他汀类与其他选择性应用于心血管系统疾病的药物间常见相互作用的管理建议

Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease

A Scientific Statement From the American Heart Association

他汀类与其他选择性应用于心血管系统疾病的药物间常见相互作用的管理建议
---美国心脏协会的科学声明


A drug-drug interaction (DDI) is a pharmacokinetic or pharmacological influence of 1 medication on another that differs from the known or anticipated effects of each agent alone.  A DDI may result in a change in either drug efficacy or drug toxicity for 1 or both of the interacting medications. Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when 1 medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion.
药物-药物相互作用 （DDI）是一种药物对另一种药物药动学或药效学的影响，有别于单个药物本身已知的或预期的效应。DDI可以导致一种药物疗效或毒性的改变，也可以是相互作用的两种药物均改变。药动学DDI导致药物吸收、分布、代谢或排泄的改变。药效学DDI 是一种药物对另一种药物药理作用产生相加、协同或拮抗作用。

This document reviews the basics of DDIs, the pharmacological differences in the various statins, and the significance of statin DDIs with select medications used to treat patients with cardiovascular disease. Recommendations on the clinical management of these DDIs are provided to enable clinicians to optimize management while minimizing untoward effects.
本文综述了DDI的基础知识，各种他汀类药物的药理差异，以及用于治疗心血管疾病时他汀类药物与部分其它药物具有显著意义的药物相互作用。关于这些药物相互作用临床管理的建议有助于临床医生优化治疗，同时尽量减少不良反应。

金属质感分割线

Recommendations for Statin-Fibrate DDIs
他汀类药物-贝特类药物DDI的建议
1. When statin-fibrate combination therapy is indicated, fenofibrate or fenofibric acid is preferred because of a reduced incidence of DDIs compared with statin-gemfibrozil combination therapy.

当具有他汀类药物-贝特类药物联合治疗指征时，首选非诺贝特或非诺贝酸，因为相比于他汀类药物-吉非罗齐联合治疗可减少DDI的发生率。

2. There are circumstances in which gemfibrozil may be the only available fibrate, cost may be a consideration, or fenofibrate may not be tolerated. Under any circumstance, the use of gemfibrozil should be avoided in combination with lovastatin, pravastatin, and simvastatin.
考虑到成本因素或非诺贝特不耐受，吉非罗齐可能会成为唯一可用的贝特类药物。但是在任何情况下，吉非罗齐应避免与洛伐他汀、普伐他汀和辛伐他汀联合使用。

3. If gemfibrozil must be used in combination with atorvastatin, pitavastatin, or rosuvastatin, consideration should be given to the use of a low statin dose to minimize risk. For example, the use of rosuvastatin in combination with gemfibrozil is included in the FDA-approved product labeling, but the labeling requires that the daily dose of rosuvastatin be limited to 10 mg daily.
如果吉非罗齐必须与阿托伐他汀、匹伐他汀或瑞舒伐他汀联合使用，应该考虑使用低剂量他汀类药物，尽量降低风险。例如，FDA批准的产品说明书中，列入了瑞舒伐他汀与吉非罗齐的联合使用，但要求瑞舒伐他汀的日剂量低于10mg。

4. Fluvastatin may be used in combination with gemfibrozil, fenofibrate, or fenofibric acid.
氟伐他汀可与吉非罗齐、非诺贝特或非诺贝酸联合使用。



Recommendations for Statin-CCB DDIs
他汀类药物-钙通道阻滞剂DDI的建议

1. Pharmacokinetic data suggest a minor increase in statin exposure with coadministration of either lovastatin or simvastatin with amlodipine, and these combination therapies may be considered.
药动学数据表明洛伐他汀或辛伐他汀与氨氯地平合用时，他汀类药物的暴露量会小幅增加，这些联合治疗是可以考虑的。

2. There is no evidence of significant interaction when amlodipine is coadministered with atorvastatin, pitavastatin, rosuvastatin, fluvastatin, and pravastatin, and these combination therapies may be considered.
当氨氯地平与阿托伐他汀、匹伐他汀、瑞舒伐他汀、氟伐他汀或普伐他汀合用时，没有显著的相互作用证据，这些联合治疗是可以考虑的。

3. Combination therapy with atorvastatin and diltiazem results in a minor increase in statin exposure and this combination therapy is reasonable.
阿托伐他汀与地尔硫卓合用可导致他汀类药物暴露量小幅增加，此联合治疗是合理的。

4. Diltiazem administered with either lovastatin or simvastatin is associated with moderate increases in statin exposure, although these combination therapies may be considered in appropriate patients.
地尔硫卓与洛伐他汀或辛伐他汀合用时，可以使他汀类药物的暴露量中等程度的增加，它们的联合治疗可考虑用于合适的患者。

5. Coadministration of verapamil with lovastatin or simvastatin results in moderate increases in statin exposure. Therefore, these combination therapies may be considered when the potential for benefit outweighs potential risks.
洛伐他汀或辛伐他汀与维拉帕米合用的结果是他汀类药物暴露量中等程度的增加。因此，这些联合治疗可以考虑用于潜在利益远大于潜在风险的患者中。

6. Doses of lovastatin or simvastatin >20 mg daily when coadministered with amlodipine are not recommended.
不推荐日剂量> 20mg的洛伐他汀或辛伐他汀与氨氯地平合用。

7. A non–CYP3A4-metabolized statin is preferred in combination with diltiazem or verapamil.
首选非CYP3A4 代谢的他汀类药物与地尔硫卓或维拉帕米合用。

8. Doses of simvastatin >10 mg daily and doses of lovastatin >20 mg daily. when used with diltiazem or verapamil are not recommended. However, it should be noted that verapamil labeling recommends a higher dose limit of lovastatin of 40 mg daily when coadministered with verapamil.
当使用地尔硫卓或维拉帕米时，不推荐合用辛伐他汀的日剂量>10mg或洛伐他汀的日剂量>20mg。然而应指出的是，维拉帕米说明书建议洛伐他汀与维拉帕米合用时的日限量更高一些，为40mg。

9. For adult patients on stable therapy with simvastatin 80 mg daily (a dose that is no longer recommended for general use), clinicians should change to a non-CYP3A4 statin such as pravastatin, rosuvastatin, or pitavastatin if therapy with diltiazem or verapamil is initiated.
对于使用日剂量80mg辛伐他汀（不再推荐作为常规使用剂量）稳定治疗的成年患者，如果开始使用地尔硫卓或维拉帕米治疗时，临床医生应改用非CYP3A4代谢的他汀类药物，如普伐他汀、瑞舒伐他汀、普伐他汀或匹伐他汀。

10. Caution should be exercised with statin-CCB combination therapy in patients of various ethnic backgrounds, particularly those of Asian descent.
他汀类药物与钙通道阻滞剂联合方案在不同的种族背景下使用应谨慎，特别是亚裔中。



Recommendations for Statin–Antiarrhythmic Agent DDIs
他汀类药物-抗心律失常药DDI的建议

1. Combination therapy with rosuvastatin, atorvastatin, pitavastatin, fluvastatin, or pravastatin and amiodarone is reasonable.
胺碘酮与瑞舒伐他汀、阿托伐他汀、匹伐他汀、氟伐他汀或普伐他汀联合使用是合理的。

2. When used in combination with amiodarone, the dose of lovastatin should not exceed 40 mg daily and the dose of simvastatin should not exceed 20 mg daily.
当与胺碘酮联合使用时，洛伐他汀的剂量不应超过每日40mg，辛伐他汀的剂量不应超过每日20mg。

3. Digoxin coadministration with any statin is reasonable if clinically indicated.
如果有临床指征，地高辛与任何他汀类药物联合使用都是合理的。

4. Higher doses of lovastatin and simvastatin may be considered if clinically indicated with close monitoring for muscle-related toxicity.
如果有临床指征，并能密切监测肌肉相关毒性，可考虑使用高剂量的洛伐他汀和辛伐他汀。

5. In patients who are already stable on lovastatin 80 mg daily or simvastatin ≥40 mg daily in combination with amiodarone, continuation of combination therapy is reasonable without dose modifications.
对那些已稳定使用日剂量80mg洛伐他汀或日剂量≥40mg辛伐他汀，并联合使用胺碘酮的病人，继续联合治疗是合理，无需进行剂量调整。

6. Dronedarone significantly increases systemic exposure of both the prodrug simvastatin and the active metabolite simvastatin acid. Therefore, the dose of simvastatin should be limited to 10 mg daily when used in combination with dronedarone.
决奈达隆可显著增加前药辛伐他汀和活性代谢产物辛伐他汀酸的全身暴露量。因此，当与决奈达隆联合使用时，辛伐他汀的剂量应限于每日10mg。

7. Although there are no specific studies evaluating lovastatin and dronedarone, it is anticipated that dronedarone may also increase the exposure of lovastatin within the same range as simvastatin.
虽然没有明确的研究来评价洛伐他汀和决奈达隆之间的相互作用，但预期决奈达隆也可能会增加洛伐他汀的暴露量，范围与辛伐他汀相同。

8. There are no clinically significant interactions between dronedarone and other statins, and these combination therapies are reasonable.
决奈达隆和其他他汀类药物不存在具有临床意义的相互作用，这些联合治疗是合理的。

9. Atorvastatin is the only statin that appears to be associated with a potential DDI when used in combination with digoxin. On the basis of the available data, patients on higher doses of atorvastatin may be at increased risk of digoxin toxicity, and closer monitoring for digoxin toxicity is recommended.
与地高辛联合使用时，阿托伐他汀是唯一的一种似乎存在潜在相关DDI的他汀类药物。根据现有的数据，患者使用高剂量的阿托伐他汀可能增加地高辛中毒的风险，建议更密切地监测地高辛毒性。



Recommendations for Statin-Warfarin DDIs
他汀类药物-华法林DDI的建议

1. Use of a statin with warfarin as combination therapy is useful when clinically indicated.
如果有临床指征，他汀类药物与华法林联合使用治疗是有用的。

2. The INR should be monitored more closely after the initiation of a statin or a change in statin dose. The impact on the INR appears lowest for pitavastatin and atorvastatin.
在开始使用他汀类药物或改变他汀类药物剂量后，应该更密切监测INR值。匹伐他汀和阿托伐他汀对INR的影响是最低的。



Recommendations for Statin-Ticagrelor DDIs
他汀类药物-替格瑞洛DDI的建议

1. Coadministration of atorvastatin with ticagrelor results in only a minor increase in statin systemic exposure and is reasonable for appropriate patients.
阿托伐他汀与替格瑞洛合用仅导致他汀类药物全身性暴露量小幅增加，对适当的病人是合理的。

2. When prescribed in combination with ticagrelor, the dose of simvastatin and lovastatin should not exceed 40 mg daily.
当开具联合使用替格瑞洛时，辛伐他汀和洛伐他汀的剂量不应超过每日40mg。

3. There are no reports of significant interactions when ticagrelor is used in combination with pravastatin, fluvastatin, pitavastatin, or rosuvastatin, and no dosing restrictions are needed.
没有替格瑞洛与普伐他汀、氟伐他汀、匹伐他汀或瑞舒伐他汀联合使用具有显著相互作用的报告，因此无给药限制。



Recommendations for Statin-Vasopressin Receptor Antagonist DDIs
他汀类药物-加压素受体拮抗剂DDI的建议

1. The combination of lovastatin or simvastatin with conivaptan is potentially harmful and should be avoided.
洛伐他汀或辛伐他汀与考尼伐坦联合使用存在潜在危害，应该避免。

2. Atorvastatin, pravastatin, fluvastatin, rosuvastatin, or pitavastatin may be considered in combination with conivaptan when clinically indicated.
有临床指征时，可考虑阿托伐他汀、普伐他汀、氟伐他汀、瑞舒伐他汀或匹伐他汀与考尼伐坦联合使用。

3. In the unlikely event of a need to use a statin while a patient is receiving conivaptan infusion, either atorvastatin or a statin that is not metabolized by CYP3A (pravastatin, fluvastatin, rosuvastatin, or pitavastatin) may be considered.
接受考尼伐坦输液的病人万一需要使用他汀类药物，可以考虑阿托伐他汀或非CYP3A代谢的他汀类药物（普伐他汀、氟伐他汀、瑞舒伐他汀或匹伐他汀）。

4. Tolvaptan may be used in combination with any statin at any approved doses.
托伐普坦可以与任何他汀类药物，以任何核准的剂量联合使用。



Recommendations for Statin–Immunosuppressive Agent DDIs
他汀类药物-免疫抑制剂DDI的建议

1. Combination therapy of lovastatin, simvastatin, or pitavastatin with cyclosporine, everolimus, tacrolimus, or sirolimus is potentially harmful and should be avoided.
洛伐他汀、辛伐他汀或匹伐他汀与环孢素、依维莫司、他克莫司或西罗莫司联合使用可能有害，应该避免。

2. The combination of rosuvastatin, atorvastatin, fluvastatin, or pravastatin with cyclosporine, tacrolimus, everolimus, or sirolimus may be considered.
可考虑瑞舒伐他汀、阿托伐他汀、氟伐他汀或普伐他汀与环孢素、他克莫司、依维莫司或西罗莫司的联合使用。

3. The combination of cyclosporine, tacrolimus, everolimus, or sirolimus with daily doses of fluvastatin, pravastatin, and rosuvastatin should be limited to 40, 20, and 5 mg daily, respectively.
与环孢素、他克莫司、依维莫司或西罗莫司的联合使用，氟伐他汀、普伐他汀和瑞舒伐他汀的日剂量应分别限于40、20和5mg。

4. The dose of atorvastatin >10 mg daily when coadministered with cyclosporine, tacrolimus, everolimus, or sirolimus is not recommended without close monitoring of creatinine kinase and signs or symptoms of muscle-related toxicity.
在没有密切监测的肌酸激酶和肌肉相关毒性症状的情况下，与环孢素、他克莫司、依维莫司或西罗莫司联合使用，不推荐阿托伐他汀的日剂量>10mg。



Recommendations for Statin-Colchicine DDIs
他汀类药物-秋水仙碱DDI的建议

1. Coadministration of rosuvastatin, fluvastatin, lovastatin, pitavastatin, or pravastatin with colchicine is reasonable when clinically indicated.
有临床指征时，瑞舒伐他汀、氟伐他汀、洛伐他汀、匹伐他汀或普伐他汀与秋水仙碱联合使用是合理的。

2. Combination therapy with atorvastatin or simvastatin and colchicine may be considered in appropriate patients.
阿托伐他汀或辛伐他汀与秋水仙碱联合治疗可考虑用于适当的患者。

3. Patients receiving statin-colchicine combination therapy should be monitored closely for muscle-related signs and symptoms, given the potential for synergistic muscle-related toxicity.
考虑到肌肉相关毒性协同的可能，接受他汀类药物-秋水仙碱联合治疗的患者应密切监测与肌肉有关的症状和体征。

4. Colchicine dose adjustments are recommended (loading doses of no more than 0.6–1.2 mg and maintenance doses of 0.3–0.6 mg daily) when used in conjunction with a CYP3A4 or P-gp inhibitor.
与CYP3A4抑制剂 或 P-糖蛋白抑制剂一起使用时，建议调整秋水仙碱剂量（负荷剂量不超过0.6-1.2mg和维持剂量每日0.3-0.6mg）。

5. Dose reductions may be considered for atorvastatin, simvastatin, and lovastatin when coadministered with colchicine, given the potential for interactions mediated by both CYP3A4 and P-gp pathways.
当与秋水仙碱联合使用时，考虑到CYP3A4和P-糖蛋白途径介导的相互作用的可能性，可以考虑减少阿托伐他汀、辛伐他汀和洛伐他汀的用药剂量。

6. In patients with renal impairment, reduced doses of colchicine should be considered when used in combination with a statin.
在肾功能损害的患者中，当与他汀类药物联合使用时，应考虑减少秋水仙碱的剂量。



Recommendations for Statin–Heart Failure Medication DDIs
他汀类药物-心衰药物DDI的建议

1. Coadministration of a statin at an approved dose with ivabridine is reasonable when clinically indicated.
有临床指征时，批准剂量的他汀类药物与伊伐布雷定合用是合理的。

2. Lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin may be considered when used in combination with sacubitril/valsartan.
当与sacubitril/缬沙坦联合使用时，可以考虑降低阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀或辛伐他汀的给药剂量。

Circulation. 2016;134:00-00. DOI: 10.1161/CIR.0000000000000456
翻译：   范辉    王江峰
杭州逸曜药学知识研究官

谢谢

学习了。。。