What Are the Differences Between Simvastatin and Lovastatin?

Simvastatin Simvastatin was extracted from Aspergillus terreus. It was first developed by Merck Pharmaceuticals and began to be used for medical purposes in 1992. The drug is listed on the World Health Organization's list of essential drugs and is one of the essential drugs in the basic medical system ^[1] . As an oral hypolipidemic drug, the common trade name is "Zoctor". This product is taken during exercise, dieting, and weight loss to avoid blood lipids. In addition, simvastatin may reduce the chance of an attack in those at high risk for heart disease. Serious side effects include myopathy, liver damage, and elevated blood sugar. Common side effects are constipation, headaches, and nausea. People with kidney problems should reduce the dose. There is evidence that taking the drug during pregnancy can cause harm to the fetus, and the product should not be used during breastfeeding. Simvastatin is a HMG-CoA reductase inhibitor, which inhibits the liver from making cholesterol.

Simvastatin Simvastatin was extracted from Aspergillus terreus. It was first developed by Merck Pharmaceuticals and began to be used for medical purposes in 1992. The drug is listed on the World Health Organization's list of essential drugs and is one of the essential drugs in the basic medical system ^[1] . As an oral hypolipidemic drug, the common trade name is "Zoctor". This product is taken during exercise, dieting, and weight loss to avoid blood lipids. In addition, simvastatin may reduce the chance of an attack in those at high risk for heart disease. Serious side effects include myopathy, liver damage, and elevated blood sugar. Common side effects are constipation, headaches, and nausea. People with kidney problems should reduce the dose. There is evidence that taking the drug during pregnancy can cause harm to the fetus, and the product should not be used during breastfeeding. Simvastatin is a HMG-CoA reductase inhibitor, which inhibits the liver from making cholesterol.

Drug Name

Simvastatin

Alias

Simvastatin dispersible tablets Xinco

Foreign name

simvastatin Capsules

Main indications

Clinically used to treat hypercholesterolemia, coronary heart disease

Introduction to Simvastatin Compounds

Simvastatin Basic Information

Chinese name: Simvastatin

Chinese alias: Sivastine; Shu Jiangzhi; Sevastopol; Ze Zhihao; Xi Zhida; Shu Jiangzhi; Xinvastatin; Xin Ke; Svastatin; Svastatin; Merck

English name: simvastatin

English alias: Zocord; Lipex; Lipovas; ZOCOR; simvasterol; Sivastatin

CAS number: 79902-63-9

Molecular formula: C ₂₅ H ₃₈ O ₅

Molecular weight: 418.56600

Exact mass: 418.27200

PSA: 72.83000

LogP: 4.58560 ^[1]

Physical and Chemical Properties of Simvastatin

Appearance and properties: white to off-white crystalline powder

Density: 1.11 g / cm ³

Melting point: 139 ° C

Boiling point: 564.9ºC at 760 mmHg

Flash point: 184.8ºC

Refractive index: 1.53

Storage conditions: low temperature, ventilated, dry and closed light

Simvastatin Safety Information

Packing level: III

Danger category: 9

Dangerous Goods Transport Code: 3077

Danger category code: R36 / 37/38

Safety instructions: S26; S36

RTECS number: EK7798000

Dangerous goods mark: Xi ^[1]

Production method of simvastatin

Lovastatin (I, 50.30 g, 0.124 mo1) and n-butylamine (42 ml, 0.42 mo1) were mixed at 25 ° C: and then heated at 80 ° C for 1 h. After cooling at 25 ° C, excess n-butylamine was distilled off under reduced pressure to obtain 59.4 g of compound (II) with a yield of 100%, which was directly used in the next reaction. The crude product of the compound (II) obtained above was dissolved in 132 ml of dimethylformamide at 25 ° C, and imidazole (19.59 g, 0.288 mo1) and tert-butyldimethylsilyl chloride (TBSCl, 44.4 g, 0.288 mo1) were added. , Heated at 60 for 6h. Cool to 12 ° C, add anhydrous methanol (5.8ml, 0.143mol), stir at 15 ° C for 30min, add 1.5L of cyclohexane and 750ml of 5% sodium bicarbonate solution, and stir vigorously. The layers were separated and the cyclohexane layer was separated and washed with 750 ml of 5% sodium bicarbonate solution and 750 ml of water. Concentrate to .580ml at normal pressure, add 600ml tetrahydrofuran dried with molecular sieve, and concentrate to 870ml at normal pressure. HPLC showed that 86.9g of compound () was obtained with a yield of 99%, which was directly used in the next reaction. Molecular sieve dried pyrrolidine (25.1ml, 0.301mo1) and 192ml tetrahydrofuran were mixed, cooled to -18 ° C, and a solution of n-butyllithium in hexane (1.60mol / L, 181ml, 0.290mo1) was added and maintained at -10 ° Add it in about 15min, and then react for another 15min at -20 . The lithium pyrrolidine solution thus obtained was cooled to -20 ° C until use. The tetrahydrofuran-cyclohexane solution of the compound (III) obtained above was cooled to -35 ° C, and under vigorous stirring, a pyrrolidinyl lithium solution cooled to -20 ° C was added and maintained at -30 ° C. After the addition is complete, stir at -35 -30 for 2h, then add methyl iodide (12.2ml, 0.196mo1) at one time. At this time, due to the exothermic reaction, the temperature will rise to 20 , and then cool to -30 , and then Stir at this temperature for 1 h. Raise to -10 and stir for 20min. Add 550ml of water, stir vigorously for 10min, separate the organic layer, and wash with 550ml of 1mol / L hydrochloric acid at 10 . It was concentrated under reduced pressure to 20% by volume, which contained compound (IV), which was used directly in the next step. To the solution of the compound (IV) obtained above was added 690 ml of methanol, 45.7 ml of water and methanesulfonic acid (1.5 ml, 0.023 mo1) were added, and the mixture was stirred at 30 ° C for 5 hours to form the compound (V), which was directly used in the next step Reaction ^[1] .

To the solution of the compound (V) obtained above, 373 ml of a 2 mol / L sodium hydroxide solution was added at 25 ° C, and the mixture was heated at normal pressure and distilled. When the gas phase temperature reached 72 to 73 ° C, the liquid phase temperature reached 78 to At 80 ° C, no more distillate was collected. The remaining solution was stirred at reflux for 2h, and then cooled to 40 ° C. Most of the methanol was distilled off under reduced pressure and diluted with 228 ml of water. Cool to 10 and adjust the pH to 6 ~ 7 with 3mol / L hydrochloric acid. Add 990ml of ethyl acetate, and continue to adjust to Ph = 5.0 with 3mol / L hydrochloric acid. After stirring, the layers were separated, the ethyl acetate layer was separated, and 225 ml of methanol was added. In 1h, add 75ml of ammonia-methanol (1: 3) solution, and then stir at 45 ° C for 15min. In 2.5h, slowly cool to -10 , and stir at -10 : 1 2h. The ammonium salt (VI) crystals were filtered off, washed with cold ethyl acetate-methanol (3.5: 1), and dried overnight at 35 ° C to obtain 51.37 ammonium salt (VI) with a yield of 90.9% (calculated as lovastatin). Analytical samples were obtained by recrystallization from acetonitrile. The crude ammonium salt (VI) was suspended in 1.03 L of toluene, and heated at 100 ° C for 6 hours under nitrogen. Cool to 25 , add 2.5g Darco KB, and stir at 25 for 30min. After filtration, the filtrate was concentrated to an oil under reduced pressure, 140 ml of cyclohexane was added, and the solution was concentrated. Another 600 ml of cyclohexane was added and completely dissolved under reflux. Cool to 10 ° C and stir for 1h. The crystals were collected by filtration, washed with 250 ml of cold cyclohexane, and dried under vacuum at 30-35 ° C to obtain 44.6 g of simvastatin with a yield of 94.2%. Recrystallized from methanol-water to obtain a sample for analysis ^[1] .

Simvastatin uses

It can reduce cholesterol, low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol ^[1] .

Simvastatin Pharmacopoeia Standard

Source (name), content (potency) of simvastatin

This product is 2,2-dimethylbutyric acid (4R, 6R) -6- [2-[(1S, 2S, 6R, 8S, 8aR) -1,2,6,7,8,8a-hexahydro -8-Hydroxy-2,6-dimethyl-1-naphthyl] ethyl] tetrahydro-4-hydroxy-2H-pyran-2-one-8-ester. Calculated on dry basis, containing C ₂₅ H ₃₈ O ₅ should be 98.0% 102.0%.

Simvastatin traits

This product is white or off-white powder or crystalline powder.

This product is soluble in acetonitrile, ethanol or methanol and insoluble in water.

Specific rotation

Take this product, weigh it accurately, add acetonitrile to dissolve and quantitatively dilute it to make a solution containing about 5mg per 1ml, and measure it at 25 ° C according to the law (Appendix VIE of the second edition of the Pharmacopoeia, 2010 edition). The specific rotation is + 285 ° to + 298 °.

Simvastatin identification

(1) In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.

(2) Take this product, dissolve and dilute it with acetonitrile to make a solution containing about 10g per 1ml, and measure it at the wavelengths of 231nm, 238nm, and 247nm by UV-visible spectrophotometry (Appendix IVA of Pharmacopoeia Part II of 2010 Edition). There is maximum absorption.

(3) The infrared light absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Drugs", 962).

Simvastatin check

relative substance

Take an appropriate amount of this product, add a solvent [acetonitrile-0.01mol / L potassium dihydrogen phosphate solution (adjust the pH to 4.0 with phosphoric acid) (60:40)] and dissolve and dilute to make a solution containing about 0.8mg per 1ml, as Test solution (measured within 3 hours); take a precise amount, and quantitatively dilute with the above solvent to make a solution containing about 4 g per 1 ml as a control solution. According to the chromatographic conditions under the content measurement item, take 10 l of the control solution. Inject into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 20% of the full range; accurately measure 10 l each of the test solution and the control solution, and inject them into the liquid chromatograph and test solution If there are chromatographic peaks in the chromatogram with the retention time of lovastatin, the peak area should not be larger than the main solution area of the control solution (0.5%), and the area of other single impurity peaks should not be greater than 0.8 times (0.4%) of the main solution area of the control solution. The sum of the peak areas of the other impurities should not be greater than two times (1.0%) the main peak area of the control solution. Any peak in the test solution that is less than 0.05 times the main peak area of the control solution can be ignored.

Loss on drying

Take this product and dry it under reduced pressure at 60 ° C for 3 hours, and the weight loss should not exceed 0.5% (Appendix L of Part Two of the Pharmacopoeia, 2010 Edition).

Residue on ignition

Take 1.0g of this product and check it according to law (Appendix N of Part Two of the 2010 Pharmacopoeia). The residual residue shall not exceed 0.1%.

Heavy metal

Take the residue left under the item of burning residue and check it according to law (Appendix H of the second edition of the Pharmacopoeia of 2010 Edition, the second method H), the content of heavy metals must not exceed 20 parts per million.

Determination of Simvastatin

It was determined by high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 Edition).

Chromatographic conditions and system suitability tests

Use octadecylsilane bonded silica as filler (column size is 4.6mm × 33mm, particle size is 3m or equivalent performance); use acetonitrile-0.1% phosphoric acid solution (50:50) as mobile phase A, 0.1% phosphoric acid The acetonitrile solution was mobile phase B, and the gradient elution was performed according to the following table; the flow rate was 3.0 ml per minute; the detection wavelength was 238 nm. Take 20mg of simvastatin reference product, put it into a 50ml measuring bottle, add 5ml of a 0.2mol / L sodium hydroxide solution-acetonitrile (1: 1) mixed solution, shake to dissolve, leave it for 5 minutes, and add diluted hydrochloric acid to neutralize , Dilute to the mark with the solvent under the relevant substance to obtain a simvastatin acid solution containing a ring-opening degradation product; take about 2 mg of each of the lovastatin reference substance and the simvastatin reference substance, place them in the same 100ml volumetric flask, and add 5ml of vastatin acid solution, dissolved with solvent and diluted to the mark, shake well, as a system suitability test solution, take 10l into the liquid chromatograph, record the chromatogram, the resolution between the simvastatin acid peak and the lovastatin peak Should meet the requirements, the resolution between the lovastatin peak and the simvastatin peak should be greater than 4.0, and the theoretical plate number calculated based on the simvastatin peak should not be less than 2000.

Time (minutes)	Mobile phase A (%)	Mobile phase B (%)
0	100	0
4.5	100	0
4.6	95	5
8.0	25	75
11.5	25	75
11.6	100	0
13	100	0

Assay

Take about 40mg of this product, weigh it accurately, put it in a 100ml measuring bottle, dissolve it with solvent and dilute it to the mark, shake it, and accurately measure 10l into the liquid chromatograph and record the chromatogram; Method determination. Calculate the peak area according to the external standard method to get ^[2] .

Simvastatin Categories

Hypolipidemic drugs.

Simvastatin Storage

Store in a sealed, nitrogen-filled, cool place.

Simvastatin preparation

(1) Simvastatin tablets (2) Simvastatin capsules

Simvastatin Drug Description

Simvastatin classification

Circulatory System Drugs> Blood Lipid Regulation and Anti-atherosclerotic Drugs> HMG CoA Reductase Inhibitors

Pharmacological effects of simvastatin

This product is a hydroxymethylglutaryl coenzyme A (HMG-COA) reductase inhibitor, which inhibits the synthesis of endogenous cholesterol and is a lipid regulator. Literature data show that it can reduce total cholesterol (TC) content in serum, liver and aorta of hyperlipidemia rabbits, reduce very low density lipoprotein cholesterol (VLDL-C), low density lipoprotein cholesterol (LDL-C) The role of level.

Pharmacokinetics of Simvastatin

Simvastatin is highly selective for the liver after oral administration, and its concentration in the liver is significantly higher than that of other non-target tissues. Most of the simvastatin is absorbed by the liver tissues, mainly acting in the liver, and then from the bile excretion. Only less than 5% of oral simvastatin active structures are found in the periphery, and 95% of them bind to plasma proteins.

Simvastatin contraindications

(1) Those who are allergic to any component of this product.

(2) Active hepatitis or unexplained persistent elevated serum aminotransferase.

(3) Pregnant and lactating women.

Simvastatin indications

1. Hyperlipidemia:

(1) For patients with primary hypercholesterolemia, heterozygous familial hypercholesterolemia, or mixed hypercholesterolemia, when diet control and other non-drug treatments are not ideal, simvastatin can be used to reduce elevation Of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. And simvastatin increases high-density lipoprotein cholesterol, thereby reducing the ratio of low-density lipoprotein / high-density lipoprotein and total cholesterol / high-density lipoprotein.

(2) For patients with homozygous familial hypercholesterolemia, when diet control and non-dietary therapy are not ideal, simvastatin can be used to reduce elevated total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B.

2. Coronary heart disease. For patients with coronary heart disease, simvastatin is used to:

(1) Reduce the risk of death.

(2) Reduce the risk of coronary heart disease death and non-fatal myocardial infarction.

(3) Reduce the risk of stroke and transient ischemia.

(4) Reduce the risk of myocardial recanalization surgery (coronary artery bypass graft and percutaneous balloon coronary angioplasty).

(5) Delay the progression of atherosclerosis, including the occurrence of new lesions and total obstruction.

Simvastatin usage and dosage

Oral: Take it if necessary.

(1) Hypercholesterolemia: Generally, the initial dose is 10mg per day, and it is taken at night. For patients with mild to moderately elevated cholesterol levels, the initial dose is 5 mg per day. If the dose needs to be adjusted, the interval should be more than four weeks. The maximum dose is 40 mg per day. When the LDL cholesterol level drops to 75mg / dL (1.94mmol / L) or the total cholesterol level falls below 140mg / dL (3.6mmol / L), the dose of simvastatin should be reduced.

(2) Homozygous familial hypercholesterolemia: Based on the results of a controlled clinical study, for patients with homozygous familial hypercholesterolemia, it is recommended that simvastatin be taken at 40 mg / d in the evening, or 20 mg in the morning at 80 mg / d.

Side effects of simvastatin

Simvastatin is generally well tolerated, and most adverse reactions are mild and transient. In controlled clinical trials, less than 2% of patients discontinued due to adverse effects of simvastatin.

In the clinical trials of the existing control group, the incidence of drug-related adverse reactions (divided into possible, suspicious, or positive) greater than or equal to 1% was: abdominal pain, constipation, flatulence. Adverse reactions with a incidence of 0.5% to 0.9% include fatigue, weakness, and headache. Reports of myopathy found to be rare.

The following adverse reactions have been reported in clinical trials without control group or post-marketing applications such as nausea, diarrhea, rash, indigestion, pruritus, hair loss, dizziness, muscle spasms, myalgia, pancreatitis, paresthesia, peripheral Neuropathy, vomiting, and anemia; rhabdomyolysis and hepatitis / jaundice are rare.

Significant allergic reaction syndromes that include one or more of the following characteristics are rarely reported, such as angioedema, lupus-like syndrome, rheumatic polymyalgia, vasculitis, thrombocytopenia, eosinophilia, Increased ESR, arthritis, joint pain, urticaria, light sensitivity, fever, flushing, dyspnea, and discomfort.

Laboratory tests have found that significant and persistent increases in serum aminotransferases are rarely reported. Liver function tests were abnormal or transient. Elevated serum phosphocreatine kinase (CK) from skeletal muscle has also been reported.

Simvastatin notes

1. Patients should receive a standard cholesterol diet before treatment with simvastatin and continue to use it during treatment.

2. Liver response. This medicine should be used with caution in patients with heavy alcohol consumption and / or history of liver disease. Simvastatin should be disabled in patients with active liver disease or unexplained elevated aminotransferases.

In clinical trials, a small number of patients taking simvastatin have significantly increased serum aminotransferases (more than three times the normal value). However, after stopping the drug, the aminotransferase can return to the level before treatment, but there is no jaundice or other related clinical symptoms or signs, and there is no allergy. It is recommended that patients with elevated aminotransferases before treatment should be strengthened and paid more attention. If the patient's aminotransferase continues to rise, especially if the aminotransferase rises more than three times the normal value and remains persistent, the drug should be discontinued.

As with other lipid-lowering drugs, moderately elevated aminotransferases (three times lower than normal) have been reported in patients treated with simvastatin. These changes usually occur shortly after treatment with simvastatin, but are generally transient and without any symptoms, so there is no need to stop the drug.

3. Muscle response. Patients treated with simvastatin generally have mild transient increases in creatine kinase (CK, from skeletal muscle), but these have no clinical significance.

Patients with diffuse myalgia, muscle weakness, and / or a significant increase in creatine kinase (CK) (more than ten times the normal value) should be considered as myopathy, so patients should be asked if they find an unexplainable Tell your doctor about signs of myopathy. If a significant increase in creatine kinase (CK) is found or myalgia is diagnosed or suspected, simvastatin treatment should be stopped immediately.

For patients with myopathies implied by acute or severe conditions, and patients with a tendency to secondary acute renal failure due to rhabdomyolysis, treatment with methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors should be stopped.

4. Eye examination. Even without any medication, the incidence of lens opacity increases with age. Long-term clinical studies have shown that simvastatin has no adverse effects on the human lens.

5. Homozygous familial hypercholesterolemia. Due to the complete lack of low-density lipoprotein (LDL) receptors in patients with homozygous familial hypercholesterolemia, simvastatin is less effective in treating such patients.

6. Hypertriglyceridemia. Simvastatin only has a moderate effect on reducing triacylglycerol, and is not suitable for the treatment of abnormal conditions mainly with elevated triacylglycerol (such as type I, IV, and V hyperlipidemia).

7. This product should be used with caution in patients with excessive alcohol consumption and / or previous liver disease history.

Women medication

1. There are no data on simvastatin for pregnant women. Simvastatin is contraindicated during pregnancy. Because atherosclerosis is a chronic process, discontinuation of lipid-lowering drugs during pregnancy has little effect on the long-term effects of treating primary hypercholesterolemia. And cholesterol and other products of its biosynthetic pathway are essential components of fetal development, including the synthesis of steroids and cell membranes. Because methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors such as simvastatin can reduce cholesterol synthesis, but also can reduce other products of the cholesterol biosynthetic pathway. So pregnant women taking simvastatin may harm the fetus. Among women of childbearing age, simvastatin can only be used for women who are less likely to become pregnant. If a woman becomes pregnant while taking the medication, simvastatin should be discontinued and informed of the possible damage to the fetus.

2. It is not known whether simvastatin and its metabolites are secreted by human milk because many drugs are secreted by human milk and have potentially serious side effects, so women taking simvastatin should not give breast milk.

Medication for children

The safety and effectiveness of pediatric medications have been established. 2008 SFDA approved for children with heterozygous familial hypercholesterolemia (age 10-17).

For children with heterozygous familial hypercholesterolemia. (10-17 years), the recommended starting dose is 10 mg per day, once a night. The recommended dose range is 10-40 mg per day. The dosage used should be adjusted individually according to the recommended treatment goals.

Medication for elderly patients

In elderly patients (greater than 65 years), in controlled clinical trials with simvastatin, its effect on reducing total and low-density lipoprotein (LDL) cholesterol was the same as that of other populations, with adverse reactions and laboratory tests abnormal The frequency of occurrence has not increased significantly.

Simvastatin Drug Interactions

1. When Simvastatin and other drugs that have a significant inhibitory effect on cytochrome P4503A4 at therapeutic doses (such as: cyclosporine, mibecill, itraconazole, ketoconazole, erythromycin, clarithromycin And nefazodone), or a fibric acid derivative or niacin, the risk of rhabdomyolysis is increased.

2. Combining this product with methyl glutaryl coenzyme A (HMG-COA) reductase inhibitors will increase the incidence and severity of myopathy. These drugs include gemfibrozil and other fibrates, and Lipid dose of niacin (1 g / d or more). In addition, high levels of methyl glutaryl coenzyme A (HMG-COA) reductase inhibitors in plasma also increase the risk of myopathy. Simvastatin and other methylglutaryl coenzyme A (HMG-COA) reductase inhibitors are metabolized by the isoenzyme 3A4 of cytochrome P450. Several drugs that have a significant inhibitory effect on this metabolic pathway at therapeutic doses can increase blood levels of methylglutaryl coenzyme A (HMG-COA) reductase inhibitors and thus increase the risk of myopathy. These drugs include cyclosporin, tetrahydronaphthols, calcium channel blockers mibedil, itraconazole, ketoconazole and other antifungal azoles, macrolide antibiotics erythromycin and carat Mycin, and the antidepressant nefazodone.

3. Coumarin derivatives: Clinical studies have found that simvastatin can moderately improve the anticoagulant effect of coumarin anticoagulants. Therefore, in the early application of anticoagulant therapy and simvastatin in adults, the prothrombin time should be checked multiple times to confirm that there is no significant change in the prothrombin time. When patients taking couma derivatives have a stable prothrombin time, it is still recommended to continue monitoring the prothrombin time within a fixed period. If there is a change in the dose of simvastatin, the same procedure should be followed. In patients not taking anticoagulants, simvastatin treatment has never been reported to have an effect on bleeding or prothrombin time.

Simvastatin poisoning

Simvastatin (Su Jiangzhi) is used to treat hypercholesterolemia in order to inhibit HMG-CoA reductase, reduce endogenous cholesterol synthesis, and reduce serum TC, LDL-C, VLDL-C levels. The usual amount is 10 to 20 mg each time, 1 to 2 / d. Mainly damage the gastrointestinal tract, liver, muscles and allergic reactions.

Clinical manifestation

Adverse reactions are as follows:

Digestive system

Such as abdominal pain, constipation, bloating, nausea and so on.

Liver

Such as elevated serum transaminase and bilirubin.

3. Muscle

Such as elevated serum creatine phosphate kinase (CPK), myalgia, fatigue, weakness, and rhabdomyolysis.

4. Allergies

Such as urticaria, joint pain, angioedema.

5. Other

Such as headache, insomnia, thrombocytopenia, skin paresthesia and hair loss.

treatment

The main points of treatment of simvastatin poisoning are:

1. Stop the medicine immediately.

2. Liver protection treatment.

3. Other symptomatic and supportive therapies ^[3] .

Simvastatin Storage

Sealed and stored below 30 ° C. Prevent transient temperature from exceeding 50 ° C.

Simvastatin Expert Reviews

Large evidence-based medicine studies abroad have shown that using simvastatin to treat patients with hypercholesterolemia, oral administration of 5 to 10 mg twice daily, TC decreased by 27%, LDL-ch decreased by 34%, TG decreased by 10%, and HDL Up 9%, the effect of simvastatin is better than that of pravastatin, a similar product, in the treatment of primary hypercholesterolemia. Simvastatin is used to treat heterozygous familial hypercholesterolemia. This disease is due to genetic defects. Their LDL receptors on the cell membrane are half as normal. After 8 weeks of simvastatin treatment, stable effects can also occur. LDL -ch decreased by 43% to 85%, TG decreased by 21% to 38%, and adverse reactions were rare ^[4] .

Information on Simvastatin Adverse Reactions

The adverse drug reaction information notification system is a system established by China's drug regulatory authorities to ensure public drug safety. The "Adverse Drug Reaction Information Bulletin" was released to the public and played an active role in promoting the monitoring of adverse drug reactions in China and ensuring the safety of medication for the general public.

The foreign information edition of the "Adverse Drug Reaction Information Report" mainly introduces the latest safety information released by the national drug regulatory authority, analyzes the background of safety information release and related technical data, and refers to the clinical use of notified varieties in China, and evaluates its The security of our country. The foreign information edition of the "Adverse Drug Reaction Information Bulletin" was issued to allow the general public, especially medical workers, to fully understand and grasp the latest monitoring information of adverse drug reactions, reduce or avoid the recurrence of serious adverse reactions, and thus protect the public's medication Build an effective barrier to safety.

The variety notified in this issue is Simvastatin. Due to the finding that the combined use of this product with amiodarone or high-dose use increased the risk of rhabdomyolysis, foreign drug regulatory agencies issued relevant warning information. Considering that this risk also exists in China's clinical application, and other serious adverse drug reactions of simvastatin cannot be ignored, in order to make the medical staff, drug manufacturers and the public understand the safety of the drug, guide the rational use of drugs The risk of this breed is notified in the form of "foreign information version".

Be wary of simvastatin combined with amiodarone or high doses increase the risk of rhabdomyolysis

Simvastatin is a lipid-lowering drug suitable for patients with hyperlipidemia, coronary heart disease combined with hypercholesterolemia, and children with heterozygous familial hypercholesterolemia. Foreign drug regulatory authorities have released safety information about the use of simvastatin to cause serious muscle damage. Considering that this risk also exists in clinical use in China, the National Center for Adverse Drug Reaction Monitoring has issued this information notice.

Simvastatin adverse reactions abroad

(A) U.S. warns of serious muscle damage risk of simvastatin

The U.S. Food and Drug Administration (FDA) has issued a notice stating that the risk of muscle damage is highest with simvastatin, the highest approved dose of 80 mg, compared with low-dose simvastatin and other "statin" drugs.

Muscle damage (also known as myopathy) is a known adverse reaction to all statins, and patients often experience muscle pain, tenderness, weakness, and elevated blood creatine kinase. The higher the statin dose, the greater the risk of myopathy. The risk of myopathy may also increase when simvastatin (especially high doses) is used in combination with certain drugs.

The most serious myopathy is called rhabdomyolysis. In addition to muscle damage, patients with this disease may also develop severe kidney damage and even develop kidney failure and cause death. Myopathy and rhabdomyolysis have been included in the instructions for simvastatin and other "statin" drugs.

This announcement is based on clinical data being evaluated by the FDA, the "Study on the Effectiveness of Lowering Cholesterol and Homocysteine" (SEARCH). The SEARCH trial evaluated the major cardiovascular events in 6031 patients taking 80mg simvastatin and 6033 patients taking 20mg simvastatin. Preliminary results showed that patients with myopathy in the 80mg simvastatin group had myopathy compared to the 20mg simvastatin group. More (52 cases [0.9%] vs. 1 case [0.02%]).

Further analysis of the original data by the FDA showed that rhabdomyolysis occurred in 11 patients in the 80 mg simvastatin group, while no cases of rhabdomyolysis occurred in the 20 mg group. FDA will update this risk information after completing the assessment.

(B) simvastatin combined with amiodarone increases the risk of rhabdomyolysis

In addition to safety risk information for high-dose simvastatin, the US Food and Drug Administration (FDA) has previously issued a safety announcement regarding the combination of simvastatin (including simvastatin-containing compounds) with amiodarone. The announcement states that simvastatin in combination with amiodarone has the risk of causing rare rhabdomyolysis and can cause kidney failure or death. The risk of this risk is dose-related and will increase when the daily dose of simvastatin exceeds 20 mg.

Simvastatin's prescribing information was updated in 2002 to warn of a new risk, rhabdomyolysis, when simvastatin is used in combination with amiodarone in daily doses greater than 20 mg. Despite this warning added to simvastatin's prescribing information, the FDA continues to receive reports of rhabdomyolysis in patients taking amiodarone and simvastatin (especially when the daily dose of simvastatin exceeds 20 mg).

All statins, whether or not they are used in combination with amiodarone, are at risk for rhabdomyolysis. But compared with other statins, simvastatin and amiodarone are more at risk for rhabdomyolysis.

The risk of rhabdomyolysis increases when higher doses of simvastatin are used in combination with amiodarone. Although the exact mechanism is not clear, it is related to the inhibition of cytochrome P450 3A4 enzyme by amiodarone, which is the enzyme that promotes the metabolism of simvastatin. When there is a risk of this interaction, prescribers should consider using other statins instead of simvastatin.

(3) Simvastatin interacts with other drugs to increase the risk of myopathy

The FDA approved amendments to simvastatin's instructions to warn Chinese patients not to use 80mg simvastatin in combination with lipid-lowering niacin products, and should also use simvastatin and niacin products in combination at 40mg or lower. careful. Because the interim results of the ongoing "Cardioprotection Study 2" (HPS2) show that the use of 40mg simvastatin in combination with lipid-lowering niacin products (1g / day) in Chinese patients, the incidence of myopathy (0.43%) The incidence of myopathy was higher than that of non-Chinese patients (0.03%).

In addition, due to the increased risk of myopathy, the FDA also requires manufacturers to modify the simvastatin instructions, stressing that if patients are taking diltiazem, doctors should avoid prescribing simvastatin to patients in daily doses exceeding 40 mg.

Dose restrictions for simvastatin include: simvastatin cannot be used in combination with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone; The combination of qi, cyclosporine and danazol should not exceed 10 mg of simvastatin; in combination with amiodarone and verapamil, the dose of simvastatin should not exceed 20 mg; in combination with diltiazem, Xin The dose of vastatin should not exceed 40 mg.

Although simvastatin's data sheet contains warnings on dose restrictions and drug interactions, a 2010 FDA review of prescription drug use data found that patients who are using drugs that increase the risk of rhabdomyolysis will still be prescribed high Dose of simvastatin.

Domestic adverse reactions to simvastatin

From January 1, 2009 to May 31, 2010, the National Adverse Drug Reaction Monitoring Center Case Report Database received a total of 1,447 cases of adverse drug reactions / events related to simvastatin, with a total of 1,868 adverse reactions.

The main adverse reactions are:

Digestive system: such as nausea, vomiting, diarrhea, abdominal pain, abnormal liver function, etc .;

Skin and accessory damage: such as rash, itching, maculopapular rash, hair loss, etc .;

Central and peripheral nervous system damage: headache, dizziness, dizziness, insomnia, visual abnormalities, drowsiness, etc .;

Musculoskeletal system: such as muscle pain, rhabdomyolysis, elevated creatine phosphokinase, joint pain, etc .;

Systemic damage: such as weakness, allergic reactions, fever, etc .;

Blood system: Leukopenia, thrombocytopenia.

Of the 1,447 reports on musculoskeletal and metabolic damage, 101 cases of myalgia were reported, followed by 24 cases of rhabdomyolysis and 22 cases of joint pain.

From January 1, 2004 to May 31, 2010, the National Center database received a total of 5 cases of "simvastatin" and "amiodarone" combined use, of which 2 cases of adverse reactions manifested as creatine kinase Elevated or rhabdomyolysis, 3 cases of adverse reactions were abnormal liver function.

Recommended Use of Simvastatin

Simvastatin is an effective drug for the treatment of hypercholesterolemia, but its serious adverse effects should not be ignored. Physicians are advised to understand the safety information of contraindications, adverse reactions, precautions, interactions, etc. of simvastatin in detail, and to ask patients' previous medical history and combined medications in detail before prescribing simvastatin, and seriously communicate with patients Benefits and risks.

All patients who have just started using simvastatin or are increasing their simvastatin dose should be informed of the risk of rhabdomyolysis, and require patients to see a doctor in time for unexpected muscle pain, tenderness, and weakness.

When prescribing simvastatin or medicines containing simvastatin, medical staff should be aware that the daily dose of simvastatin for patients receiving amiodarone should not exceed 20mg, and the risk of rhabdomyolysis is increased when the daily dose exceeds 20mg. .

Patients are advised to consult a medical professional in the event of muscle pain, tenderness, weakness, abnormal urine color, and unexplained weakness.

It is recommended that drug manufacturers further improve the risk warning information in product instructions and labels, and effectively transfer this information to medical staff and patients. Strengthen the monitoring of adverse reactions and adopt effective risk management measures to minimize the occurrence of adverse reactions.

Contraindications to use of simvastatin

1. Those who are allergic to any ingredient.

2. Active hepatitis or unexplained persistent serum aminotransferase elevation.

3. Combined with tetrahydronaphthol calcium channel blocker mibediil. ^[5]