| Generic Name |
Simvastatin Tablets |
| Strength |
20mg |
| Packing |
2*14 tablets/box |
| Origin |
China |
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Product name:
Simvastatin Tablets 20mg
Character:
This product is a pink oval film coating, one side is engraved with "MSD749"; White or near-white after removing the film.
Indications:
Hyperlipidemia In patients with primary hypercholesterolemia including heterozygous familial hypercholesterolemia, hyperlipidemia, or mixed hyperlipidemia, when dietary control and other non-pharmacological treatments are not ideal, in combination with dietary control, this product can be used to reduce elevated total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. It can also raise HDL cholesterol, thereby reducing the ratio of LDL cholesterol to HDL cholesterol and total cholesterol to HDL cholesterol. In patients with homozygous familial hypercholesterolemia, combined with dietary control and non-dietary therapy, this product can be used to reduce elevated total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B.
Coronary heart disease For patients with coronary heart disease combined with hypercholesterolemia, this product is suitable for: Decrease the risk of death from coronary heart disease and non-fatal myocardial infarction Decrease the risk of stroke and transient cerebral ischemia Decrease the risk of cardiac revascularization surgery (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty) Delay the progression of coronary atherosclerosis including reduced formation of new lesions and total blockages
Pediatric patients with heterozygous familial hypercholesterolemia In adolescent boys and girls aged 10-17 years (at least 1 year after menarche) with heterozygous familial hypercholesterolemia, in combination with dietary control, this product can be used to lower total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides.
Pharmacology and toxicology:
Simvastatin reduces both normal and elevated levels of low-density lipoprotein cholesterol (LDL-C). LDL is formed from very low-density lipoproteins (VLDL) and is catabolized primarily by high-affinity LDL receptors. The mechanism of simvastatin reducing LDL-C mainly includes: lowering the concentration of VLDL cholesterol, inducing LDL receptors, leading to the reduction of LDL cholesterol and increasing the catabolism of LDL-C. Levels of apolipoprotein B (apo B) also decreased significantly during simvastatin treatment. Since each LDL particle contains one molecule of apo B, and apo B is rarely found in other lipoproteins, this suggests that simvastatin not only causes cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, simvastatin can increase the concentration of high-density lipoprotein sterol (HDL-C) and decrease plasma triglycerides (TG). These can lead to the reduction of total cholesterol /HDL-C and LDL-C/HDL-C.
Animal studies, pathology, and clinical studies have all demonstrated the role of LDL-C in atherosclerosis. Epidemiological studies have shown that high levels of total cholesterol, LDL-C, and apo B are risk factors for coronary heart disease while higher levels of HDL-C and apo A-I reduce the risk.
The oral LD50 of simvastatin is about 3.8g/kg in mice and about 5g/kg in rats.
The administration of large doses of simvastatin and related analogues to a variety of animals showed some tissue changes. Given the large doses used, the efficacy of these drugs in inhibiting mevalonate synthesis, and the fundamental role of the target enzyme in maintaining intracellular environmental homeostasis, these changes are not unexpected. The large amount of data obtained from these changes shows that they are the overperformance of the biochemical effects of these drugs at the high end of the dose-response curve. Thus, morphological changes in rat liver, squamous hyperplasia in rat and mouse cardiac sinus, and liver toxicity in rabbits have all been shown to be directly related to inhibition of HMG-CoA reductase.
Studies with dogs have found that high doses of simvastatin can cause cataracts, although the incidence is very low. Although there is no clear association between the extent of the decrease in serum lipid levels and the development of cataracts, a consistent relationship has been observed between simvastatin and related HMG-CoA reductase inhibitors that trigger cataracts and high serum levels of the drug.
The minimum cataract-inducing dose of simvastatin given to dogs was 50mg/kg per day, and the serum concentration of the drug (expressed as the total inhibitor) was five times higher than that expected for humans at the maximum therapeutic dose of 1.6mg/kg (calculated as 80mg per day for 50kg men).
Elevated serum transaminase levels were observed in dogs receiving simvastatin. About 10-40% of dogs that received the drug experienced either slow, low levels of elevated serum aminotransferase or excessive, rapid elevations. No signs of disease were found in the dogs with elevated transaminase levels; Despite continued administration, elevated transaminase levels did not cause significant liver necrosis. In all dogs treated with simvastatin, no histopathological changes were observed in the liver.
Testicular degeneration was found in two simvastatin safety studies in dogs. Because these effects are poorly reproducible and independent of dose, serum cholesterol levels, or duration of treatment, special studies designed to elucidate these changes have not been successful. Studies of dogs given simvastatin at 50mg/kg a day for up to 2 years did not find any effect on the testicles.
In a study administered to rats with simvastatin 90mg/kg twice daily, necrosis of skeletal muscle was observed, but in rats this dose was a lethal dose.
Reproductive and developmental toxicity
At maximum tolerated doses in rats and rabbits, simvastatin did not cause fetal malformation and had no effect on fertility, reproductive function, or neonatal development. However, 60mg/kg daily administration of simvastatin active hydroxylation metabolites in rats resulted in maternal weight loss, increased fetal absorption, and increased skeletal muscle malformations. Continued studies using this metabolite have shown that fetal absorption and skeletal muscle malformations are secondary to maternal toxicity (anterior stomach damage associated with maternal weight loss) occurring only in rodents, and are rarely the result of direct effects on the developing fetus. Although simvastatin has not been tested, other similar HTG-COA reductase inhibitors of 80mg/kg and 400mg/kg daily (10 and 52 times the maximum therapeutic recommended dose based on body surface area mg/m2, respectively) have been shown to reduce fetal plasma mevalonate levels in pregnant rats.
Genotoxicity and carcinogenicity
A wide range of in vitro and in vivo genotoxicity tests have been conducted against simvastatin and L-654,969. These tests include mutagenesis of microorganisms, mutagenesis of mammalian cells, analysis of single-strand DNA breaks, and tests for chromosomal aberrations. These findings do not provide evidence of an interaction between simvastatin or L-654,969 and genetic material, and these studies were conducted at the highest soluble non-cytotoxic concentrations tested in an in vitro analysis system, or at the highest tolerated doses in vivo.
Initially, studies of the carcinogenicity of simvastatin in rats and mice used dosages ranging from 1mg/kg daily to 25mg/kg daily. There was no evidence of drug-related tumor types in any of the tissues of the mice. There was a statistically significant (p < 0.05) increase in the incidence of thyroid follicular cell adenoma in female rats receiving 25mg/kg of simvastatin daily (equivalent to 16 times the maximum recommended dose for humans). This benign tumor was limited to female rats; Similar changes were not seen in male rats or in female rats receiving lower doses (up to 5mg/kg daily). These tumors reflect the secondary effect of simvastatin mediating increased thyroid hormone clearance in female rats. No statistically significant increase in the incidence of other tumors was found in all tissues of the rats receiving simvastatin.
Data from both studies indicated that squamous epithelial proliferation of the cardiac sinuses occurred at all dose levels. These changes in the stomach are limited to a certain anatomical structure that has not been found in humans. But there was no effect on the same cells elsewhere (the esophagus and anorectal junction in rats, mice and dogs).
Another 73-week carcinogenics study in mice receiving simvastatin up to 400mg/kg daily (equivalent to 250 times the maximum recommended dose for humans at 50kg body weight) showed an increased incidence of hepatocellular adenomas and hepatocellular carcinomas, lung adenomas, and adenomas of the paracrimal gland. Results from this study, as well as from another initial 92-week carcinogenicity study in mice, established a non-active dose of 25mg/kg per day (equivalent to 16 times the maximum recommended dose for humans).
A 106-week carcinogenicity study in rats receiving simvastatin doses ranging from 50mg/kg daily to 100mg/kg daily (31 to 63 times the maximum recommended dose for humans) showed an increase in the incidence of hepatocellular tumors associated with the use of the drug. The non-active dose of 25mg/kg per day (equivalent to 16 times the maximum recommended dose for humans) is consistent with the results of previous studies on carcinogenicity. At the same time, the incidence of thyroid hyperplasia increased. However, this result is consistent with previous findings that this is a generation-specific response and that it has no effect on people.
Storage:
Sealed and stored below 30ºC.
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