ST LOUIS (MD Consult) - On March 19, 2010, the US Food and Drug Administration (FDA) issued a warning about an increased risk of muscle injury (myopathy) in patients taking the highest approved dose of the cholesterol-lowering medication Zocor (simvastatin) 80 mg, compared with patients taking lower doses of simvastatin–and possibly other drugs in the same class. Simvastatin is sold as a single-ingredient generic medication and under the brand name, Zocor. It is also sold in combination with ezetimibe as Vytorin, and with niacin as Simcor.
Myopathy is a known adverse effect of all statin medications. Patients with myopathy generally have muscle pain, tenderness or weakness, and elevated blood creatine kinase levels. The higher the dose of statin used, the greater the risk for myopathy. The risk of myopathy is also increased when simvastatin, especially at the higher doses, is used with certain other drugs (listed below).
A 2010 review of prescription drug-use data conducted by the FDA found that, despite dose limitations and drug-to-drug interaction precautions included in the simvastatin drug label, patients are continuing to receive prescriptions for higher doses of simvastatin with other medications that are known to increase the risk for rhabdomyolysis.
The FDA is reviewing data from clinical trials, observational studies, and adverse-event reports and data on prescription use of simvastatin to better understand the relationship between high-dose simvastatin use and myopathy.
Clinical trial data being reviewed include that from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial. Investigators from the SEARCH trial are examining the occurrence of major cardiovascular events over a period of 6.7 years in 6031 patients receiving 80 mg of simvastatin, compared with 6033 patients receiving 20 mg of simvastatin. All study participants have a history of myocardial infarction.
Preliminary SEARCH trial results revealed that more patients in the simvastatin 80 mg group experienced myopathy compared with patients in the simvastatin 20 mg group (52 [0.9%] cases vs 1 case [0.02%]). Furthermore, the FDA's preliminary analyses of the primary data suggest that 11 (0.02%) of the patients in the simvastatin 80 mg group experienced rhabdomyolysis compared with no patients in the simvastatin 20 mg group.
The FDA has also approved a labeling revision for simvastatin on the basis of interim results from an ongoing clinical trial known as the Heart Protection Study 2 (HPS2). The revised label states that patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products. Moreover, the revised label recommends caution when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products. The interim HPS2 results showed that the incidence of myopathy was higher in patients of Chinese descent (0.43%) compared with patients not of Chinese descent (0.03%) taking 40 mg simvastatin plus cholesterol-modifying doses (≥1 g/d) of a niacin-containing product. It is not known whether the increased risk for myopathy observed in these patients applies to other patients of Asian descent.
Additionally, the FDA has requested that the sponsor of simvastatin change the product labeling to instruct health care professionals to avoid prescribing simvastatin doses higher than 40 mg daily when patients are also taking diltiazem because of an increased risk for myopathy.
Health care professionals need to consider the potential risks and known benefits of simvastatin compared with other cholesterol-lowering therapies when deciding to prescribe simvastatin. A careful review of a patients' medications should be conducted and the potential for drug-to-drug interactions evaluated before prescribing or dispensing simvastatin. The benefits and risks, including the risk of myopathy and rhabdomyolysis, of simvastatin therapy should be discussed with patients.
Simvastatin Dose Limitations
These limitations apply to ALL patients taking simvastatin.
Do not use simvastatin with these medications:
· Itraconazole
· Ketoconazole
· Erythromycin
· Clarithromycin
· Telithromycin
· HIV protease inhibitors
· Nefazodone
Do not use more than 10 mg of simvastatin with these medications:
· Gemfibrozil
· Cyclosporine
· Danazol
Do not use more than 20 mg of simvastatin with these medications:
· Amiodarone
· Verapamil
Do not use more than 40 mg of simvastatin with this medication:
· Diltiazem
圣路易斯(MD Consult)——2010年3月19日，美国食品药品管理局(FDA)发布了一项警告，内容为，与服用较低剂量的辛伐他汀或其他他汀类药物相比，服用最高获准剂量(80 mg)的降胆固醇药物Zocor(辛伐他汀)发生肌肉损伤(肌病)的风险增加。市售的辛伐他汀为一种成分单一的常用药，商品名为Zocor。其他市售形式还有与依折麦布联合组成的复方制剂Vytorin，以及与烟酸联合组成的复方制剂Simcor。
肌病是一种所有他汀类药物的已知不良反应。肌病患者通常表现为肌肉疼痛、压痛或无力以及血肌酸激酶水平升高。使用的他汀剂量越高，发生肌病的风险就越大。当辛伐他汀与其他某些特定药物(见下表)联用时，特别是在辛伐他汀剂量较高的情况下，肌病风险亦增加。
2010年FDA对处方药使用数据进行审查发现，尽管在辛伐他汀药品说明书中对剂量进行了限制，而且列出了药物间相互作用的注意事项，但患者仍继续收到较高剂量辛伐他汀与其他已知会增加横纹肌溶解风险的药物配伍治疗的处方。
FDA目前正在对临床试验、观察研究和不良事件报告的数据以及有关使用辛伐他汀的处方数据进行审查，以便更好地理解使用高剂量辛伐他汀与肌病之间的关联。
审查中的临床试验数据源自“进一步降低胆固醇和同型半胱氨酸的有效性研究”(SEARCH)试验。SEARCH试验的研究者正对6,031例接受80 mg辛伐他汀治疗的患者6.7年内重大心血管事件的发生情况与6,033例接受20 mg辛伐他汀治者进行比较。所有受试者均有心肌梗死病史。
SEARCH试验初步结果显示，80 mg 辛伐他汀治疗组患者中肌病的发生率高于20 mg辛伐他汀治疗组[52例(0.9%) 对 1 例(0.02%)]。另外，FDA对原始数据的初步分析结果表明，80 mg辛伐他汀治疗组患者中有11例(0.02%)发生了横纹肌溶解，而20 mg辛伐他汀治疗组中为0。
基于正在进行的“心脏保护研究2”(HPS2)的中期结果，FDA还批准了辛伐他汀的说明书(修订版)。新修订的说明书标明，华裔患者不应接受80 mg辛伐他汀与胆固醇调节剂量的含烟酸药品联合治疗。而且，修正后的说明书建议，这类患者接受辛伐他汀 ≤40 mg联用胆固醇调节剂量的含烟酸药品时应谨慎行事。中期HPS2结果表明，同样是服用40 mg辛伐他汀+胆固醇调节剂量(≥1 g/d)的含烟酸药品，华裔患者中的肌病发病率高于非华裔患者。这些患者中观察到的肌病风险增加是否可以外推至其他亚裔患者，对此尚不清楚。
另外，FDA已经要求辛伐他汀赞助商更改产品说明书，以指导医护人员在患者同时还服用地尔硫卓时，鉴于肌病增加的风险，应避免所开的辛伐他汀剂量高于40 mg/d。
医护人员在决定开具辛伐他汀处方时，需要考虑辛伐他汀与其他降胆固醇治疗相比的潜在风险与已知收益；应该对患者服用的药物进行仔细审查，并在开辛伐他汀处方或发药之前对药物间相互作用的可能性进行评估；应该与患者就辛伐他汀的风险和收益进行讨论，其中包括肌病和横纹肌溶解的风险。
辛伐他汀剂量限定
这些限定适用于服用辛伐他汀的所有患者。
禁止将辛伐他汀与下列药物联用：
· 伊曲康唑
· 酮康唑
· 红霉素
· 克拉霉素
· 泰利霉素
· HIV蛋白酶抑制剂
· 奈法唑酮
禁止将10 mg以上的辛伐他汀与下列药物联用：
· 吉非罗齐
· 环孢素
· 达那唑
禁止将20 mg以上的辛伐他汀与下列药物联用：
· 胺碘酮
· 维拉帕米
禁止将40 mg以上的辛伐他汀与下列药物联用：
· 地尔硫卓
