Simvastatin Tablets

Indication

Hypercholesterolemia For patients with primary hypercholesterolemia, simvastatin can be given when diet control and other non-pharmacological treatments are not ideal. Simvastatin not only lowers total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B and triglycerides, but also raises high-density lipoprotein cholesterol, thereby lowering low-density lipoprotein cholesterol/high-density lipoprotein cholesterol and total cholesterol /High-density lipoprotein cholesterol ratio... (see instructions)

Clinical pharmacology

Simvastatin reduces normal and elevated levels of low-density lipoprotein cholesterol (LDL-C). Low-density lipoprotein (LDL) is produced by very low-density lipoprotein (VLDL) and is primarily catabolized by high-affinity LDL receptors. Simvastatin reduces LDL by reducing VLDL cholesterol concentration and inducing LDL receptor production, resulting in reduced LDL-C production and/or increased catabolism. Apolipoprotein B (ApoB) also decreased significantly during simvastatin treatment. Because each LDL microparticle contains one molecule of ApoB, few ApoBs are found in lipoproteins in patients with elevated LDL-C (not accompanied by elevated VLDL), suggesting that simvastatin can not only remove cholesterol from LDL, Moreover, the concentration of circulating LDL particles can be reduced. In addition, simvastatin reduces VLDL and triglycerides (TG) and raises HDL-C. The effects of simvastatin on lipoprotein (a), fibrinogen, and other biochemical markers of coronary heart disease are unclear.

Dosage

Patients should receive a standard cholesterol-lowering diet and continue to maintain during the course of treatment with simvastatin. Use different doses depending on the condition... (see instructions)

Formulation

tablet

specification

5mg

Instruction manual

Approved date: May 8, 2007

Date of revision: October 1, 2010

December 10, 2013 2015-11-25 (increased packaging specifications)

December 01, 2015

Simvastatin tablets

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

【Drug Name】

Generic name: Simvastatin tablets

English name: Simvastatin Tablets

Pinyin: Xinfatating Pian

【Ingredients】 The main ingredient of this product is simvastatin.

Chemical name: 2,2-dimethylbutyric acid (4R,6R)-6-[2-[(1S,2S,6R,8S,8αR)-1,2,6,7,8,8α-hexahydrogen -8-Hydroxy-2,6-dimethyl-1-naphthyl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one-8-ester.

Chemical Structure:

Molecular formula: C25H38O5          Molecular weight: 418.57

【Properties】 This product is white or off-white.

【indications】

Hypercholesterolemia  

For patients with primary hypercholesterolemia, simvastatin can be given when diet control and other non-drug treatments are not ideal. Simvastatin not only lowers total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B and triglycerides, but also raises high-density lipoprotein cholesterol, thereby lowering low-density lipoprotein cholesterol/high-density lipoprotein cholesterol and total cholesterol / High density lipoprotein cholesterol ratio.

Simvastatin lowers cholesterol levels in patients with hypercholesterolemia and hypertriglyceridemia who are predominantly hypercholesterolemia.

Coronary heart disease

For patients with coronary heart disease complicated with hypercholesterolemia, simvastatin is suitable for:

- Reduce the risk of death.

- Reduce the risk of death from coronary heart disease and non-fatal myocardial infarction.

- Reduce the risk of myocardial recanalization (coronary artery bypass grafting and percutaneous balloon coronary angioplasty) due to coronary events.

- Delaying the progression of coronary atherosclerosis, including reducing the formation of new lesions and total occlusion.

【Specification】5mg.

【Dosage】

Patients should receive a standard cholesterol-lowering diet and continue to maintain during the course of treatment with simvastatin.

1, hypercholesterolemia: the general starting dose of 10mg per day, evening service. For patients with mild to moderate elevated cholesterol levels, the starting dose is 5 mg per day. If you need to adjust the dose, it should be more than four weeks, the maximum dose is 40mg per day, and the evening service.

Cholesterol levels should be monitored regularly, and if the cholesterol level is significantly below the target range, consideration should be given to reducing the dose of simvastatin.

2, coronary heart disease: patients with coronary heart disease can be 20mg / day as the starting dose. If you need to adjust the dose, it should be more than four weeks apart. The maximum dose is 40mg per day.

3. Combined medication: Simvastatin is effective when applied alone or in combination with a bile acid sequestrant. In general, avoid using it simultaneously with fibrates or niacin. In patients taking an immunosuppressive agent (such as cyclosporin), the initial dose of simvastatin is 5 mg/day and does not exceed 10 mg/day.

4, patients with renal insufficiency: Because simvastatin is mainly excreted by bile, the amount of excretion by the kidney is small, so patients with moderate renal insufficiency do not have to adjust the dose. Patients with severe renal insufficiency (creatinine clearance <30ml/min) should be used with caution. The initial dose of such patients should be 5mg/day. When the dose exceeds 10mg/day, it should be closely monitored.

【Adverse reactions】

Simvastatin is generally well tolerated and most of the adverse reactions are mild and transient. In the clinical control study, less than 2% of patients discontinued the drug due to the adverse reactions of simvastatin.

In clinical controlled studies, adverse reactions associated with drugs with an incidence of ≥1% were abdominal pain, constipation, and flatulence. The incidence of 0.5 to 0.9% of adverse reactions was fatigue and headache.

Reports of myopathy are rare.

The following adverse reactions have been reported in clinical observation and post-marketing applications: nausea, diarrhea, rash, indigestion, itching, hair loss, dizziness, muscle spasm, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting, and anemia . Rhabdomyolysis and hepatitis/jaundice rarely occur. Significant allergic reaction syndromes including one or more of the following symptoms are rarely reported: angioedema, lupus-like syndrome, rheumatic polymyalgia, vasculitis, thrombocytopenia, eosinophilia, ESR Elevation, arthritis, joint pain, urticaria, light sensitivity, fever, flushing, difficulty breathing, and discomfort.

Laboratory tests have found that significant and sustained elevations in serum transaminases are rarely reported. Alkaline phosphatase and gamma-glutamate transpeptidase have been reported to be elevated. Abnormal liver function tests are generally mild or transient. The rise of serum creatine kinase (CK) derived from skeletal muscle has been reported.

Post-marketing surveillance of statins has reports of hyperglycemia, impaired glucose tolerance, elevated glycated hemoglobin levels, new-onset diabetes, worsening glycemic control, and some statins have reports of hypoglycemia.

Post-marketing experience: There are rare cognitive impairment reports in the post-marketing surveillance of statins, which are characterized by memory loss, memory loss, confusion of thinking, etc., mostly non-severe, reversible reactions, which can be recovered after drug withdrawal. .

【taboo】

Those who are allergic to any of the ingredients of this product; active liver disease or unexplained serum transaminases continue to rise; pregnant and lactating women.

【Precautions】

1, muscle function:

HMG-CoA reductase inhibitors occasionally cause myopathy, manifested as muscle pain or weakness with a significant increase in CK (10 times higher than the upper limit of normal). Rhabdomyolysis of acute renal failure with or without secondary myoglobinuria is rarely reported. In the Nordic Simvastatin Survival Study, 1 case of myopathy occurred in 1399 patients taking simvastatin 20 mg daily, and 822 patients who received simvastatin 40 mg daily did not develop myopathy during the median 5.4 years. In two 6-month clinically controlled studies, 1 of 436 patients taking simvastatin 40 mg developed myopathy, and 699 patients with simvastatin 80 mg developed 5 myopathy. The combination of simvastatin and certain drugs increases the risk of myopathy, and some of these drugs were excluded from the study design.

Myopathy caused by drug interactions:

HMG-CoA reductase inhibitors, when combined with drugs that cause myopathy alone, increase the incidence and severity of myopathy, including gemfibrozil and other fibrates, as well as lipid-lowering doses ( Niacin (nickic acid) ≥ 1 g/day.

In addition, an increase in the activity of HMG-CoA reductase inhibitors in plasma also increases the risk of myopathy. Simvastatin and other HMG-CoA reductase inhibitors are metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4). Some drugs that have a significant inhibitory effect on this metabolic pathway at therapeutic doses can increase the blood levels of HMG-CoA reductase inhibitors and thus increase the risk of myopathy. These include cyclosporin, antifungal ipraconazole and ketoconazole, macrolide antibiotic erythromycin and clarithromycin, HIV protease inhibitors, and the antidepressant nefazodone.

Reduce the risk of myopathy:

(1) General measures: Patients should be informed of the risk of myopathy at the beginning of simvastatin treatment and promptly report muscle pain, tenderness or weakness due to unexplained causes. A patient's CK level is 10 times higher than the upper limit of normal and accompanied by an unexplained muscle symptom indicating a myopathy. If diagnosed or suspected of myopathy, simvastatin should be discontinued. For most cases, muscle symptoms and CK increase will recover after timely termination of treatment.

Many patients with rhabdomyolysis have a history of comorbidities. Some patients have a history of renal insufficiency, which is often secondary to long-term diabetes. For such patients, caution should be exercised when increasing the dose. At the same time, simvastatin should be discontinued in the first few days before a larger surgery and in the case of a more serious acute medical or surgical disease, due to the inability to ascertain the poor secondary symptoms of short-term interruption of treatment.

(2) Measures to reduce the risk of myopathy caused by drug interactions (see above): The pros and cons should be weighed when planning to use simvastatin in combination with any other interacting drug, and the patient's muscle pain should be carefully monitored. Signs or symptoms of tenderness or weakness, especially during the first few months of treatment and during dose escalation. In this case, consider checking CK regularly, but this does not ensure that myopathy can be prevented.

Simvastatin should be avoided in combination with fibrates or niacin unless the benefits of altered lipid levels are likely to exceed the increased risk of this combination. In small, short-term, and carefully monitored clinical studies, small doses of simvastatin in combination with fibrates or niacin did not cause myopathy. HMG-CoA reductase inhibitors in combination with these drugs generally do not lower HDL cholesterol, but can further reduce triglycerides and increase HDL cholesterol. Clinical practice has shown that the risk of myopathy occurring with simvastatin in combination with niacin is lower than in patients with fibrates.

Due to the increased risk of myopathy occurring at larger doses, the dose of simvastatin is generally not more than 10 mg/day for patients taking cyclosporin, fibrate or niacin (see usage, synergy). treatment). Combinations of simvastatin with itraconazole, ketoconazole, erythromycin and clarithromycin, HIV protease inhibitors or nefazodone are not recommended. Since there is no report of adverse effects on long-term lipid-lowering effects due to short-term withdrawal, it may be temporarily discontinued when it is necessary to use itraconazole, ketoconazole, erythromycin or clarithromycin for short-term treatment. Simvastatin. Simvastatin should be avoided in combination with other drugs that are indicative of a potential CYP3A4 inhibitor, unless the benefits of the combination therapy outweigh the increased risk.

2, liver function:

In clinical studies, a small number of adult patients receiving simvastatin showed a sustained increase in serum transaminase (three times higher than the upper limit of normal). After discontinuation or discontinuation of these patients, transaminase levels are usually slowly reduced to pre-treatment levels. This elevation of transaminase is not associated with jaundice or its clinical signs or symptoms, and no allergic manifestations. Some of these patients had abnormal liver function tests before simvastatin treatment and/or had consumed a large amount of alcohol.

It is recommended that all patients undergo a liver function test at regular intervals (eg, once every six months) before the start of treatment and during the first year after the start and after the dose is increased. For patients with elevated serum transaminases, liver function should be reviewed in a timely manner and the frequency of examination should be increased. If the transaminase level shows an upward trend, especially if it rises to 3 times the upper limit of the normal value and continues to decline, the drug should be discontinued.

This medicine should be used with caution in patients who drink large amounts of alcohol and/or have a history of previous liver disease. Simvastatin is contraindicated in patients with active liver disease or elevated levels of transaminase.

As with other lipid-lowering drugs, there was a report of elevated serum transaminase (three times lower than the upper limit) after simvastatin treatment. These changes occur shortly after the start of simvastatin treatment, but are often transient, without any symptoms and without interrupting treatment.

3. Ophthalmic examination:

Even in the absence of any medication, the incidence of lens opacity increases with age. Long-term clinical studies have shown that simvastatin has no adverse effects on the human lens.

4, homozygous familial hypercholesterolemia:

Because of the lack of low-density lipoprotein receptors in patients with homozygous familial hypercholesterolemia, simvastatin is not effective in these patients.

5, hypertriglyceridemia:

Simvastatin only moderately lowers the effect of triglycerides, so it is not suitable for the treatment of dyslipidemia (such as type I, IV and V hyperlipidemia) with elevated triglycerides.

【Pregnant women and lactating women】

Because atherosclerosis is a chronic process, the use of lipid-lowering drugs during pregnancy has little effect on the long-term treatment of primary hypercholesterolemia. Moreover, cholesterol and other products of its biosynthetic pathway are essential components of fetal development, including the synthesis of cholesterol-like and cell membranes. Because HMG-CoA reductase inhibitors such as simvastatin reduce the synthesis of cholesterol and other products of its biosynthetic pathway, pregnant women ban simvastatin. Among women of childbearing age, simvastatin can only be used in women who are less likely to become pregnant. If a woman is pregnant while taking the drug, she should immediately discontinue simvastatin and be informed of possible damage to the fetus.

It is not known whether simvastatin and its metabolites are secreted by human milk. Because many drugs are secreted by human milk and may cause serious adverse reactions, women who take simvastatin should not breastfeed (please refer to [taboo]).

【Children's medication】The safety and efficacy of children's medication have not been determined. Simvastatin is currently not recommended for children.

【Geriatric Use】

In a clinically controlled study of simvastatin in elderly patients (>65 years), the effects of lowering total cholesterol and low-density lipoprotein cholesterol were similar to those in other populations, and the incidence of adverse reactions and laboratory abnormalities was not significant. increase.

【medicine interactions】

1, gemfibrozil and other fibrates, niacin (niacin) at a lipid-lowering dose (≥1g/day): the increased risk of myopathy in combination with simvastatin may be due to these When the drug is used alone, it can cause myopathy (see [Precautions] Muscle Effect). There is no evidence that these drugs have an effect on the pharmacokinetics of simvastatin.

2. Interaction with CYP3A4: Simvastatin has no CYP3A4 inhibitory activity, therefore, it is speculated that it does not affect the plasma levels of other drugs metabolized by CYP3A4. However, simvastatin itself is a substrate for CYP3A4. During the simvastatin treatment period, a strong inhibitor of CYP3A4 may increase the risk of myopathy by increasing the level of plasma HMG-CoA reductase inhibitor activity. These strong inhibitors include cyclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone (see [Precautions] Muscles) .

Grapefruit juice contains one or more ingredients that inhibit CYP3A4 and increases plasma levels of drugs metabolized by CYP3A4. The conventional consumption (250 ml per day) produced little effect (by measuring the area under the concentration-time curve, plasma HMG-CoA reductase inhibitory activity increased by 13%) and was of no clinical significance. However, if consumed in large amounts during the simvastatin treatment period (more than 1 liter per day), the level of plasma HMG-CoA reductase inhibitory activity is significantly increased and should be avoided (see [Precautions] Muscles).

3. Coumarin Derivative: In a clinical study involving a healthy volunteer and another patient with hypercholesterolemia, taking simvastatin 20-40 mg/day can moderately increase the coumarin anticoagulant. Anticoagulant effect. Based on the international normalized ratio (INR) of prothrombin time, the healthy volunteer group was extended from 1.7 to 1.8 seconds in the baseline, and the hypercholesterolemic patient group was extended from 2.6 to 3.4 seconds. For patients taking coumarin anticoagulants, prothrombin time should be measured prior to the use of simvastatin and often measured early in the treatment to ensure no significant change in prothrombin time. Once stable prothrombin time is recorded, patients should be advised to regularly monitor prothrombin time during coumarin anticoagulants. The above steps should be repeated if the simvastatin dose is adjusted or discontinued. For patients who did not take coumarin anticoagulants, bleeding or prothrombin time changes were not associated with simvastatin.

4. Other drug interactions:

Cyclosporin or danazol: Simultaneous use with cyclosporin or danazol increases the risk of myopathy/rhabdomyolysis, especially when combined with high-dose simvastatin.

Amiodarone or verapamil: Amiodarone or verapamil combined with high doses of simvastatin increases the risk of myopathy/rhabdomyolysis.

Diltiazem: Patients taking both diltiazem and simvastatin 80 mg have a slightly increased risk of myopathy.

Fusidic acid: Patients taking both phorididin and simvastatin may have an increased risk of myopathy.

【Drug overdose】

There were a few reports of overdose, the patient had no special symptoms, and all patients recovered without sequelae. The maximum dose is 450 mg. Routine measures are generally taken to handle overdose.

【Pharmacology and Toxicology】

Pharmacological action

Simvastatin reduces normal and elevated levels of low-density lipoprotein cholesterol (LDL-C). Low-density lipoprotein (LDL) is produced by very low-density lipoprotein (VLDL) and is primarily catabolized by high-affinity LDL receptors. Simvastatin reduces LDL by reducing VLDL cholesterol concentration and inducing LDL receptor production, resulting in reduced LDL-C production and/or increased catabolism. Apolipoprotein B (ApoB) also decreased significantly during simvastatin treatment. Because each LDL microparticle contains one molecule of ApoB, few ApoBs are found in lipoproteins in patients with elevated LDL-C (not accompanied by elevated VLDL), suggesting that simvastatin can not only remove cholesterol from LDL, Moreover, the concentration of circulating LDL particles can be reduced. In addition, simvastatin reduces VLDL and triglycerides (TG) and raises HDL-C. The effects of simvastatin on lipoprotein (a), fibrinogen, and other biochemical markers of coronary heart disease are unclear.

Toxicological research

Genotoxicity

Microbial mutation assay (Ames), in vitro rat liver cell alkali elution analysis, mammalian V-79 cell forward mutagenesis study, in vitro CHO cell chromosomal mutation study or in vivo mouse bone marrow cell chromosome mutation analysis experiment, no discovery Mutation.

Reproductive toxicity

The daily dose of simvastatin rats was 25 mg/kg or 10 mg/kg for rabbits, and no teratogenicity was observed. Both doses were three times the human exposed body surface area (mg/m2). However, in another study of structurally related HMG-CoA reductase inhibitors, skeletal malformations in rats and mice were found. Simvastatin 25 mg/kg (4 times the maximum exposure level of humans at a patient dose of 80 mg/day) was administered for 34 weeks, and fertility decreased in male rats. However, in the subsequent fertility experiment in which a male rat took 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 testis were observed under either of the two experimental microscopes. Vas degeneration (necrosis and damage of the seminiferous epithelium) was observed at 180 mg/kg/day (this dose is 22 times higher than the maximum exposure level of the human dose of 80 mg/kg/day). Dogs taking 10 mg/kg/day (about 2 times the human exposure dose of 80 mg/day in AUC) showed drug-related testicular atrophy, decreased sperm production, spermatocyte degeneration and giant cell formation. The clinical significance of the above findings is not clear.

Carcinogenicity The mice were given citastatin 25, 100 and 400 mg/kg/day for 72 weeks. The carcinogenicity test showed that the mean blood concentration was higher than about 1, 4 and 8 of the average oral blood concentration of 80 mg. Times (with AUC as total inhibitory activity). In the high-dose female group and the medium- and high-dose male group, the incidence of liver cancer was significantly increased, and the highest incidence rate in the male group was 90%. The incidence of hepatic adenomas in the middle and high dose males was significantly increased. The incidence of lung adenomas in the female and male neutralizing high dose groups was also significantly increased. In the high-dose female group, the adenoma of the accessory lacrimal gland (the gland of the rodent eye) was significantly increased compared with the control group. There was no effect on carcinogenicity in the 25 mg/kg/day group. In the 92-week study in which mice were administered at a dose of 25 mg/kg/day, no carcinogenic effects were observed (average plasma drug concentrations were calculated by AUC, which was more than double the human oral 80 mg simvastatin plasma concentration). Rats were given simvastatin 25 mg/kg/day for two consecutive years. The incidence of thyroid follicular adenoma in female rats was statistically significantly increased. The exposure level was higher than that of human simvastatin 80 mg by AUC. 11 times. Rats were tested for carcinogenicity at doses of 50 and 100 mg/kg/day for two consecutive years, and hepatocellular adenomas and carcinomas were found (two dose groups for females and 100 mg/kg/day for males). In both male and female dose groups, thyroid follicular cell adenoma increased, and female thyroid follicular cell carcinoma increased in the 100 mg/kg/day group. Other HMG-CoA reductase inhibitors have found an increased incidence of thyroid tumors. Its plasma drug concentration (AUC) is equivalent to 7 and 15 times (male) and 22 and 25 times (female) of the average daily plasma drug exposure level of human daily dose of 80 mg.

【Pharmacokinetics】

After oral administration of 14C-labeled simvastatin in male adults, plasma total radioactivity (simvastatin and 14C-metabolite) peaked for a period of 4 hours, then rapidly decreased, and dropped to 10% of peak value 12 hours after administration. The simvastatin oral administration test was conducted in both animals, and the absolute bioavailability of oral administration was about 85%. Simvastatin is highly selective for liver after oral administration, and its concentration in the liver is significantly higher than in other non-target tissues. The liver is the main site of simvastatin, and most simvastatin is first passed in the liver. Ingestion, simvastatin entering the systemic circulation is less than 5% of the dose administered, and 95% of them bind to plasma proteins. This product is mainly excreted by bile.

【Storage】shading, sealed, and stored in a cool place (not more than 20 ° C).

【Packing】aluminum-plastic packaging, 24 pieces / box, 28 pieces / box, 36 pieces / box.

【Validity period】30 months.

【Executive Standards】 "Chinese Pharmacopoeia" 2015 Edition 2

【Approval No.】National Drug Standard H20030705.

【manufacturer】

Company Name: Lunan Beite Pharmaceutical Co., Ltd.

Production address: No. 243, Yinqueshan Road, Linyi City, Shandong Province

Postal code: 276006

Phone number: 0539-8336336 (Sales)        8336337 (Quality Management Department)

Fax number: 0539-8336029 (Sales)             8336338 (Quality Management Department)

Website: www.LUNAN.com.cn

24-hour customer service hotline: 400-0539-310