Simvastatin Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
[Drug Name
Generic Name: Simvastatin Tablets
Trade Name: Kybixin
English Name:Simvastatin Tablets
Hanyu Pinyin:Xinfatating Pian
[Ingredients
The active ingredient of this product is simvastatin.
Chemical name:2,2-dimethylbutyric acid(4R,6R)-6-[2-[(1S,2S, 6R,8S,8aR)-1,2,6,7,8,8a-hexahydrogen-8- =”font-family:Arial”>hydroxy-2,6-dimethyl-1-Naphthyl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-ketone-8-ester ester.
Chemical structure formula:
Molecular Formula:C25H38O5 Molecular weight:418.57
[Properties
This product is a pink oval film-coated tablet, which appears white or off-white after removing the coating. .
[Indications]
Hyperlipidemia
In patients with primary hypercholesterolemia including heterozygous familial hypercholesterolemia, hyperlipidemia, or mixed hyperlipidemia, when dietary control and other non-pharmacologic treatments are suboptimal, in combination with dietary control, this product can be used to reduce elevated total cholesterol, LDL cholesterol, ApoB and triglycerides, and can elevate HDL cholesterol, thereby lowering LDL cholesterol/HDL cholesterol and total cholesterol/Ratio of HDL cholesterol.
In patients with pure-onset familial hypercholesterolemia, in combination with dietary control and non-dietary therapies, this product may be used to reduce elevated total cholesterol, LDL cholesterol, and apolipoproteinB.
Coronary heart disease
For patients with coronary artery disease combined with hypercholesterolemia, this product is indicated:
reduce the risk of death;
Reduced risk of coronary heart disease death and non-fatal myocardial infarction;
Reduces the risk of stroke and transient ischemia;
Reduces the risk of cardiac revascularization procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty);
slowing the progression of coronary atherosclerosis, including reducing the formation of new lesions and total blockages.
Childhood patients with heterozygous familial hypercholesterolemia
For children with heterozygous familial hypercholesterolemia10 span>to17year-old adolescent boys and girls (at least after menarche1year), in combination with dietary control, this product can be used to lower total cholesterol, LDL cholesterol, triglycerides and apolipoproteinB.
[Specifications]
20mg
[dosage]
Patients should receive a standard cholesterol-lowering diet prior to treatment with this product and continue to maintain it during the course of treatment.
Recommended dose range is 5 per dayto40 mg in the evening, with the dose used being based on basal LDL cholesterol The dose used should be individualized based on basal LDL cholesterol levels, recommended therapeutic goals, and patient response. Dose adjustments should be made at intervals of4weeks or more.
The recommended starting dose is10 mg per dayor20mg in a single evening dose. For patients at high risk forCHDevents due to the presence of a history of coronary heart disease, diabetes mellitus, peripheral vascular disease, stroke, or other cerebrovascular disease The recommended starting dose is 20to40 mg/day. For patients who require only moderate LDL cholesterol reduction, the starting dose is 10 mg.
—-Limits80mg/day dose use
Due to the increased risk of causing myopathy, including rhabdomyolysis (especially within the first year of use), this product80 mg dose is limited to those who have been using it for a long time (≥ 1year) and tolerated that dose and did not develop myopathy. For patients who have used and tolerated 80 mg although they have used and tolerated80 mg, if a combination of drugs with interactions is required and the drug is a combined contraindicated for dosing or the combination is dose limiting, the product should be switched to another statin with a lower potential for drug interaction. Patients who fail to achieve LDL cholesterol targets at a dose of 40 mg/day should not increase the dose but should be switched to another more efficacious therapy. The patient should not increase the dose but should switch to other therapies that are more effective.
—-Combination of other medications
Concomitant use of verapamil, diltiazem, or dronedarone: the dose of this product should not exceed10 mg/day;
concurrently taking amiodarone, amlodipine, ranolazine, or drugs containingelbasvir, grazoprevir: the dose should not exceed20 mg/day.
—-Purex Familial Hypercholesterolemia
The recommended dose of this product for patients with purex familial hypercholesterolemia, based on the results of a controlled clinical study, is40 mg in a single evening dose. This product may be used in combination with other lipid-lowering therapies (e.g., LDL plasma isolation and replacement methods) or alone when these methods are not available.
Concurrently taking lomitapide, the dose of this product should not exceed40 mg/day.
—-Patients with renal insufficiency. family:Times New Roman”>
Dose adjustment is not required in patients with mild to moderate renal insufficiency because of insignificant renal excretion of this product. However, it should be used with caution in patients with severe renal insufficiency (creatinine clearance<30 ml/minute), and the starting The starting dose should be 5 mg daily with close monitoring.
—-Children with heterozygous familial hypercholesterolemia () “font-family:Times New Roman”>10to17years old)
For heterozygous familial hypercholesterolemia1010 family:Arial”>to17year-old pediatric patients, the recommended starting dose of this product is10 mg in one dose in the evening. The recommended dose range is 10to40mg, the recommended maximum dose is40mg per day. The dose used should be individualized according to the recommended therapeutic target.
—-Fat-regulating doses of niacin or niacin-containing drugs for Chinese patients
Chinese patients combined with simvastatin40mg/ family:Arial”>day with lipid-modifying doses of niacin or niacin-containing drugs is associated with an increased risk of myopathy; therefore, Chinese patients combining more than20 mgdose of simvastatin with lipid-modifying doses of niacin or niacin-containing drugs with caution. Because the risk of myopathy is dose-related, Chinese patients should not combine 80 mgdoses of simvastatin with lipid-modifying doses of niacin or niacin-containing niacin-containing drugs. The reason for the increased risk of myopathy in Chinese patients is unclear. It is not clear whether the combination leads to an increased risk of myopathy in patients of other Asian descent.
[Adverse Reactions]
Simvastatin tablets were generally well tolerated, with most adverse reactions being mild and transient. In controlled clinical studies less than2% of patients discontinued due to adverse effects of simvastatin tablets.
In premarketing controlled clinical studies, investigators considered drug-related (categorized as probable, likely, or definite) with an incidence≥1% of adverse reactions were abdominal pain, constipation, and gastrointestinal distention; the incidence was0.5 “font-family:Arial”>to0.9% of adverse reactions were fatigue and headache.
Myopathy has been reported very rarely. See Caution, Myopathy/Rhabdomyolysis.
In the HPSstudy, a total of20,536patients took daily simvastatin tablets40mg(n=10269 ) or placebo (n=10267), with a mean observation time of 5years and a similar safety profile between the two groups. This large trial only recorded the number of serious adverse reactions and withdrawals from the study due to side effects. The percentage of withdrawals due to adverse reactions was similar between the two groups (simvastatin group4.8%, placebo5.1%). The incidence of myopathy in the simvastatin group was 0.1%. The percentage of elevated transaminases (above the upper limit of normal3fold in repeated tests) in the simvastatin and placebo groups, respectively, was0.21%(n=21) and0.09%(n=9).
In the Nordic Simvastatin Survival Study (4S), 444444 patients took daily simvastatin tablets20to40 mg(n=2221) or placebo (n=2223), with a median follow-up time of 5.4years, with similar safety and tolerability between the two groups.
The following adverse reactions have been reported in uncontrolled clinical studies or post-marketing applications: nausea, diarrhea, rash, dyspepsia, pruritus, alopecia, dizziness, muscle cramps, myalgia, pancreatitis, sensory abnormalities, peripheral neuropathy, insomnia, depression, vomiting, anemia erectile dysfunction and interstitial lung disease. Rarely, rhabdomyolysis and hepatitis/jaundice occur, and very rarely, fatal and nonfatal liver failure occurs.
Rarely, immune-mediated necrotizing myopathy associated with statin use (IMNM) style=”font-family:Arial”>) (an autoimmune myopathy) was reported. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase (symptoms persist after discontinuation of statin); muscle biopsy shows no significant inflammation in necrotizing myopathy; improvement with immunosuppressive agents (see Caution, Myopathy/Rhabdomyolysis).
Significant allergic reaction syndromes including one or more of the following symptoms have been reported rarely: anaphylactic reaction, angioneurotic edema, lupus-like syndrome, rheumatic polymyalgia, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, erythrocyte sedimentation rate (ESR) elevation, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnea, and malaise.
Post-marketing experience: Rare reports of cognitive impairment, manifesting as memory loss, memory loss, and confusion, have been reported in foreign post-marketing surveillance of statins, and are mostly non-serious, reversible reactions that generally recover upon discontinuation.
Laboratory findings
Significant and persistent elevations of serum transaminases have been reported rarely. Elevations in alkaline phosphatase and γ-glutamate transpeptidase have been reported. Abnormal liver function tests are mild and transient. Elevations of serum creatine kinase (CK) originating from skeletal muscle have been reported (see Caution).
Hyperglycemic reactions, abnormal glucose tolerance, elevated glycosylated hemoglobin levels, new-onset diabetes, and worsening glycemic control have been reported in postmarketing surveillance of statins, and hypoglycemic reactions have been reported with some statins.
For simvastatin, elevated glycated hemoglobin and fasting glucose have been reported.
Pediatric patients (age10to17years old)
In an item that includes age10to17years of age in a study of pediatric heterozygous familial hypercholesterolemia patients (n=175), the safety and tolerability of the simvastatin-treated group was overall similar to that of the placebo-treated group (see Precautions; Pediatric Dosing).
[Contraindicated]
—Allergic to any of the ingredients of this product =”font-family:Times New Roman”>
.
—Active liver disease or unexplained persistent elevation of serum transaminases.
–Pregnant and lactating women (see PRECAUTIONS, Pregnancy and Lactation Dosage for Women).
—with StrongCYP3A4inhibitors in combination (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIVprotease inhibitors, poprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, or drugs containingcobicistat (see Precautions, myopathy/Rhabdomyolysis and Drug Interactions).
— in combination with gemfibezil, cyclosporine, or danazol (see Precautions, Rhabdomyolysis/Rhabdomyolysis and Drug Interactions).
[Precautions]
Myopathy/Rhabdomyolysis
Simvastatin can occasionally cause myopathy as muscle pain, tenderness, or weakness with creatine kinase (CK) is elevated above the upper limit of normal10fold. Myopathy sometimes forms rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and fatal events from this are rare. The increased risk of myopathy with very high plasma levels of HMG-CoAreductase inhibitors (ie, blood levels of simvastatin versus simvastatin acid elevated), which may be due in part to the interacting drugs interfering with simvastatin metabolism and/ or transport pathways (see Drug Interactions). Predictable factors causing myopathy include old age (≥65 years), female, uncontrolled hypothyroidism and renal insufficiency.
myopathy/The risk of rhabdomyolysis is dose-related. In a database of clinical trials, there were41,413 patients treated with simvastatin. Of these studies 24,747 people (about 60%) with a median follow-up period of at least4 “font-family:Arial”>year,20,40and80 mg/day incidence of myopathy was about 0.03%, respectively The company’s growth rate is expected to increase by 3.8%0.08%and0.61%0.61%. In these trials, patients were carefully monitored and certain interactions with drugs were excluded.
In a clinical trial, a total of12,064patients with a history of myocardial infarction with a mean follow-up6.7years receiving simvastatin. 80 mg/day for myopathy was about1.0%, while the incidence of myopathy after receiving20 mg/ “font-family:Arial”>day was 0.02% for patients. The incidence of rhabdomyolysis in patients treated with simvastatin80 mg/day was approximately0.4%, while patients receiving20 mg /day was 0%. In about half of the cases of myopathy, it occurs in the first1year of treatment. In each1year of subsequent treatment, the incidence of myopathy was approximately10.1%.
Receiving simvastatin80 mg compared with patients receiving similar LDL-Creducing effects of other statin class-based therapy compared with a higher risk of myopathy.
All patients starting simvastatin therapy, or who are increasing their simvastatin dose, should be warned of the risk of myopathy, including rhabdomyolysis, and told to promptly report any unexplained muscle pain, tenderness, or muscle weakness. If myopathy is diagnosed or suspected, simvastatin should be discontinued immediately. These symptoms occur andCKlevels exceed10 times the upper limit of normal, indicating the development of myopathy. In most cases, muscle symptoms andCKelevation can resolve when patients discontinue treatment in a timely manner (see Adverse Reactions). Periodic measurement of CK may be considered in patients starting simvastatin therapy or who are on increasing doses. This monitoring does not necessarily prevent myopathy.
The majority of patients who develop rhabdomyolysis during simvastatin therapy have a complex medical history. These histories include renal insufficiency-often resulting from long-term diabetes mellitus. Such patients should be monitored more closely. Simvastatin therapy may be suspended for a few days prior to elective major surgery and in the setting of any serious medical or surgical illness.
In a clinical trial, patients at high risk for cardiovascular disease received40 mg/day simvastatin (median follow-up period of 3.9years ) treatment, the results showed that the incidence of myopathy in patients of non-Chinese descent (n=7367) was approximately0.05%, compared to patients of Chinese descent (n=5468) had an incidence of 0.24%. However, this clinical trial evaluated only patients of Chinese descent in an Asian population, and therefore caution should be exercised when prescribing simvastatin to Asian patients and the lowest necessary dose should be used.
Drug Interactions
Simvastatin in combination with the following drugs can increase myopathy/rhabdomyolysis risk:
Drugs contraindicated in combination
CYP3A4Strong inhibitors: Combinations of drugs listed in the instructions that are strong inhibitors of CYP3A4 at therapeutic doses are prohibited. inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIVprotease inhibitors, boeprevir, telaprevir, nefazodone, or cobicistatcontainingmedications). If short-term application of CYP3A4strong inhibitor therapy is unavoidable, suspend simvastatin therapy for the duration of this treatment (see Contraindications ; drug interactions)
.
Giffibezil, cyclosporine, or danazol: Simvastatin is contraindicated in combination with these drugs (see Contraindications; Drug Interactions).
Other Drugs
Fusidic acid: Patients treated with fusidic acid concurrently with Simvastatin therapy may increase the risk of myopathy/rhabdomyolysis
(see Drug Interactions, Other Drug Interactions, Pharmacokinetics). Co-administration of fusidic acid during simvastatin therapy is not recommended. For those patients requiring systemic fusidic acid, it is necessary to consider discontinuing simvastatin for the entire duration of fusidic acid dosing. In exceptional circumstances where extended systemic use of fusidic acid is required, such as to treat a serious infection, each patient should be specifically analyzed and the need for simvastatin in combination with fusidic acid should be considered under close medical monitoring.
Other Betablockers: Caution should be exercised when prescribing other betablockers other than gemfibrozil and simvastatin concurrently with caution, as both classes of drugs can cause myopathy when used alone. And the risk of myopathy is increased when the two are combined. The benefits of use should be carefully weighed against the risks.
Amiodarone, amlodipine, or ranolazine: Patients on combined amiodarone, amlodipine, or ranolazine should not receive more than a daily dose of simvastatin20 mg.
Verapamil, diltiazem, or dronedarone: In patients on combination verapamil, diltiazem, or dronedarone, the dose of simvastatin should not exceed daily style=”font-family:Times New Roman”>10 mg.
Lomitapide: InHoFHpatients taking both lomitapide and simvastatin, the dose of simvastatin should not exceed40 mg per day(see Drug Interactions, Other Drug Interactions).
CYP3A4Medium-acting inhibitors: The application instructions listed forCYP3A4patients with moderate inhibitory effects of drugs in combination with simvastatin, especially at higher doses, their risk of myopathy is increased. Dose adjustment of simvastatin is necessary when simvastatin is combined with CYP3A4medium-acting inhibitors.
Breast cancer resistance protein inhibitors (BCRP): Combination applicationBCRPinhibitors (e.g.elbasvirandgrazoprevir), it can lead to increased blood levels of simvastatin thereby increasing the risk of myopathy, necessitating dose adjustment of simvastatin.
No comparisons have been made between simvastatin and elbasvirandgrazoprevir in combination; study data in combinationelbasviror In patients on grazoprevir, the dose of simvastatin should not exceed20 mg per day(see Drug Interactions, Other Drug Interactions).
Liver function impairment
In clinical studies, approximately1%adult patients treated with simvastatin developed persistently elevated serum transaminases (above the upper limit of normal3fold). After interruption or discontinuation of medication in these patients, transaminase levels usually slowly decrease to pretreatment levels. This transaminase elevation was not accompanied by jaundice or other signs or symptoms, there were no signs of allergy, and a subset of these patients had abnormal liver function tests prior to simvastatin therapy and /or have consumed large amounts of alcohol.
In the Nordic Simvastatin Survival Study, more than one transaminase elevation above the upper limit of normal throughout the study period3fold, there was no significant difference between the simvastatin and placebo groups[14(0.7%)):12(0.6%)]. Simvastatin groupSGPT(ALT) single elevation to the upper limit of normal3fold was significantly more frequent in the first year of the study (20:8,P=0.023), but it was no longer significant thereafter. The elevation of transaminases led to a significant increase in the simvastatin-treated group (n=2221) in8 patients and the placebo group (n=2223) in5 patients discontinued the drug. 4Sstudies in which patients treated with simvastatin1986 patients had liver function tests at baseline (LFTs) were normal and only 8 () 0.4%) in 5.4years (median follow-up period) in which transaminases exceeded the upper limit of normal values for 3 consecutivefold and/ or discontinued due to elevated transaminases. The starting dose of simvastatin in all patients in this study was20 mg, with37% of patients adjusted to 40mg during the course of treatment .
Including 1105 patients in 2controlled clinical studies in which persistent drug-related elevations in hepatic transaminases were considered6month incidence at 40 mgand80mgdose groups, respectively The dose groups were0.7%andand1.8%.
In the HPSstudy 20,536 patients were randomly assigned to take simvastatin daily40 mgor placebo, with transaminase elevations above the upper limit of normal33 span>fold incidence in the simvastatin and placebo groups was0.21% respectivelyand0.09%.
Liver function tests are recommended before the start of therapy and subsequently when clinically indicated. Particular attention should be paid to patients presenting with elevated serum transaminases, for whom repeat measurements should be made promptly and the frequency of liver function tests increased thereafter. If transaminase levels show an increasing trend, especially if transaminase values rise to the upper limit of normal values3fold and do not decrease, the drug should be discontinued. It should be noted that alanine aminotransferase may be muscle-derived, and therefore elevated alanine aminotransferase accompanied by elevated creatine kinase may indicate myopathy (see Caution, Myopathy/Rhabdomyolysis).
There have been very few post-marketing reports of fatal and non-fatal liver failure in patients taking statins, including this one. If severe liver injury with clinical symptoms occurs during treatment with this product, and / or hyperbilirubinemia, or jaundice occurs, immediately discontinue Apply this product. If the causative agent is not found, do not reapply the product.
For people who drink large amounts of alcohol and//or a history of prior liver disease, the drug should be used with caution. Simvastatin is contraindicated in patients with active liver disease or unexplained elevated transaminases.
As with other lipid-lowering drugs, there is a moderate serum transaminase (below the upper limit of normal3fold) elevations have been reported. These changes appear soon after the start of simvastatin therapy, but are often transient, are not associated with any symptoms and do not require interruption of therapy.
Ophthalmologic examination
The incidence of lens clouding increases with age, even in the absence of any medication. Data from long-term clinical studies show that simvastatin has no adverse effects on the human lens.
[For pregnant and lactating women]
Pregnant women
Safety data are not available for simvastatin in women who are pregnant. Controlled clinical trials of simvastatin have not been conducted in pregnant women. Congenital defects due to the use of HMG-CoA during pregnancy have also been reported rarely. However, in a study of approximately200 patients who had used simvastatin or other closely related drugs in the first trimester of pregnancy style=”font-family:Times New Roman”>A retrospective analysis of patients with HMG-CoAinhibitors found a similar incidence of congenital defects to the general population. The number of patients in this retrospective has been able to statistically exclude that the incidence of congenital defects is no more than 2.5fold or higher than the general occurrence.
Although there is no clear evidence that simvastatin use in pregnant women causes an increased occurrence of birth defects, simvastatin reduces fetal levels of mevalonate, a precursor to cholesterol biosynthesis. Atherosclerosis is a chronic process, so discontinuing lipid-lowering drugs during pregnancy has little impact on the long-term outcome of treating primary hypercholesterolemia. Therefore, this product is contraindicated in women during pregnancy, in women who are preparing to become pregnant or who may become pregnant. The use of this product should be suspended during pregnancy (see Contraindications).
Lactating women
It is not known whether simvastatin and its metabolites are secreted through human milk, and because of the serious adverse effects that many drugs are secreted through human milk and may cause, women taking this product should not breastfeed (see Contraindications).
[For Children]
Simvastatin in children aged10to17years of age in patients with heterozygous familial hypercholesterolemia The safety and effectiveness have been evaluated in a controlled trial conducted in adolescent boys and girls (at least 1year after menarche). Adverse events in patients in the simvastatin-treated group were overall similar to those in the placebo group. Studies with doses greater than 40 mg were not conducted in this population. In this limited controlled study, no significant effects of simvastatin on growth or sexual maturation in adolescent males or females, or on the length of the menstrual cycle in adolescent females were found (see Dosage; Adverse Reactions).
Appropriate contraceptive methods are recommended for simvastatin therapy in adolescent females (see Contraindications; Precautions; Use in Pregnant and Lactating Women). Simvastatin has not been studied in patients younger than 10 years of age and in girls before menarche.
[Geriatric use]
In elderly patients (>65 “font-family:Arial”>years) in a controlled clinical study of simvastatin, its effect on lowering total and LDL cholesterol was similar to the results in other populations, and the overall incidence of adverse effects and abnormal laboratory tests was not significantly increased. However, in a clinical trial in which patients received 80 mg/day of simvastatin treatment, =”font-family:Times New Roman”>65years and older had a relatively higher risk of myopathy, including rhabdomyolysis, than did patients65years of age and younger.
[Drug Interactions]
Multiple mechanisms may cause interactions with HMG Co-Areductase inhibitors. Inhibition of certain enzymes (e.g.CYP3A4) and/ or transporter proteins (such asOATP1B =”font-family:Arial”>) pathway or herbal products may elevate blood levels of simvastatin and simvastatin acid, leading to myopathy/increased risk of rhabdomyolysis.
Review prescribing information for all co-drugs for potential interactions with simvastatin and/or changes in enzymes, transport mechanisms, and additional information on dosing and regimen adjustments.
Drug Contraindications
Co-administration of the following drugs is contraindicated:
CYP3A4Strong inhibitors:
Simvastatin is inhibited byCYP3A4metabolism but notCYP3A4inhibitory activity; therefore it does not affect the activity throughCYP3A4metabolized by other drugs in plasma concentration. PotentCYP3A4inhibitors (below) increase the risk of myopathy by decreasing the elimination of simvastatin. The combination of drugs listed in the instructions as strong inhibitors of CYP3A4 (eg, itraconazole, ketoconazole posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIVprotease inhibitors, poprivir, telaprevir, nefazodone, or drugs containing cobicistat) in combination (see Contraindications; Precautions, Myopathy/rhabdomyolysis).
Giffibezil, cyclosporine or danazol: is contraindicated in combination with simvastatin (see Contraindications; Precautions, Myopathy/Rhabdomyolysis).
Other drug interactions
Other Betablockers: Coadministration of betablockers other than gemfibrozil increases the risk of myopathy; the benefits and risks should be carefully weighed when combined.
Amiodarone: When amiodarone is combined with simvastatin, myopathy/rhabdomyolysis risk may be increased span style=”font-family:Times New Roman”>
(see Dosage; Precautions, Myopathy/Rhabdomyolysis).
Calcium channel blockers: verapamil, diltiazem, or amlodipine in combination with simvastatin in myopathy/Rhabdomyolysis risk may be increased (see Dosage; Precautions; Myopathy/Rhabdomyolysis).
Lomitapide: Patients on combined lomitapide and simvastatin had myopathy/Rhabdomyolysis may occur at increased risk (dosage; precautions, drug interactions).
CYP3A4Medium-acting inhibitors: application instructions listed for CYP3A4with moderate inhibitory effects may have an increased risk of myopathy in patients who are coadministered simvastatin, especially at higher doses.
OATP1B1Transport Protein Inhibitors: Simvastatin Acid is a substrate of OATP1B1transporter protein. When combined with OATP1B1transporter protein inhibitors, it may cause elevated plasma concentrations of simvastatin acid and increase the risk of myopathy .
Breast cancer resistance protein inhibitors (BCRP): simvastatin is a substrate of the efflux transporterBCRP, and the combination BCRPinhibitors (e.g.elbasvirandgrazoprevir), will result in an increase in simvastatin blood levels thereby increasing the risk of myopathy. In combination of simvastatin with elbasviror or grazoprevir in patients in whom dose adjustment of simvastatin is necessary (see Dosage; Precautions, Other Drugs).
Niacin (≥1g/day ): myopathy was observed in the combination of simvastatin with lipid-modifying doses of niacin (≥1g/day)/rhabdomyolysis cases (see Precautions, Myopathy/Rhabdomyolysis).
Fusidic acid: co-administration of fusidic acid may increase myopathyrhabdomyolysis risk (see Precautions, Myopathy/Rhabdomyolysis; pharmacokinetics).
Colchicine:
There are reports showing, that in In patients with renal insufficiency, the combined application of colchicine and simvastatin causes myopathy and rhabdomyolysis. Close clinical monitoring is recommended for patients, who are coadministered these drugs.
Other interactions
Grapefruit juice contains one or more inhibitors ofCYP3A4constituents that increase the metabolism of drugs viaCYP3A4. Plasma levels. The effect of regular consumption (one glass250ml per day) was minimal (by measuring the concentration-time area under the curve, plasma HMG-CoAreductase inhibitory activity increased by 13%) and was not clinically significant. However, larger amounts significantly increased plasmaHMG-CoAreductase inhibitor activity, and therefore, during simvastatin therapy should be Avoid grapefruit juice (see Precautions, Myopathy/Rhabdomyolysis).
Coumarin derivatives
In a clinical study involving healthy volunteers and another patient with hypercholesterolemia, daily doses of simvastatin20to40 mg, which moderately improved the anticoagulant effect of coumarin-based anticoagulants in terms of the international normalized ratio of prothrombin time (INR) The prothrombin time in the healthy volunteer group was prolonged from 1.7at baseline to 1.8seconds, and in the hypercholesterolemic group from2.6prolonged to 3.4seconds. In patients on coumarin anticoagulants, prothrombin time should be measured prior to the use of simvastatin and frequently during the initial phase of therapy to ensure that there are no significant changes in prothrombin time. Once a stable prothrombin time has been recorded, patients should be advised to monitor their prothrombin time regularly while taking coumarin-based anticoagulants. These steps should be repeated if the simvastatin dose is adjusted or if the drug is discontinued. In patients not taking coumarin-based anticoagulants, bleeding or prothrombin time changes are not associated with the administration of simvastatin.
Digoxin
One study found that concomitant administration of digoxin and simvastatin resulted in mildly elevated blood levels of digoxin. Digoxin blood levels should be monitored when digoxin and simvastatin are combined.
[Drug overdose]
A few overdoses have been reported; the maximum dose taken was3.6g. All patients recovered with no sequelae. Routine measures are generally taken to manage overdose.
[Pharmacology and Toxicology]]
Pharmacological effects
Simvastatin is a prodrug that is hydrolyzed after administration to the active formβ-hydroxamic acid, which is simvastatin acid. Simvastatin is a specificinhibitor of HMG-CoAreductase, which acts as a rate-limiting enzyme for cholesterol biosynthesis and catalyzesconversion of HMG-CoAto mevalonate. Simvastatin reduces plasma very low density lipoprotein (VLDL) and triglycerides (). “font-family:Times New Roman”>TG) concentrations and elevated plasma HDL cholesterol (HDL-C) concentrations.
Toxicological studies
Central Nervous System (CNS) toxicity: dogs given simvastatin180 mg/kg/day orally (based on The exposure level is extrapolated to approximately 80mg/day of the human dose. family:Times New Roman”>12times or higher), administered continuously14weeks, and optic nerve degeneration was seen.
Dogs given orally a drug chemically similar to simvastatin60 mg/ kg/day (extrapolated based on total enzyme inhibitory activity, approximately the maximum recommended human dose of 30) “font-family:Arial”>fold or higher), visible optic nerve degeneration (retinal-geniculate (nerve) (Waller(s) degeneration of fibers), the effect is dose-related. Simvastatin180 mg/kg/day was administered orally to dogsconsecutively14weeks, as seen in the vestibular (ear) cochlea of the Wallerian-likelike degeneration and retinal ganglion cell staining plasmolysis, This dose produced mean plasma drug levels comparable to those at a daily60 mg/kg/day dose at similar levels.
CNSvascular damage: dogs given simvastatin at doses up to 360 mg/kg/day (extrapolated from exposure levels, approximately human80 mg/80mg/day14fold or higher), perivascular hemorrhage and edema, perivascular gap mononuclear cell infiltration, perivascular gap fibrin deposition, and small vessel necrosis were seen, and similar CNSvascular lesions.
Simvastatin was given orally to female rats50. family:Arial”>and100 mg/kg/day (based on exposure levels extrapolated to approximately humandays, respectively). span>80 mg/day of 2222and25fold), given continuouslyfor 2years; dogs given simvastatin transorally90mg/kg/day (19) times) for 3 consecutivemonths, and span>50mg/kg/day (5times) consecutive2year, the animals were seen to develop cataracts.
Genotoxicity:
Microbial mutagenicity of simvastatin in rats or mice with or without hepatic metabolic activation (Ames) assay, the rat hepatocyte genetic material damage assay,V-79mammalian cell forward mutation assay and CHOcell chromosome aberration assay. and in vivo mouse micronucleus test results were negative.
Reproductive toxicity:
Repeated oral administration of simvastatin25 mg/kg in male rats, administered for 34weeks, a reduction in fertility was seen ( Based on exposure levels extrapolated to approximately human80 mg/day of family:Times New Roman”>4 times), but in subsequent male rats repeatedly given simvastatin 25 mg/kg of11week toxicity test, observed up to complete sperm cycle, including epididymal maturation, no significant impairment of fertility and no significant histopathological changes in the testes, but at 180 mg/kg(extrapolated based on exposure levels, about 80mg/day of human22times) degeneration of the germinal tubules (necrosis and loss of germinal epithelial cells) was seen. Dogs were repeatedly given simvastatin10 mg/kg (extrapolated from exposure levels, approximately human80mg/day2of span>fold) Drug-related testicular atrophy, reduced spermatogenesis, spermatocyte degeneration, and giant cell formation were seen, and the clinical relevance is unclear.
Simvastatin25 mg/kgwas administered orally to pregnant rats and rabbits, respectively. style=”font-family:Arial”>and10mg/kg (approximately the human exposure). span>3fold), no embryonic Roman”>-fetal litter growth and development were significantly abnormal, but other structurally similar statins were seen in the offspring of rats and rabbits with skeletal muscle malformations. The active hydroxylated metabolite of simvastatin given orally to rats60 mg/kg/day was seen to result in decreased maternal body weight, increased embryonic uptake, and increased skeletal muscle deformities. Subsequent similar trials showed that embryonic resorption and skeletal muscle deformities occurred only in rodents and were associated with maternal toxicity (antral damage with weight loss).
Carcinogenicity:
Mice given simvastatin orally25 “font-family:Arial”>,100and400mg/kg/day, administered72. span>weeks, the mean plasma drug levels were approximately equivalent to the human dose80 mg/day exposure1, 4and8fold, the incidence of hepatocellular carcinoma was elevated in high-dose females and medium- and high-dose males in the model, with a maximum incidence of 90% in males =”font-family:Arial”>, with elevated incidence models for female liver adenomas in the middle and high dose groups, and for adenomas of the Harder’s gland (rodent eye gland) in the high dose group, not seen25 mg/kg. span>evidence of a tumorigenic effect in the group. In an independent92week mouse carcinogenicity study, noweek mouse carcinogenicity study was observed. family:Times New Roman”>25mg/kggroup (extrapolated based on exposure levels, approximately equivalent to human 80 mg/day) for evidence of tumorigenic effects.
Rats2year carcinogenicity test,25 mg/kgdose group of female animals, the incidence of thyroid follicular cell adenoma was significantly increased and the exposure level approximately 80 mg/day of human doseexposure :Times New Roman”>11 times the exposure.
Another study in rats2year carcinogenicity test,50andand100 mg/kgdose groups increased the incidence of hepatocellular adenoma and hepatocellular carcinoma (in females in both dose groups and in males in the high dose group), and in both dose groups the thyroid follicular cell adenoma in both males and females The incidence of thyroid follicular cell adenoma was significantly increased in females in both dose groups, 100 mg/kg, and the above thyroid tumors The increased incidence of thyroid tumors was similar to that of other drugs in the statin class and was about 80 mg/day of plasma exposure level in humans, respectively. span style=”font-family:Times New Roman”>7fold and15fold and15fold of the plasma exposure level. span>fold (male) and22fold and25 times (females).
[Pharmacokinetics]
Simvastatin is highly selective for the liver after oral administration, and its concentration in the liver is significantly higher than in other non-target tissues. The majority of simvastatin undergoes extensive first-pass absorption in the liver, acting primarily in the liver and subsequently excreted via the bile. Only less than5% of the dose of simvastatin active ingredient was found in the periphery, and of these95%are bound to plasma proteins.
A pharmacokinetic trial showed that concomitant administration of diltiazem resulted in an increase in simvastatin acid exposure by 2.7fold, presumably caused by CYP3A4 caused by inhibition (see Caution, Myopathy/Rhabdomyolysis).
A pharmacokinetic trial showed that concomitant administration of amlodipine resulted in an increase in simvastatin acid exposure of 1.6fold (see Caution, Myopathy/rhabdomyolysis).
A pharmacokinetic trial showed that2g of family:Arial”>single-dose extended-release niacin in combination with simvastatin20 mg can lead to a significant increase in simvastatin and simvastatin AUCand simvastatin acid plasma concentrationElevation of Cmax (see Caution, Myopathy/Rhabdomyolysis).
The specific hepatic metabolic pathway of fusidic acid is unknown, but it is still suspected that fusidic acid and transCYP3A4metabolizedHMG-CoAreductase inhibitors have interactions (see Caution, Myopathy/rhabdomyolysis).
[Storage]
Seal and store at 30C or below.
Polyvinyl chloride/ Polyethylene/Polyvinylidene Chloride Solid Pharmaceutical Laminated rigid tablets, pharmaceutical aluminum foil,7tabletstablets family:Times New Roman”>×1plate/boxes,14pieces×1plate/boxes,14tablets×2Plates/box.
[Expiration date]
24months
[Approval number]
State Drug CertificateH20000009
[Manufacturer]
Company Name: Zhejiang Jingxin Pharmaceutical Co.
Production Address: East Xinchang Avenue, Yulin Street, Xinchang County, Zhejiang Province800No.
Postal Code:312500
Sales Hotline:(0575)86096832
Complaints:(0575)86098209
Fax Number:(0575)86096898
Web
Address:www.jingxinpharm. com