathy risk.

 

Because simvastatin is sensitive to CYP3A4, the FDA's revised instructions prohibit the use of simvastatin in combination with HIV protease inhibitors or HCV protease inhibitors (poprevir and telaravir).

 

[drug overdose]

 

Minor overdoses were reported in patients with no specific symptoms and all patients recovered without sequelae. The maximum dose was 450mg. Routine measures are usually taken to deal with drug overdoses.

 

【 pharmacology and toxicology 】

 

Pharmacological effects:

 

Simvastatin lowers normal and elevated levels of low-density lipoprotein cholesterol (ldl-c). Low-density lipoprotein (LDL) is produced by extremely low-density lipoprotein (VLDL) and is catabolized mainly by high-affinity LDL receptors. Simvastatin lowers LDL by lowering VLDL cholesterol and inducing the formation of LDL receptors, leading to reduced ldl-c production and/or increased catabolism. Apo B also decreased significantly during simvastatin treatment. Because each LDL particle contains one molecule of Apo B, very little Apo B was found in lipoproteins of patients who were primarily elevated in ldl-c (without accompanying VLDL elevation), suggesting that simvastatin not only removes cholesterol from LDL, but also reduces the concentration of circulating LDL particles. In addition, simvastatin can reduce VLDL and triglyceride (TG) and increase hdl-c. The effect of simvastatin on lipoprotein (a), fibrinogen, and other biochemical indicators of coronary heart disease is unclear.

 

Toxicology:

 

Genetic toxicity: no mutagenesis was found in Ames, alkaline elution analysis of rat liver cells in vitro, positive mutagenesis of mammalian v-79 cells, in vitro mutation of CHO cells or in vivo mutation analysis of mouse bone marrow cells.

 

Reproductive toxicity: daily dose of simvastatin was 25mg/kg in rats or 10mg/kg in rabbits, no teratogenicity was observed. Both doses were three times the dose of the exposed body surface area (mg/m2). However, in another structurally related study of hmg-coa reductase inhibitors, skeletal malformations were found in rats and mice. For 34 weeks, male rats were given simvastatin at 25mg/kg(at the AUC of 80mg/ day, which was 4 times of the maximum exposed body surface area), and their fertility was reduced. However, no effect on fertility was observed in a subsequent study in which a male rat received the same dose of simvastatin for 11 weeks (the complete cycle of sperm development, including epididymal maturation). The testicular changes in rats were not observed under microscope in these two experiments. Vasectomy (necrosis and injury of spermatogenic epithelium) was observed at 180mg/kg/ day (a dose measured by body surface area, 22 times higher than the maximum exposed body surface area dose of 80mg/kg/ day in humans). Dogs taking 10mg/kg/ day (about twice the dose of 80mg/ day in terms of AUC) showed drug-related testicular atrophy, decreased sperm production, spermatogenesis, and giant cell formation. The clinical significance of these findings is unclear.

 

Carcinogenicity: mice were given simvastatin 25, 100 and 400mg/kg/ day for 72 weeks, and the carcinogenicity test showed that the average blood concentration was about 1, 4 and 8 times higher than the average blood concentration of 80mg orally (AUC was used as the total inhibitory activity). The incidence of liver cancer increased significantly in the high-dose female group and the medium-high dose male group, and the highest incidence was 90% in the male group. The incidence of hepatic adenoma increased significantly in medium and high dose female groups. The incidence of lung adenoma was also significantly increased in female and male medium and high dose groups. Adenomas in the accessory lacrimal glands (glands in the eyes of rodents) increased significantly in the high-dose males compared with controls. No effect on carcinogenicity was observed in the 25mg/kg/ day group. No carcinogenicity was observed during the 92 weeks of administration of 25mg/kg/ day in mice (the average plasma drug concentration, calculated by AUC, was more than twice that of 80mg simvastatin in humans). Rats were given simvastatin at 25mg/kg/ day for two consecutive years, and the incidence of thyroid follicular adenoma in female rats was statistically significantly increased. According to the calculation of AUC, the exposed body surface area dose was 11 times higher than 80mg simvastatin in humans. Carcinogenicity studies in rats at doses of 50 and 100mg/kg/ day for two consecutive years found hepatocellular adenomas and carcinomas (in both the female dose group and the male 100mg/kg/ day group). In both male and female dose groups, thyroid follicular cell adenoma increased, while in female 100mg/kg/ day group, thyroid follicular cell carcinoma increased. Other hmg-coa reductase inhibitors all showed an increased incidence of thyroid tumors. The blood concentration (AUC) was 7 and 15 times of the average daily dose of 80mg of plasma drug exposure body surface area (male) and 22 and 25 times of the average daily dose of 80mg of plasma drug exposure body surface area (female).

 

[pharmacokinetics]

 

The total plasma radiation activity (simvastatin and 14C- metabolite) peaked at 4 h after oral administration of simvastatin with 14C label in male adults, then decreased rapidly and decreased to 10% of the peak at 12 h after administration. Simvastatin was administered orally in two animals with an absolute bioavailability of about 85%. Simvastatin after oral has high selectivity to the liver, its concentration in the liver significantly higher than that of other non target groups, the liver is the main effect of simvastatin, most of simvastatin in liver was the first intake, into the systemic circulation of simvastatin is lower than 5% of the dose, and 95% of them combined with plasma proteins. This product is excreted mainly through bile.

 

[storage] shading, sealing, storage in a cool place (no more than 20℃).

 

[packaging] aluminum-plastic packaging, 6 pieces per box; 10 tablets per box; 12 tablets per box; Each box contains 30 tablets.

 

[validity period] 24 months

 

[executive standard] the second edition of Chinese pharmacopoeia in 2015

 

[approval document no.] Chinese medicine approval number H20066221

 

[production enterprise]

 

Company name: guangdong peidi pharmaceutical co., LTD

 

Production address: 66 peidi avenue, yueshan town, kaiping city, guangdong province

 

Zip: 529331

 

Telephone number: 0750-2789348 2783621

 

400-8899-328 (national service telephone number)

 

Fax number: 0750-2789348

 

Web site: http://www.pdpharm.com

 

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