What Factors Affect a Sufficient Simvastatin Dose?

Simvastatin tablets, prescription drugs, and simvastatin tablets are indicated for hyperlipidemia, coronary heart disease with hypercholesterolemia, and children with heterozygous familial hypercholesterolemia. In combination with diet control, this product can be used to reduce total Cholesterol, LDL cholesterol, apolipoprotein B and triglycerides.

Simvastatin reduces the normal and elevated levels of LDL-C by reducing the very low-density lipoprotein cholesterol (VLDL-C) concentration, inducing the low-density lipoprotein (LDL) receptor High low-density lipoprotein cholesterol (LDL-C) concentration. In addition, simvastatin can increase the concentration of high-density lipoprotein cholesterol (HDL-C) and reduce plasma triglycerides (TG). All of these can lead to a reduction in total cholesterol / HDL-C and LDL-C / HDL-C.

In 2009, simvastatin became the only statin listed in the National Essential Drug List.

Drug Name: Simvastatin tablets
Foreign name: Simvastatin Tablets
Whether prescription drugs: prescription

Dosage form: tablet
Drug type: Prescription drugs, essential drugs
Use classification: Lipid-lowering drugs

Basic Information of Simvastatin

[Common name] Simvastatin tablets

[English name] Simvastatin Tablets

[Chinese Pinyin] Xinfatating Pian

[Ingredients] The main ingredient of this product is simvastatin

[Formulation] Tablet

[Packing] Aluminum-plastic board, 5 pieces / box, 7 pieces / box

[Storage] Sealed and stored below 30 ° C.

[Validity] 24 months

[Executive Standard] JX20010323

[Approval Number] National Medicine Standard J20130181; Import Drug Registration Certificate Number: H20130677

[Chemical name] The main ingredients of this product and its chemical name are: simvastatin, [1S- [1, 3, 7, 8, (2S *, 4S *) 8]]-1, 2, 3, 7, 8 , 8a-hexahydro-3,7-dimethyl-8- [2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -1-naphthyl- 2,2-dimethylbutyrate.
Structural formula:

Molecular formula: C ₂₅ H ₃₈ O ₅
Molecular weight: 418.57

[Properties] This product is a pink oval film-coated tablet with "MSD749" engraved on one side; it is white or almost white after removing the film.

Indications for Simvastatin

Hyperlipidemia For patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia, hyperlipidemia, or mixed hyperlipidemia, when diet control and other non-drug treatments are not ideal, combine diet Control, this product can be used to reduce elevated total cholesterol, low density lipoprotein cholesterol, apolipoprotein B and triglycerides, and can increase high density lipoprotein cholesterol, thereby reducing low density lipoprotein cholesterol / high density lipoprotein Cholesterol and total cholesterol / high density lipoprotein cholesterol ratio. For patients with homozygous familial hypercholesterolemia, combined with diet 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: reducing the risk of death, reducing the risk of death from coronary heart disease and non-fatal myocardial infarction, reducing the risk of stroke and transient cerebral ischemia, and reducing cardiovascular disease The risks of reconstructive surgery (coronary artery bypass graft and percutaneous transluminal coronary angioplasty) delay the progression of coronary atherosclerosis including reducing the formation of new lesions and total obstruction

Children with heterozygous familial hypercholesterolemia For adolescent boys and girls aged 10-17 years (at least one year after menarche) with heterozygous familial hypercholesterolemia, this product can be used to reduce diet Total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides.

Simvastatin tablets dosage

Before receiving this product, patients should receive a standard cholesterol-lowering diet and continue to maintain it during treatment.

The recommended starting dose is 5-40 mg daily, once a night. For patients with a high risk of CHD events due to a history of coronary heart disease, diabetes, peripheral vascular disease, stroke, or other cerebrovascular disease, the recommended starting dose is 10 mg or 20 mg per day. For patients who only need a moderate reduction in LDL cholesterol, the starting dose is 10 mg. The dosage used should be adjusted individually based on the underlying LDL cholesterol level, recommended treatment goals, and patient response. Dosage adjustments should be performed at intervals of 4 weeks or more.

---- Limit the use of 80mg / day dose

Due to increased risk of myopathy including rhabdomyolysis (especially within the first year of use), this product

The 80 mg dose is limited to patients who have been using it for a long time (1 year) and have tolerated the dose without developing myopathy. Correct

In patients who have already used and tolerated 80mg, if there is a need to combine drugs with interactions, and the

If the drug is contraindicated or if there is a dose limit for this product, the drug should be converted to a drug phase.

Other statins are less likely to interact. For those who failed to achieve the LDL cholesterol level at 40 mg / day

Patients should not increase the dose, but should switch to other more effective therapies.

---- Combined use of other drugs

Concomitant use of verapamil, diltiazem or dronedarone: the dose of this product should not exceed 10mg / day;

Simultaneously taking amiodarone, amlodipine, or ranolazine: the dose of this product cannot exceed 20mg / day;

---- Homozygous familial hypercholesterolemia

According to the results of a controlled clinical study, for patients with homozygous familial hypercholesterolemia, the recommended dose of this product is 40 mg per day. This product can be used in combination with other lipid-lowering therapies (such as low-density lipoprotein plasma separation Replacement method), when these methods cannot be used, this product can also be used alone.

---- Patients with Renal Insufficiency

Because the excretion of this product through the kidneys is not obvious, patients with mild to moderate renal insufficiency do not need to adjust the dose. However, this product should be used with caution in patients with severe renal insufficiency (creatinine clearance <30ml / min). The starting dose of such patients should be 5mg per day and closely monitored.

---- Children with heterozygous familial hypercholesterolemia ( age 10-17 )

For children with heterozygous familial hypercholesterolemia 10-17 years old, the recommended starting dose of this product is 10 mg daily, once a night. The recommended dose is 10-40 mg per day and the maximum recommended dose is 40 mg per day. The dosage used should be adjusted individually according to the recommended treatment goals.

---- Chinese patients use niacin or niacin-containing drugs for lipid-lowering doses

Chinese patients use simvastatin 40mg / day combined with lipid-lowering niacin or niacin-containing drugs, the risk of myopathy increases. Therefore, Chinese patients use simvastatin with a lipid-lowering dose of niacin or Be cautious with niacin drugs. Because the risk of myopathy is related to the dose, Chinese patients should not combine 80mg simvastatin with lipid-lowering niacin or niacin-containing drugs. The reason for the increased risk of myopathy in Chinese patients is unknown. It is unclear whether the combined application increases the risk of myopathy in other Asian patients.

Side effects of simvastatin tablets

This product is generally well tolerated, most of the adverse reactions are mild and transient. In controlled clinical studies, less than 2% of patients discontinued due to adverse reactions to this product.

In the pre-marketing controlled clinical study, the researchers believed that the adverse reactions related to the drug (divided into possible, likely or positive) and the incidence of 1% were abdominal pain, constipation and flatulence; the incidence was 0.5-0.9% The adverse reactions were fatigue and headache.

Reports of myopathy are rare. See Notes, Myopathy / Rhabdomyolysis.

In the HPS study (see clinical trials), a total of 20,536 patients took 40 mg (n = 10269) or placebo (n = 10267) of this product daily. The average observation time was 5 years. The safety between the two groups was similar. This large trial only recorded serious adverse reactions and the number of people who dropped out of the study due to adverse reactions. The proportion of withdrawals due to adverse reactions was similar between the two groups (4.8% in the simvastatin group and 5.1% in the placebo). The incidence of myopathy in the simvastatin group was less than 0.1%. The percentages of elevated transaminases (3 times or more above the upper limit of normal) in the simvastatin and placebo groups were 0.21% (n = 21) and 0.09% (n = 9), respectively.

In the Nordic Simvastatin Survival Study (4S), 4,444 patients took 20-40 mg (n = 2221) or placebo (n = 2223) of this product daily. The median follow-up time was 5.4 years. Safety and tolerance are similar.

The following adverse reactions have been reported in uncontrolled clinical studies or post-marketing applications: nausea, diarrhea, rash, indigestion, pruritus, hair loss, dizziness, muscle spasm, myalgia, pancreatitis, paresthesia, peripheral neuropathy, insomnia , Depression, vomiting, anemia, erectile dysfunction and interstitial lung disease. Rarely rhabdomyolysis and hepatitis / jaundice occur, and fatal and nonfatal liver failure occurs.

Rarely, there have been reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy when used in combination with statins. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persists after stopping statin therapy; muscle tissue sections show necrotizing myopathy without meaningful inflammation; can be improved by immunosuppressive agents (see note Matters, myopathy / rhabdomyolysis).

Clearly reported allergic reaction syndromes that include one or more of the following symptoms: angioedema, lupus-like syndrome, rheumatic polymyalgia, dermatomyositis, vasculitis, thrombocytopenia, eosinophils Increased, increased red blood cell sedimentation rate (ESR), arthritis, joint pain, urticaria, light sensitivity, fever, flushing, difficulty breathing, and discomfort.

Post-marketing experience: There are reports of rare cognitive impairments in overseas post-marketing monitoring of statins, manifested as memory loss, memory loss, confusion, etc., most of which are non-serious and reversible reactions, which can usually be recovered after drug withdrawal .

Laboratory inspection found

Significant and persistent increases in serum transaminase have rarely been reported. Elevations of alkaline phosphatase and -glutamate transpeptidase have been reported. Liver function tests were abnormal and transient. Elevated serum creatine kinase (CK) from skeletal muscle has been reported (see Precautions).

Post-marketing monitoring of statins has reported reports of hyperglycemia, impaired glucose tolerance, elevated glycated hemoglobin levels, new-onset diabetes, and worsened glycemic control. Some statins have also reported hypoglycemic reactions.

For simvastatin, there have been reports of elevated glycated hemoglobin and fasting blood glucose.

Pediatric Patients (Age 10-17 )

In a study of patients with heterozygous familial hypercholesterolemia aged 10-17 years (n = 175), the safety and tolerability of the simvastatin group was similar to that of the placebo group. (See Precautions; Pediatric Use; Clinical Trials).

Taboos of simvastatin

---- Those who are allergic to any ingredient of this product

---- People with active liver disease or unexplained elevated serum aminotransferases

---- Pregnant and lactating women (see Precautions, medications for pregnant and lactating women)

--- Combined with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boprevir, tilarive, erythromycin, clarithromycin (Tetracycline, telithromycin, and nefazodone) (see Precautions, Myopathy / Rhabdomyolysis, and Drug Interactions).

--- Combined with gemfibrozil, cyclosporin or danazol (see notes, myopathy / striated muscle lysis and drug interactions)

Precautions for simvastatin tablets

Myopathy / rhabdomyolysis

Simvastatin can occasionally cause myopathy, manifested as muscle pain, tenderness, or fatigue, and is accompanied by an increase in creatine kinase (CK), which is more than 10 times the upper limit of normal. Myopathy sometimes forms rhabdomyolysis, with or without acute renal failure secondary to myoglobinuria, with very few fatal events. High levels of HMG-CoA reductase inhibitors in plasma increase the risk of myopathy. Predictable causes of myopathy include age (65 years), women, uncontrolled hypothyroidism, and renal insufficiency.

The risk of myopathy / striated muscle lysis is dose related. In a clinical trial database, 41,413 patients were treated with simvastatin. 24,747 (approximately 60%) of these studies had a median follow-up period of at least 4 years, and 20, 40, and 80 mg / day myopathy occurred. The rates are approximately 0.03%, 0.08% and 0.61%. In these trials, patients were carefully monitored and certain interacting drugs were excluded.

In a clinical trial, a total of 12064 patients with a history of myocardial infarction were enrolled, with an average follow-up of 6.7 years. The incidence of myopathies receiving simvastatin 80 mg / day was about 1.0%, compared with 0.02 for patients receiving 20 mg / day %. The incidence of rhabdomyolysis is approximately 0.4% in patients receiving simvastatin 80 mg / day and 0% in patients receiving 20 mg / day. About half of cases of myopathy occur during the first year of treatment. In each subsequent year of treatment, the incidence of myopathy is approximately 0.1%.

Patients receiving simvastatin 80 mg have a higher risk of myopathy compared to other statin- based treatments with similar LDL-C reduction effects .

All patients who have started simvastatin therapy or who are increasing their simvastatin dose should be reminded of the risk of myopathy including rhabdomyolysis and informed that they should promptly report any unexplained muscle pain, tenderness or weakness . If myopathy is diagnosed or suspected, simvastatin should be discontinued immediately. The onset of these symptoms, and CK levels exceeding 10 times the normal upper limit, indicate the occurrence of myopathy. In most cases, muscle symptoms and elevated CK can be alleviated when patients stop treatment in time (see Adverse Reactions). In patients who have started simvastatin treatment or are increasing their dose, consider periodically measuring CK. This monitoring does not necessarily prevent myopathy.

Most patients with rhabdomyolysis during simvastatin treatment have a complex medical history. These medical history include renal insufficiency-usually caused by long-term diabetes. Such patients should be monitored more closely. Simvastatin treatment can be suspended for several days before major elective surgery and in the event of any serious medical or surgical illness.

In a clinical trial, patients at high risk of cardiovascular disease received 40 mg / day of simvastatin (median follow-up period of 3.9 years). The results showed that the incidence of myopathy in non-Chinese patients (n = 7367) About 0.05%, compared with 0.24% in Chinese patients (n = 5468). However, this clinical trial only evaluated Chinese patients in Asian populations. Therefore, caution should be exercised in prescribing simvastatin to Asian patients and the lowest necessary dose should be used.

medicine interactions

Simvastatin can increase the risk of myopathy / rhabdomyolysis when used concurrently with:

Contraindications

CYP3A4 inhibitors : Do not use drugs listed in the combined instructions that have strong inhibitory effects on CYP3A4 at therapeutic doses (such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, Telithromycin ( telithromycin ) , HIV protease inhibitors, boprevir, tilarivvir, or nefazodone ). (See drug interactions, contraindications)

If treatment with a strong inhibitor of CYP3A4 is unavoidable in the short term, simvastatin treatment should be suspended during this treatment period. (See contraindications; drug interactions)

Gefitizil, cyclosporin or danazol : Simvastatin is contraindicated in combination with these drugs. (See contraindications; drug interactions).

Other drugs

Other fibrates : Caution should be exercised when prescribing fibrates other than gemfibrate and simvastatin at the same time, because these two drugs can cause myopathy when used alone. The risk of myopathy increases when the two are used in combination. The benefits and risks of use should be carefully weighed.

Amiodarone, Amlodipine, or Ranolazine: Combination Amiodarone: For patients in combination with Amiodarone, Amlodipine or Ranolazine, the dose of simvastatin should not exceed 20 mg per day.

Verapamil, diltiazem, or dronedarone: In patients who are taking verapamil, diltiazem, or dronedarone, the dose of simvastatin should not exceed 10 mg per day.

Fusidic acid: Taking fusidic acid and simvastatin together may increase the risk of myopathy / striated muscle. (See Drug Interactions, Other Drug Interactions; Pharmacokinetics). Fusidic acid is not recommended during simvastatin treatment. For those patients who need systemic fusidic acid, it is necessary to consider discontinuing simvastatin throughout the fusidic acid administration. In special cases, prolonged systemic use of fusidic acid is required. For example, in order to treat severe infections, the condition of each patient should be analyzed specifically, and the need for simvastatin combined with fusidic acid should be considered under strict medical monitoring. .

CYP3A4 medium-acting inhibitors : Patients listed in the application note for drugs that have moderate inhibitory effects on CYP3A4 in combination with simvastatin, especially higher doses of simvastatin, have an increased risk of myopathy. When simvastatin is used in combination with a CYP3A4 intermediate inhibitor, it is necessary to adjust the dose of simvastatin.

Niacin (1g / day): When simvastatin was used in combination with a lipid-lowering dose (1g / day) of niacin, cases of myopathy / striated muscle were observed. In a clinical trial (median follow-up period of 3.9 years), patients at high risk of cardiovascular disease and well-controlled LDL-C levels received 40 mg / day sim with or without 10 mg ezetimibe The results of vastatin treatment showed that increasing the lipid-lowering dose (1 g / day) of niacin did not increase the benefit of cardiovascular outcomes. Therefore, when using simvastatin in combination with niacin, the benefits of combined use should be carefully weighed against their potential risks. In addition, in this trial, the incidence of myopathy in Chinese patients receiving simvastatin 40mg or ezetimibe simvastatin 10 / 40mg was approximately 0.24%, compared with that of patients receiving simvastatin 40mg or The incidence of myopathy in Chinese patients treated with ezetimibe simvastatin 10 / 40mg and slow-release laropiram 2g / 40mg was 1.24%. However, this clinical trial only evaluated Chinese patients in Asian populations. Since the incidence of myopathy in Chinese patients is higher than that of non-Chinese patients, this product and lipid-lowering dose ( 1g / day ) are not recommended. The use of acid in the Asian population. (See Drug Interactions, Other Drug Interactions).

Liver function impairment

In clinical studies, approximately 1% of adult patients receiving simvastatin experienced persistently elevated serum aminotransferases (3 times above the upper limit of normal). After intermittent or discontinuation of these patients, transaminase levels usually slowly decrease to pre-treatment levels. This elevation of transaminase is not accompanied by jaundice or other symptoms or signs, and there is no manifestation of allergies. Some of these patients have abnormal liver function tests and / or have consumed large amounts of alcohol before simvastatin treatment.

In the Nordic Simvastatin Survival Study, the number of patients with more than one transaminase elevation above the upper limit of normal during the study period did not differ significantly between the simvastatin group and the placebo group [14 (0.7%): 12 (0.6%)]. The frequency of single elevations of SGPT (ALT) in the simvastatin group reaching three times the upper limit of normal was significantly higher in the first year of the study (20: 8, P = 0.023), but it was no longer significant after that. Elevated aminotransferases led to discontinuation of treatment in 8 patients in the simvastatin group (n = 2221) and 5 patients in the placebo group (n = 2223). In the 4S study, 1986 patients treated with simvastatin had normal liver function tests (LFTs) at baseline, and only 8 (0.4%) consecutively transaminase exceeded the upper limit of normal by 3 times in 5.4 years (median follow-up period). And / or discontinuation due to elevated transaminase. The starting dose of simvastatin in all patients in this study was 20 mg, of which 37% were adjusted to 40 mg during treatment.

In two controlled clinical studies including 1105 patients, the incidence of drug-related liver transaminase continued to increase for 6 months, which was 0.7% and 1.8% in the 40 mg and 80 mg dose groups, respectively.

In the HPS study, 20,536 patients were randomly assigned to take simvastatin 40 mg daily or placebo, and the incidence of transaminases rose more than three times the upper limit of normal. In the simvastatin group and placebo group, they were 0.21% and 0.09% .

Liver function tests are recommended before treatment begins and when clinical signs follow. Special attention should be paid to patients with elevated serum transaminase, and these patients should be repeated in time and the frequency of liver function tests should be increased thereafter. If the transaminase level shows an upward trend, especially if the transaminase value rises to 3 times the upper limit of the normal value and continues to drop, the drug should be discontinued. It should be noted that alanine aminotransferase may come from muscle, so alanine aminotransferase is accompanied by an increase in creatine kinase, which may indicate myopathy (see Precautions, Myopathy / Rhabdomyolysis).

There have been very few post-market reports on the use of statins, including this product, in patients with fatal and non-fatal liver failure. If severe liver injury accompanied by clinical symptoms, and / or hyperbilirubinemia, or jaundice occurs during the treatment with this product, stop using this product immediately. If no cause is found, do not reapply this product. It 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 unexplained elevated transaminase.

As with other lipid-lowering drugs, simvastatin has been reported to have a moderate (3-fold lower than normal upper limit) increase in serum transaminase. These changes occur shortly after the start of simvastatin treatment, but are often temporary, without any symptoms, and without interruption of treatment.

Eye examination

Even without any medication, the incidence of lens opacities increases with age. Data from long-term clinical studies show that simvastatin has no adverse effects on the human lens.

Simvastatin tablets for pregnant and lactating women

Women during pregnancy

This product is contraindicated in pregnant women.

There are no safety data on simvastatin in pregnant women. No controlled clinical trials of simvastatin have been conducted in pregnant women. Congenital defects due to the use of HMG-CoA during pregnancy are also rarely reported. However, a retrospective analysis of approximately 200 patients who had used simvastatin or other closely related HMG-CoA inhibitors during the first three months of pregnancy found that the incidence of birth defects was similar to that of the general population. The number of patients reviewed in this review has statistically been able to rule out that the incidence of birth defects is no higher than 2.5 times or more common.

Although there is no clear evidence that the use of simvastatin in pregnant women causes an increase in birth defects, simvastatin can reduce mevalonate (a precursor of cholesterol biosynthesis) in the fetus. Atherosclerosis is a chronic process, so discontinuation of lipid-lowering drugs during pregnancy has little effect on the long-term effect of treating primary hypercholesterolemia. Therefore, this product is contraindicated in pregnant women, women who are planning to become pregnant or who may become pregnant. The use of this product should be suspended during pregnancy (see contraindications).

Lactating women

It is currently unknown 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 taking this product should not breastfeed (see contraindications).

Simvastatin tablets for children

The safety and effectiveness of simvastatin in patients with heterozygous familial hypercholesterolemia aged 10-17 years has been evaluated in a controlled trial in adolescent boys and girls (at least one year after menarche). Adverse events in patients treated with simvastatin were generally similar to those in the placebo group. No studies with doses greater than 40 mg were performed in this population. In this limited controlled study, simvastatin was not found to have a significant effect on the growth or sexual maturity of adolescent men or women, or on the length of the menstrual cycle in adolescent women. (See Dosage and Administration; Adverse Reactions; Clinical Trials).

Adolescent women are advised to use appropriate contraceptives when treating simvastatin (see contraindications; precautions; medication for pregnant and lactating women). Simvastatin studies have not been performed in patients younger than 10 years of age and in girls before menarche.

Simvastatin tablets for elderly

In controlled clinical studies of simvastatin in elderly patients (> 65 years), the effect of reducing total cholesterol and low-density lipoprotein cholesterol was similar to that of other populations, and the incidence of adverse reactions and laboratory abnormalities was not significant increase. However, in a clinical trial in which patients received simvastatin at 80 mg / day, patients 65 years of age and older were at a higher risk of developing myopathy, including rhabdomyolysis, than patients younger than 65 years.

4 drug interactions

Drug contraindication

The following drugs are contraindicated:

CYP3A4 strong inhibitor:

Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it does not affect the plasma concentrations of other drugs metabolized by CYP3A4. Effective CYP3A4 inhibitors (below) increase the risk of myopathy by reducing the elimination of simvastatin. Do not use drugs listed in the combined instructions that have strong inhibitory effects on CYP3A4 (for example, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors , Bopreprevir, pravavir, nefazodone). (See contraindications; precautions, myopathy / rhabdomyolysis)

Gemfibrozil, cyclosporin or danazol: combined use with simvastatin is prohibited (see contraindications; precautions,

Myopathy / rhabdomyolysis).

Other drug interactions

Other Bates :

When other fibrates other than gemfibrozil are used in combination with simvastatin, the risk of myopathy is increased; the benefits and risks should be carefully weighed when used in combination.

Niacin ( 1 g per day ) : Cases of myopathy / striated muscle lysis have been observed in combination of simvastatin with a lipid-adjusted dose of niacin (1 g / day) (see Precautions, Myopathy / Striated Muscles).

Calcium channel blockers : Verapamil, diltiazem, or amlodipine in combination with simvastatin may increase the risk of myopathy / rhabdomyolysis (see Dosage and Administration; Precautions; Myopathy / rhabdomyolysis).

CYP3A4 medium-acting inhibitors : Patients listed in the application note for drugs with moderate inhibitory effects on CYP3A4, combined with simvastatin, especially higher doses of simvastatin, may increase the risk of myopathy.

Amiodarone : The risk of myopathy / rhabdomyolysis may increase when amiodarone is used in combination with simvastatin. (See Precautions, Myopathy / Rhabdomyolysis)

Fusidic acid: Combining fusidic acid may increase cases of myopathy / striated muscle. (See Precautions, Myopathy / Striated Myolysis; Pharmacokinetics)

Colchicine: It has been reported that in patients with renal insufficiency, the combined use of colchicine and simvastatin can cause myopathy and rhabdomyolysis. Close clinical monitoring is recommended for patients who use these drugs in combination.

Other interactions

Grapefruit juice contains one or more ingredients that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of regular consumption (250 ml a cup per day) was small (by measuring the area under the concentration-time curve, the plasma HMG-CoA reductase inhibitory activity increased by 13%) and had no clinical significance. However, drinking larger amounts significantly increases the activity of plasma HMG-CoA reductase inhibitors. Therefore, drinking grapefruit juice should be avoided during simvastatin treatment (see Precautions, Myopathy / Rhabdomyolysis).

Coumarin derivatives

In a clinical study of a healthy volunteer and another patient with hypercholesterolemia, taking simvastatin 20-40 mg daily can moderately improve the anticoagulant effect of coumarin anticoagulants. According to the International Normalized Ratio of Time (INR), the prothrombin time in the healthy volunteer group was extended from 1.7 to 1.8 seconds at baseline, and the hypercholesterolemia group was extended from 2.6 to 3.4 seconds. For patients using coumarin anticoagulants, the prothrombin time should be measured before using simvastatin and often measured at the beginning of treatment to ensure that there is no significant change in prothrombin time. Once the stable prothrombin time is recorded, patients should be advised to monitor the prothrombin time regularly while taking coumarin anticoagulants. If the dose of simvastatin is adjusted or the drug is discontinued, the above steps should be repeated. For patients not taking coumarin anticoagulants, bleeding or prothrombin time changes were not related to taking simvastatin.

Digoxin

One study found that taking digoxin and simvastatin at the same time slightly increased the blood concentration of digoxin. The concentration of digoxin should be monitored when using digoxin and simvastatin in combination.

Simvastatin overdose

There are a few reports of overdose; the maximum dose is 3.6g. All patients recovered without sequelae. General measures are usually taken to deal with overdose.

5 clinical trials

In the Nordic Simvastatin Survival Study (4S), the overall mortality rate for simvastatin treatment was observed. A total of 4,444 patients with coronary heart pain were observed. The baseline total cholesterol level was 212-309 mg / dl (5.5-8.0 mmol / l), and the median follow-up time was 5.4 years. In this multicenter, randomized, double-blind, placebo-controlled study, simvastatin reduced total mortality, coronary heart disease mortality, and hospital-proven risk of non-fatal myocardial infarction by 30%, 42 % And 37%. Simvastatin reduces the risk of myocardial recanalization (coronary artery bypass graft or percutaneous transluminal coronary angioplasty) by 37%. In diabetic patients, simvastatin can reduce the main coronary artery by 55% Risk of pulse events. In addition, simvastatin significantly reduced the incidence of fatal / non-lethal cerebrovascular events (stroke and transient cerebral ischemia) by 28%.

In the Heart Protection Study (HPS), the therapeutic effects of simvastatin were evaluated. A total of 20536 patients were observed with an average observation time of 5 years. These patients are associated with or without hyperlipidemia, and are at high risk for coronary heart disease events due to diabetes, history of stroke, or other cerebrovascular disease, peripheral vascular disease, or coronary heart disease. At baseline, 33% of patients had LDL levels below 116 mg / dl, 25% of patients had between 116 mg / dl and 135 mg / dl, and 42% had higher than 135 mg / dl.

In this multi-center, randomized, double-blind, placebo-controlled study, simvastatin 40 mg daily compared to placebo reduced mortality from coronary heart disease (18%) and reduced overall risk of death 13%. At the same time, simvastatin reduces the risk of major coronary events (non-fatal myocardial infarction or death from coronary heart disease), requires coronary recanalization (coronary artery bypass graft and percutaneous coronary angioplasty) and requires peripheral The proportion of non-coronary recanalization was 27%, 30% and 16%, respectively. Simvastatin can reduce the risk of stroke by 25% and the risk of hospitalization caused by angina by 17%. In patients with or without coronary heart disease. Including diabetes and peripheral vascular disease, cardio-cerebral vascular disease, simvastatin can reduce the risk of major coronary events and major vascular events (major coronary events, stroke or recanalization) by 25%. In addition, in patients with diabetes, simvastatin reduced the risk of developing macrovascular complications, including peripheral recanalization, lower extremity resection, or leg ulcers, by 21%. Regardless of the patient's age, gender, basic LDL-C, HDL-C, TG, Apo A-1, apo B levels, whether accompanied by hypertension, muscle enzyme levels at the time of enrollment reached 2.3 mg / dl, whether baseline with cardiovascular drugs (Aspirin, -receptor blocker, ACE inhibitor or calcium channel antagonist), smoking, drinking, and obesity, simvastatin reduces the risk of major vascular events and major coronary events are significant and consistent . By 5 years, 32% of patients in the placebo group had also taken statins (external treatment), so the observed reduction in risk was lower than the actual effect of simvastatin.

In a multicenter, placebo-controlled clinical study, a total of 404 patients were observed using quantitative coronary angiography, and the results showed that simvastatin could slow the progression of atherosclerosis. Reduce the progress of new injuries and occlusions. In patients receiving standard treatment, atherosclerotic damage continued to worsen over 4 years.

Results of two subgroup studies totaling 147 hypertriglyceridemia patients (Fredrickson type IV hyperlipidemia) showed that daily simvastatin 20 to 80 mg reduced TG by 21% to 39% (placebo-11% to -13%), LDL-C23% -35% (placebo + 1% to + 3%), non-HDL-C26% -43% (-1% to -3%), increase HDL-C9% -14% (3% of placebo).

Analysis of the results of another 7 subgroup of patients with abnormal serum -lipoprotein (Fredrickson type III hyperlipidemia). Simvastatin 80 mg daily reduced LDL-C (including medium density lipoprotein (IDL) by 51%) (Placebo: 8%), reduced VLDL-C + IDL by 60% (placebo: 4%).

Clinical studies in pediatric patients ( 10-17 years)

In a double-blind, placebo-controlled study, 175 (99 adolescent boys and 76 post-menarche) children aged 10-17 with heterozygous familial hypercholesterolemia (heFH) were randomized 24-week placebo or this product treatment (baseline study). The criteria for inclusion in this study also included: baseline LDL-C was between 160-400 mg / dl, and at least one of their parents had LDL-C> 189 mg / dl. The dose of this product is 10 mg for the first 8 weeks (once in the evening), 20 mg for the second eight weeks, and then 40 mg for eight weeks. After 24 weeks, 144 patients continued to take this product 40mg or placebo.

This product can significantly reduce plasma total cholesterol, LDL-C, TG, and Apo B levels. The results extended to 48 weeks were similar to those observed in the baseline study.

After 24 weeks of treatment, the average LDL-C of the 40mg dose group reached 124.9mg / dl (range 64.0-289.0mg / dl), while the placebo group was 207.8mg / dl (range 128.0-334.0mg / dl). ).

Compared with the baseline average, this product can reduce total cholesterol by 26.5% (placebo: 1.6% increase from baseline value) and reduce LDL-C by 36.8% (placebo: 1.1% increase from baseline value ). Lowering TG by 7.9% (placebo: 3.2%) reduced Apo levels by an average of 32.4% (placebo: 0.5%) and increasing HDL-C by an average of 8.3% (placebo: 3.6%).

The safety and effectiveness of daily doses above 40 mg have not been studied in children with heterozygous familial hypercholesterolemia. The long-term efficacy of pediatric patients in reducing morbidity and mortality in adulthood has not been established.

Pharmacology and Toxicology of Simvastatin Tablets

Simvastatin lowers normal and elevated low-density lipoprotein cholesterol (LDL-C) concentrations. LDL is formed by very low-density lipoprotein (VLDL), which is primarily catabolized by high-affinity LDL receptors. The mechanism of simvastatin to reduce LDL-C mainly includes: reducing the concentration of VLDL cholesterol, inducing LDL receptors, leading to a decrease in LDL cholesterol and increasing the catabolism of LDL-C. Apolipoprotein B (apo B) levels also decreased significantly during simvastatin treatment. Since each LDL particle contains a molecule of apo B, and apo B rarely appears in other lipoproteins, this also suggests that simvastatin can not only lose cholesterol from LDL, but also reduce circulating The concentration of LDL particles. In addition, simvastatin can increase the concentration of high-density lipoprotein sterols (HDL-C) and reduce plasma triglycerides (TG). All of these can lead to a reduction in total cholesterol / HDL-C and LDL-C / HDL-C.

Animal experiments, pathology, and clinical studies have demonstrated the role of LDL-C in atherosclerosis. Epidemiological studies have shown that high concentrations of total cholesterol, LDL-C, and apo B are risk factors for coronary heart disease, while higher HDL-C and apo AI levels reduce risk.

The oral LD50 of simvastatin is about 3.8 g / kg in mice and about 5 g / kg in rats.

High doses of simvastatin and related analogues to various animals showed some tissue changes. Given that the dosages used are large, and that these drugs have the effect of inhibiting mevalonate synthesis, while the target enzymes play a basic role in maintaining the homeostasis of the cell, these changes are not unexpected. A large amount of data obtained from these changes indicates that they are the extraordinary performance of the biochemical effects of these drugs at the high end of the dose-response curve. Therefore, morphological changes in rat liver, cardiac squamous epithelial hyperplasia in rats and mice, and liver toxicity in rabbits have all been directly related to inhibition of HMG-CoA reductase.

Studies in dogs have found that high doses of simvastatin cause cataracts, although the incidence is very low. Although there is no clear link between the extent of the decline in serum lipid levels and the formation of cataracts, it has been observed that simvastatin and related HMG-CoA reductase inhibitors trigger cataracts and high serum levels of the drug Consistent relationship.

When simvastatin was given to dogs at a minimum cataract-causing dose of 50 mg / kg a day, the serum concentration of the drug (expressed as a total inhibitor) was higher than the maximum expected human therapeutic dose of 1.6 mg / kg (calculated based on a 50 kg man taking 80 mg daily) The serum concentration is 5 times higher.

Elevated serum aminotransferase levels were observed in dogs receiving simvastatin. This occurs in about 10-40% of dogs receiving the test drug, and serum transaminase may rise in a slow low-level form or a transient, rapid rise. No symptoms of the disease were found in these dogs with elevated aminotransferase levels; despite continued administration, the elevated aminotransferase levels did not cause significant liver necrosis. In all dogs treated with simvastatin, no histopathological changes in their liver were observed.

Testicular degeneration was found in two simvastatin safety studies conducted with dogs. Because these effects are poorly reproducible and have nothing to do with dose, serum cholesterol level, or duration of treatment, special studies designed to clarify these changes have not been successful. No effect on testicles was found in dogs given simvastatin at 50 mg / kg a day for 2 years.

In a study given to rats simvastatin 90 mg / kg twice daily, necrosis of skeletal muscle was observed, but for rats, this dose was a lethal dose.

Reproductive and developmental toxicity

When given the maximum tolerated dose to rats and rabbits, simvastatin did not cause fetal malformations and had no effect on fertility, reproductive function or development of the newborn. However, rats taking simvastatin active hydroxyacid metabolites at 60 mg / kg daily can cause maternal weight loss, increased fetal absorption, and increased skeletal muscle malformations. Continued research using this metabolite found that fetal absorption and skeletal muscle malformations are secondary reactions that occur only in rodents and are maternal toxicity (pregastric damage accompanied by maternal weight loss), with few possible direct effects Results in developing fetuses. Although it has not been tested with simvastatin, pregnant rats use other similar HMG-CoA reductase inhibitors at 80 mg / kg and 400 mg / kg daily (based on body surface area mg / m ² , which are the maximum recommended therapeutic doses, respectively). 10x and 52x) studies have shown that it can reduce fetal plasma mevalonic acid levels.

Genotoxicity and carcinogenicity

A wide range of in vitro and in vivo genotoxicity tests have been performed on simvastatin and L-654,969. These tests include mutagenesis of microorganisms, mutagenesis of mammalian cells, analysis of single-stranded DNA breaks, and tests of chromosomal aberrations. The results of these studies failed to provide evidence of an interaction between simvastatin or L-654,969 and genetic material. These studies were performed at the highest soluble non-cytotoxic concentration tested in an in vitro analysis system, or the largest in vivo Performed at a tolerated dose.

Initially in rats and mice, the doses used by the Carcinogenicity Institute for Simvastatin ranged from 1 mg / kg to 25 mg / kg per day. There was no evidence of any tumor-related tumor types in any tissue of the mice. In female rats receiving simvastatin 25 mg / kg daily (equivalent to 16 times the maximum recommended human dose), the incidence of thyroid follicular adenomas increased statistically (p0.05). . This benign tumor is limited to female rats; no similar changes were seen in male rats or female rats receiving lower doses (up to 5 mg / kg daily). These tumors are a reflection of secondary effects of simvastatin-mediated increased thyroid hormone clearance in female rats. No statistically significant increase in the incidence of other tumors was found in all tissues of rats receiving simvastatin.

Data from these two studies indicate that squamous epithelial cell proliferation of the cardia sinus occurred at all dose levels. These changes to the stomach are limited to a certain anatomical structure that has not been found in humans. However, it had no effect on the same cells in other parts (esophagus and anorectal junction of rats, mice and dogs).

Another 73-week carcinogenicity study was performed in mice receiving simvastatin up to 400 mg / kg daily (based on a human body weight of 50 kg, which is equivalent to 250 times the maximum recommended human dose). It showed increased incidence of hepatocellular adenoma and hepatocellular carcinoma, lung adenoma, and para- lacrimal adenoma. Based on the results of this study and another initial 92-week carcinogenicity study in mice, the ineffective dose was determined to be 25 mg / kg daily (equivalent to 16 times the maximum recommended human dose).

A 106-week carcinogenicity study was performed in rats receiving simvastatin doses ranging from 50 mg / kg to 100 mg / kg daily (equivalent to 31 to 63 times the maximum recommended human dose). This indicates that the incidence of hepatocellular tumors shows an increase related to medication. The ineffective dose of 25 mg / kg daily (equivalent to 16 times the maximum recommended human dose) is the same as the results of previous carcinogenicity studies. At the same time, an increased incidence of thyroid hyperplasia has been observed; however, this result is consistent with previous findings that this is a species-specific response that has no effect on people.

Pharmacokinetics of Simvastatin Tablets

Simvastatin is highly selective for the liver after oral administration, and its concentration in the liver is significantly higher than other non-target tissues. Most of the simvastatin undergoes extensive first-pass absorption in the liver, mainly acting on the liver, and subsequently Excreted by bile. Only less than 5% of the active ingredient of simvastatin is found in the periphery, and 95% of it can bind to plasma proteins.

A pharmacokinetic trial showed that simultaneous administration of diltiazem caused a 2.7-fold increase in simvastatin acid exposure, presumably due to the inhibitory effect of CYP3A4 (see Precautions, Myopathy / Rhabdomyolysis).

A pharmacokinetic trial showed that concurrent exposure to amlodipine resulted in a 1.6-fold increase in simvastatin acid exposure (see Precautions, Myopathy / Rhabdomyolysis).

A pharmacokinetic test showed that a 2 g single-dose sustained-release nicotinic acid in combination with simvastatin 20 mg could lead to an increase in the AUC of simvastatin and simvastatin and an increase in plasma Cmax of simvastatin (see note Matters, myopathy / rhabdomyolysis).

The specific metabolic pathway of fusidic acid in the liver is unknown, but it is still suspected that fusidic acid interacts with HMG-COA reductase inhibitors metabolized by CYP-3A4 (see Precautions, Myopathy / Rhabdomyolysis).

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