NANXIN SIMCOR Simvastatin Dispersible Tablets For High Cholesterol 20mg*10

[Drug Name]
Generic Name: Simvastatin Dispersible Tablets
Trade Name: Simvastatin Dispersible Tablets 20mg x 10 Tablets

[Main Ingredient]
The main ingredient of this product is simvastatin.

[Appearance]
This product is white or off-white tablets.

[Indications/Main Functions]
1. Simvastatin can be used to lower total cholesterol and LDL-C in patients with primary hypercholesterolemia when dietary therapy and other non-drug treatments are inadequate. Simvastatin also increases HDL-C, thereby lowering the LDL-C/HDL-C and total-C/HDL-C ratios. It can also be used to lower elevated cholesterol levels in patients with both hypercholesterolemia and hypertriglyceridemia, where hypercholesterolemia is the primary abnormality. 2. For secondary prevention of coronary heart disease. For patients with coronary artery disease, simvastatin is indicated for: 2.1 Reducing the risk of death; 2.2 Reducing the risk of coronary artery disease death and non-fatal myocardial infarction; 2.3 Reducing the need for myocardial revascularization procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty); and 2.4 Delaying the progression of atherosclerosis, including the development of new lesions and complete blockage.

[Specifications]
20mg*10 tablets

[Dosage and Administration]
Patients should follow a standard cholesterol diet before starting simvastatin treatment and continue this diet during treatment. 1. Hypercholesterolemia: The general initial dose is 10 mg daily, taken in the evening. For patients with mild to moderately elevated cholesterol levels, the initial dose is 5 mg daily. Any dose adjustment should be done at least four weeks apart, with a maximum dose of 40 mg daily, taken in the evening. When the LDL cholesterol level drops to 75 mg/dL (1.94 mmol/L) or the total cholesterol level drops below 140 mg/dL (3.6 mmol/L), the simvastatin dose should be reduced. 2. Coronary Artery Disease: Patients with coronary artery disease can take 10 mg daily as a starting dose. If dose adjustment is necessary, refer to the instructions above (Usage and Dosage for Hypercholesterolemia). 3. Concomitant Therapy: Simvastatin is effective when used alone or in combination with a bile acid sequestrant. For patients taking concomitant immunosuppressants, the recommended dose of simvastatin is 10 mg daily. 4. Patients with Renal Impairment: Because simvastatin is not significantly excreted by the kidneys, no dose adjustment is necessary for patients with moderate renal impairment. However, for patients with severe renal impairment (creatinine clearance <30 ml/min), using a dose exceeding 10 mg daily should be considered with caution. Adverse Reactions: Simvastatin is generally well tolerated, with most adverse reactions being mild and transient. In controlled clinical trials, fewer than 2% of patients discontinued simvastatin due to adverse reactions. In controlled clinical trials, adverse reactions (classified as possibly, suspected, or definitely related) reported at a rate greater than or equal to 1% included abdominal pain, constipation, and flatulence. Adverse reactions reported at a rate of 0.5% to 0.9% included fatigue, asthenia, and headache. Reports of myopathy were rare. The following adverse reactions have been reported in uncontrolled clinical trials or postmarketing use: nausea, diarrhea, rash, dyspepsia, pruritus, alopecia, dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting, and anemia. Rhabdomyolysis and hepatitis/jaundice have rarely occurred. Rare reports of overt hypersensitivity syndromes including one or more of the following features have occurred, including angioedema, lupus-like syndrome, polymyalgia rheumatica, vasculitis, thrombocytopenia, eosinophilia, elevated erythrocyte sedimentation rate (ESR), arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnea, and malaise. Laboratory findings: Significant and persistent elevations in serum aminotransferases have been reported rarely. Liver function test abnormalities are mild or transient. Elevated serum creatine phosphokinase (CK) derived from skeletal muscle has also been reported.

[Contraindications]
1. Hypersensitivity to any component. 2. Active hepatitis or unexplained persistent elevations in serum aminotransferases. 3. Concomitant use with the tetralin calcium channel blocker mibefradil. [Drug Interactions] (1) When simvastatin is used in combination with other drugs that have a significant inhibitory effect on cytochrome P450 3A4 at therapeutic doses (such as cyclosporine, mibefradil, itraconazole, ketoconazole, erythromycin, clarithromycin, and nefazodone) or fibrates or hydrochloric acid, the risk of rhabdomyolysis is increased. (2) The incidence and severity of myopathy may be increased by co-administration of this product with hydroxymethylglutaryl coenzyme A (HMG-COA) reductase inhibitors, including gemfibrozil and other fibrates, and lipid-lowering doses of niacin (greater than or equal to 1g/d). In addition, increased plasma levels of hydroxymethylglutaryl coenzyme A (HMG-COA) reductase inhibitors may also increase the risk of disease. Simvastatin and other hydroxymethylglutaryl coenzyme A (HMG-COA) reductase inhibitors are metabolized by the cytochrome P450 isoenzyme 3A4. Several drugs that significantly inhibit this metabolic pathway at therapeutic doses can increase plasma levels of hydroxymethylglutaryl coenzyme A (HMG-COA) reductase inhibitors and thus increase the risk of myopathy. These drugs include cyclosporine, tetralins, the calcium channel blocker mibefradil, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, and the antidepressant nefazodone. (3) Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase plasma levels of drugs metabolized by CYP3A4. The effect of regular consumption (one 250ml glass per day) is small (a 13% increase in plasma HMG-CCA reductase inhibitor activity as measured by the area under the concentration-time curve) and is of no clinical significance. However, large amounts of drinking (more than 1 liter per day) significantly increase plasma HMG-CCA reductase inhibitor activity during simvastatin treatment and should be avoided. (4) Coumarin derivatives: In two clinical studies, simvastatin was found to moderately enhance the anticoagulant effect of coumarin. Prothrombin time should be checked frequently before early anticoagulant therapy and before simvastatin use in adults to confirm that the prothrombin time has not changed significantly. Continued prothrombin time monitoring for a fixed period is recommended after a patient taking coumarin derivatives has achieved a stable prothrombin time. The same procedure should be followed if the simvastatin dose is changed. In patients not taking anticoagulants, simvastatin treatment has not been reported to affect bleeding or prothrombin time.

[Precautions]
1. Patients should follow a standard cholesterol-lowering diet before starting simvastatin therapy and continue using it during treatment. 2. Hepatic reactions. This drug should be used with caution in patients who consume large amounts of alcohol and/or have a history of liver disease. Simvastatin should be contraindicated in patients with active liver disease or unexplained elevations in aminotransferases. In clinical trials, a small number of patients taking simvastatin experienced significant, persistent elevations in serum aminotransferases (more than three times the normal value). 3. Muscle Reactions. Simvastatin-treated patients commonly experience mild, transient elevations in creatine kinase (CK, derived from skeletal muscle), but these elevations are clinically insignificant. Myopathy should be considered in cases of diffuse myalgia, muscle weakness, and/or significant elevations in creatine kinase (CK) (more than ten times the normal value). Therefore, patients should be advised to immediately inform their physician if they experience any unexplained signs of myopathy. Simvastatin treatment should be discontinued immediately if a significant elevation in CK is detected or myalgia is diagnosed or suspected. Methylmetholone should be discontinued in patients with acute or severe conditions suggestive of myopathy and those at risk for secondary acute renal failure due to rhabdomyolysis. Treatment with hydroxyglutaryl coenzyme A (HMG-COA) reductase inhibitors. 4. Ophthalmological examination. Even without any medication, the incidence of lens opacities increases with age. Long-term clinical study data show that simvastatin has no adverse effects on the human lens. 5. Homozygous familial hypercholesterolemia. Because patients with homozygous familial hypercholesterolemia completely lack low-density lipoprotein (LDL) receptors, simvastatin is less effective in treating this condition. 6. Hypertriglyceridemia. Simvastatin has only a moderate effect on lowering triglycerides and is not suitable for treating conditions characterized by elevated triglycerides (such as Types I, IV, and V hyperlipidemia). 7. This product should be used with caution in patients with excessive alcohol consumption and/or a history of liver disease.

[Pediatric Use]
The safety and efficacy of simvastatin for pediatric use have not been established. Simvastatin is not currently recommended for use in children.

[Elderly Use]
In controlled clinical trials of simvastatin in elderly patients (over 65 years of age), its efficacy in lowering total cholesterol and low-density lipoprotein (LDL) cholesterol was comparable to that observed in other populations, without a significant increase in the frequency of adverse reactions or laboratory abnormalities.

[Overdose]
The data are unknown.

[Pharmacology and Toxicology]
Pharmacological Action: This drug is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-COA) reductase, inhibiting endogenous cholesterol synthesis and acting as a lipid-lowering agent. Simvastatin can lower both normal and elevated low-density lipoprotein cholesterol (LDL-C) levels. Low-density lipoproteins (LDLs) are produced from very low-density lipoproteins (VLDL) and metabolized primarily through binding to LDL receptors. The mechanism of simvastatin's LDL-lowering effect lies in reducing VLDL cholesterol concentrations and LDL receptor induction, leading to reduced LDL-C production and/or increased catabolism. Apolipoprotein B (ApoB) also decreases during simvastatin treatment. Because each LDL particle contains one molecule of ApoB, and because only very low levels of ApoB are found in patients with elevated LDL-C (without concomitant VLDL elevation), this suggests that simvastatin not only lowers cholesterol by lowering LDL but also reduces peripheral LDL particle concentrations. Furthermore, simvastatin lowers VLDL and triglycerides (TG) while increasing HDL-C. Simvastatin also has a negative effect on lipoprotein (a), fibroblasts, and lipoprotein (fibroblast). The effects on proprotein and other biochemical markers of coronary artery disease are unknown. Toxicological studies: Genotoxicity: No mutagenic effects were observed in microbial mutagenicity tests (Ames), in vitro rat hepatocyte alkaline elution assays, mammalian V-79 cell forward mutagenicity studies, in vitro CHO cell chromosomal mutation studies, or in vivo mouse bone marrow cell chromosomal mutation assays. Reproductive toxicity: Simvastatin was not teratogenic in rats at daily doses of 25 mg/kg or 10 mg/kg. Both doses reached three times the human body surface area exposure (mg/m²). In studies with another structurally related HMG-CoA reductase inhibitor, skeletal deformities were observed in rats and mice. Simvastatin was administered at a dose of 25 mg/kg (four times the maximum human exposure level based on AUC in patients) for 34 weeks. In a fertility study in which males were treated with simvastatin for 11 weeks (the complete cycle of sperm development, including epididymal maturation), no effects on fertility were observed. No microscopic changes were observed in the rat testes in either study. At 180 mg/kg/day (a dose 22 times higher than the maximum human exposure level of 80 mg/kg/day, based on body surface area), degeneration of the vas deferens (necrosis and damage of the seminiferous epithelium) was observed. In dogs, doses of 10 mg/kg/day (approximately twice the human exposure level of 80 mg/day, based on AUC) resulted in drug-related testicular atrophy, decreased spermatogenesis, spermatocyte degeneration, and giant cell formation. The clinical significance of these findings is unknown. Carcinogenicity: Mice were given simvastatin at 25, 100, and 400 mg/kg/day for 72 weeks. Carcinogenicity studies showed that mean plasma concentrations were approximately 1, 4, and 8 times higher than the mean human plasma concentration of an 80 mg oral dose (measured as total inhibitory activity using AUC). The incidence of liver cancer was significantly increased in the high-dose female group and the medium- and high-dose male groups, with the highest incidence in the male group reaching 90%. The incidence of hepatic adenomas was significantly increased in the medium- and high-dose groups. The incidence of lung adenomas was also significantly increased in both female and male groups. Adenomas in the accessory lacrimal gland (a gland in the rodent eye) were significantly increased in the high-dose male group compared to the control group. No effect on carcinogenicity was observed in the 25 mg/kg/day dose group.A 92-week study in mice at doses of up to 25 mg/kg/day showed no carcinogenic effects (measured by AUC, the mean plasma concentration was more than double the human plasma concentration of an 80 mg oral dose of simvastatin). Simvastatin was administered to rats. Continuous administration of simvastatin at 25 mg/kg/day resulted in a statistically significant increase in the incidence of thyroid follicular adenomas in female rats, an exposure level 11-fold higher than that observed in humans taking 80 mg of simvastatin, as measured by area under the curve (AUC). A two-year carcinogenicity study in rats at doses of 50 and 100 mg/kg/day observed hepatocellular adenomas and carcinomas (at both doses in females and at 100 mg/kg/day in males). Increased thyroid follicular cell adenomas were observed in both male and female doses, and increased thyroid follicular cell carcinomas were observed in females receiving 100 mg/day. Other HMG-CoA reductase inhibitors have also been associated with an increased incidence of thyroid tumors. The plasma concentrations (AUC) were equivalent to 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma exposure at a daily dose of 80 mg.