降血脂藥物
Dyslipidemia


Atorva 10mg/tab.  Lipitor 40mg/Tab.  (Atorvatatin 10mg/40mg per Tablets)

Caduet 5mg/10mg per Tablets. (Amlodipine 5mg/Atorvastatin 10mg)

Crestor 5mg/Tab. (Rosuvastatin 5mg/Tab.)

Sivasin Film coated 20mg Tab. (Simvastatin20mg/Tab.)

Fenogal 200mg/Cap. ( Fenofibrate 200mg/Cap.)

 


各種 Statin 降血脂藥的比較

Based on U.S. product labeling and relevant studies-- Updated March 2004 

 

Lovastatin
(Mevacor)

Pravastatin
(Mevalotin)

Simvastatin
(Zocor)

Fluvastatin
(Lescol)

Atorvastatin
(Lipitor)

Rosuvastatin
(Crestor)

Potency:
Average Decrease in LDL-Chol.

20 mg: 29%
40 mg: 31%
80 mg: 40%-48%

10 mg: 19%
20 mg: 24%
40 mg: 34%
80 mg: 40%

10 mg: 28%
20 mg: 35%
40 mg: 40%
80 mg: 48%

20 mg: 17%
40 mg: 23%
80 mg: 33%

10 mg: 38%
20 mg: 46%
40 mg: 51%
80 mg: 54%

5 mg: 43%
10 mg: 50%
20 mg: 53%
40 mg: 62%

Renal Function

Use lower doses for severe renal impairment (creatinine clearance < 30 mL/min).

Use lower doses for significant renal impairment (reduce initial dose to 10 mg daily).

Use lower doses for severe renal impairment (reduce initial dose to 5 mg daily).

No dose adjustment necessary for reduced renal function. (not studied at doses >40 mg in patients with severe renal impairment).

No dose adjustment necessary for reduced renal function.

Use lower doses for severe renal impairment (creatinine clearance <30 mL/min).

Liver Function Monitoring

LFTs at baseline. Also, at 6 and 12 weeks after start of therapy or elevation of dose. Then every 6 months thereafter.

LFTs at baseline. Also, prior to elevation of dose, and when otherwise clinically indicated.

LFTs at baseline and thereafter when clinically indicated. Patients titrated to 80 mg should receive an additional test before titration, 3 months after titration, and every 6 months for the 1st year.

LFTs at baseline. Also, at 12 weeks after initiation or elevation of dose.

LFTs at baseline. Also, at 12 weeks following both the initiation of therapy and dose elevation. Check every 6 months thereafter.

LFTs at baseline. Also, at 12 weeks after initiation or elevation of dose. Then every 6 months thereafter.

Drug Interactions

Metabolized by CYP3A4 enzyme system. Watch for interactions with drugs that inhibit this enzyme including: erythromycin, clarithromycin, ketoconazole, verapamil, diltiazem, nefazodone, fluvoxamine, cyclosporine, grapefruit juice, etc.

Not significantly metabolized by cytochrome P450 and may be less likely to be involved in drug interactions. Cyclosporine can increase pravastatin levels.

Metabolized by CYP3A4 enzyme system. Watch for interactions with drugs that inhibit this enzyme including: amiodarone, erythromycin, clarithromycin, ketoconazole, verapamil, diltiazem, nefazodone, fluvoxamine, cyclosporine, grapefruit juice, etc.

Metabolized primarily by CYP2C9 enzyme system and may be less likely to be involved in drug interactions. Fluvastatin can increase levels of phenytoin. Rifampin can lower fluvastatin levels.

Metabolized by CYP3A4 enzyme system, but less than lovastatin and simvastatin. Some drugs that inhibit CYP3A4 include: erythromycin, clarithromycin, ketoconazole, verapamil, nefazodone, fluvoxamine, cyclosporine, grapefruit juice, etc.

Not significantly metabolized by cytochrome P450 and may be less likely to be involved in drug interactions. Use lower doses for patients taking cyclosporine or gemfibrozil (both drugs increase rosuvastatin levels). Rosuvastatin with warfarin results in increased INR.

Food Interactions

Take with dinner.

Take without regard to meals.

Take without regard to meals.

Take without regard to meals.

Take without regard to meals.

Take without regard to meals.

 

 

 

Statins類降血脂藥物所引發肌肉毒性

 

z 前言

    HMG-CoA還原酵素抑制劑(3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor)一般通稱為Statins類的降血脂藥物,它是臨床上眾多治療高血脂症的藥物中使用率最高的一類。拜耳(Bayer)藥廠所生產的Baycolâ(cerivastatin)因為在全球引起31例的橫紋肌溶解致死事件,所以拜耳在20018月主動將其自市場上撤回。可是另一方面,又有許多文獻指出,在急性冠狀動脈症候群(acute coronary syndrome)發生後提早使用statins類藥物可預防在短時間內再一次的急性冠狀動脈事件(acute coronary event)的發生1,2。拜耳藥廠自市場撤銷Baycolâ的舉動引起了許多正在使用其他種類statins 藥物患者的恐慌。所以Statins藥物在臨床上的益處及副作用都應該詳細地加以探討。

    高膽固醇血症及粥狀動脈硬化發生是一種長期的慢性疾病,因此長期治療是必需的。目前有許多臨床研究皆證實Statins類藥物具有正面的安全性及耐受性,而它的副作用則包括便秘、腹脹、胃口不佳及一般的腸胃不適,有時也有肝功能指數(GOT, GPT)上升之現象。較嚴重的藥物不良反應則有肌肉毒性(發生率介於1~7%之間),如肌肉病變、橫紋肌溶解(特別是在與Gemfibrozil的合併療法)

z Statins類藥物所導致的肌肉毒性2,3,4

    FDA將橫紋肌溶解(rhabdomyolysis)定義為嚴重的肌肉分解,造成creatine kinase (CK)大於10000U/L (正常值17-149U/L);而臨床試驗則將肌病變(Myopathy)定義為與肌肉有關,其CK值上升超過正常值上限(ULN)的十倍。橫紋肌溶解指的是肌肉細胞膜的完整性受到了破壞,造成細胞內容物,尤其是肌球素(myoglobin)被釋放至血漿中,大量在全身游離,可能症狀包括: 肌肉疼痛、虛弱、發燒、尿液顏色變深、噁心及嘔吐,最後可能導致急性腎衰竭甚至死亡。

    Statins類引起肌肉病變的機轉尚未知,可能是與某些受質(substrate)缺乏有關。當statins在高劑量,或因藥物交互作用使其AUC增加,或因其親脂性增加生體可用率時,均會使得substrate缺乏更加明顯,而導致肌肉病變危險性增高。

    MevalonateHMG-CoA經過HMG-CoA reductase還原產生的中間產物,同時也是許多物質的前驅物,包括與蛋白質合成有關的isopentenyl,細胞內訊息傳遞相關的geranyl, farnesyl,能量代謝有關的ubiquinone (Coenzyme Q10)。有一假說提出,ubiquinone參與粒線體電子傳遞系統,是氧化磷酸化過程重要的一環,ubiquinone缺乏是statins引起肌病變的原因。有研究報告lovastatin會降低心肌ubiquinone濃度約33%simvastatin也有同樣報告降低血清中ubiquinone濃度,這些物質若受到阻斷時,可能會造成肌肉之毒性。  

    Statins進入肝臟細胞,靠主動運輸的方式,所以肝臟內濃度與其親脂性高低無關,但在肝臟外的細胞(如肌肉細胞),則是利用擴散方式來通過細胞膜,因此,親脂性的Statins類藥物有較高的肌肉細胞穿透能力,故被認為較具有肌肉毒性,但是臨床上發生與親脂性Statins有關的肌肉炎的案例仍屬罕見。Cerivastatin在下市前是statins類中親脂性最高者,其次為simvastatin, lovastatin,接著是atorvastatin, fluvastatin,最低為pravastatin

    另一重要因素不可忽略的,statins之濃度高低也是造成肌病變的主因。有報告認為高劑量下,發生率較大,因此可以解釋的當任何原因導致其AUC增加,危險性也隨之增加。例如常見的藥物交互作用之問題,大部份的statins是藉由肝臟酵素系統(CYP)代謝,若共同服用其他相同代謝系統(substrate)、抑制劑(inhibitor)、誘導劑(inducers)時,都會影響statinsAUC的變化。例如,若同時使用會抑制CYP的藥物如Cyclosporin, ItraconazoleErythromycin,將導致Statins的生體可用率增加,因而增加了肌肉毒性的危險。

    各種不同的CYP異構物之活性並不能充分解釋為何Statins類藥物會引發肌肉毒性,因為CerivastatinCYP2C8 CYP3A4 代謝卻仍然有較高的肌肉毒性;此外Simvastatin Pravastatin同樣有肌肉毒性,但Pravastatin 卻不是由CYP 酵素系統代謝。Statins類藥物所引發的心肌毒性與劑量成正比關係。在一項實驗中PravastatinSimvastatinLovastatin 比起來有較少的肌肉毒性,其原因可能與其親水性及肌肉細胞對藥物有較低的回收率有關。

z Fibrate-statins合併療法有關的肌肉毒性5

    Statins類藥物的肌肉毒性(特別是在橫紋肌溶解方面)statinsfibrate合併療法中,是一項屬於已確認的併發症。在與Cerivastatin 橫紋肌溶解有關的致死案例中有近25%使用了CerivastatinGemfibrozil 的合併療法。Statins fibrate二者本身就已有可能引發肌肉病變,可以解釋為何當二者合併使用時有較高的危險性。

    Fibrates類藥物的降血脂作用是經由活化peroxisome proliferator- activated receptor (PPAR) 家族,特別是在PPAR-[alpha]PPAR-[gamma], fibrates類藥物在與statins類藥物合併使用時可使交互作用的危險性增加,因為PPAR家族已知能影響CYP2,3,4 的調控及功能。Fibrate類與statin類合併使用在混合型高血脂的病患,有助於降低LDL及非HDL的數值,但合併使用時必須特別小心。以下一些建議將有助於減小肌肉毒性的危險性:

1.  如果須要加入降三酸甘油酯藥物時,儘可能選用菸鹼酸類,其肌肉毒性的危險性較低;若要使用fibrates類時,fenofibrate則優於gemfibrozil,因其肌肉毒性的危險性較低。

2.  Statin類與fibrates類合併時,應使用最低的有效劑量。

3.  fibrates類在早上服用,而Statin類在晚上服用(此建議是基於理論考量,並未有証據支持可降低肌肉毒性的危險性)

4.  避免再加入其他會干擾statin代謝的藥物。

5.  教導病患去了解並報告肌肉毒性的相關症狀,如肌肉虛弱、疼痛等。

6.  如果有肌肉毒性症狀,且CK值超過正常值上限的十倍時,應停止治療。

z statins類之肌肉毒性的監測及處理方法

1.開始使用statins類治療前,應先評估病患的肌肉症狀,如肌肉疼痛或觸痛等。

2.獲得CK基準值,且開始治療後的6-12週及之後每次門診作追蹤。

3.獲得肝功能基準值,開始治療後12週及之後每年追蹤。肝功能檢查主要是監測肝臟之安全性,而非橫紋肌溶解之危險性,但因肝功能損傷會降低statins的肝臟代謝且增加肌肉毒性。

4.若有肌肉不適或虛弱,尿液顏色變茶色等,應立即回診,並重新評估CK值。

5.若病患有肌肉症狀,且CK值是正常值上限的3-10倍時,則應每週檢查CK值至穩定為止,若症狀持續進展或CK值持續上升,則應短暫停止治療或降低劑量。

6.若病患未有任何症狀,但CK值超過正常值上限的10倍,也應考慮是否要停止治療。

7.病患有肌肉症狀或CK值上升,也應考慮是否有其他疾病或新的藥物加入等因素。

z 結論

    目前對statins 類藥物所引發相關的肌肉炎,其正確的病生理機轉仍不清楚。在橫紋肌的溶解方面,因為Cerivastatin (Baycolâ)比起其他的statin有高出10倍的橫紋肌溶解率,所以它從市場中被撤銷。故statins類藥物可能具有潛在威脅生命的副作用,且此作用與劑量有關的現象不容我們忽視。

    許多statins療法的研究皆證明了以statins類藥物長期治療下對心血管有益,因此可預期全球性statins類藥物的使用量會增加。拜耳藥廠將 Cerivastatin (Baycolâ)從市場上撤銷的經驗,將可作為許多的降血脂藥上市後藥物不良反應監測的範本。無論如何,當使用statins類藥物時,需考慮的不只是治療的立即結果,也應包括了治療的準則、費用及長期治療的安全性監測等等,如此才能取其利而避其害,達到理想的藥物治療目的。 

z 參考資料

1.   Sposito, Andrei C.. Chapman, M. John. Statin Therapy in Acute Coronary Syndromes: Mechanistic Insight Into Clinical Benefit. Arteriosclerosis, Thrombosis & Vascular Biology. 2002;22,1524

2.   Straus, Sharon E. MD. Majumdar, Sumit R. MD. McAlister, Finlay A. MD. New Evidence for Stroke Prevention: Scientific Review. JAMA. 2002;288,1388

3.   Sinzinger, H. Wolfram, R. Peskar, BA. Muscular Side Effects of Statins. Journal of Cardiovascular Pharmacology. 2002;40,163

4.   Evans, Marc; Rees, Alan. The myotoxicity of statins. Curr Opin Lipidol, 2002;13 ,415

5.   Sinzinger, Helmut *+. Wolfram, Roswitha . Peskar, Bernhard A. Muscular Side Effects of Statins. Journal of Cardiovascular Pharmacology. 2002;40,163

6.   Kastrup EK et al, eds. Drug Facts and Comparisons. 55th ed. St. Louis, MO : Facts and Comparisons. 2001 : 548.  

 

Statins治療高脂血症可以預防腦中風

最近的臨床試驗以及巨量分析(meta-analyses)已証明HMG-CoA還原抑制劑(hydroxy-methylglutaryl coenzyme A reductase inhibitors, 簡稱statins)可降低有冠狀動脈疾病的病人發生缺血性腦中風的機率,不論他們有或沒有血中膽固醇上升。

  對於患有心臟血管疾病的病人使用statins已顯示出可降低中風的發生率將近30%Statins具有抗粥狀動脈硬化及抗血栓形成的特性,可能是這類藥物可降低腦血管疾病的藥理基礎。Statins可以降低動脈硬化斑塊發炎、增生和形成血栓的過程,進而減少它破裂。此外,這類藥物可改善高膽固醇血症所導致的動脈內膜功能異常和使血小板活化性(platelet activation) 逆轉,和可能降低血栓的傾向。

  高膽固醇血症已再度被凸顯為缺血性腦中風的一個危險因子,statins透過在血管內多重的良性效應提供保護以避免腦血栓。膽固醇是否為缺血性腦中風的一重要危險因子,以及statin治療對患有腦血管疾病病患所帶來的益處,有待更多的資料來支持。

  儘管已知高膽固醇血症是冠狀動脈疾病的主要危險因素,但並非是腦血管疾病的一個重要危險因子。最近的臨床報告結果顯示HMG-CoA還原抑制劑(statin)可以預防腦中風,和減緩頸動脈動脈粥狀樣硬化。這些報告指出statin治療腦血管疾病的好處和凸顯statin除了降低膽固醇外的保護作用。

  傳統上血管疾病的危險因子在不同的血管部位有不同的意義。高膽固醇血症被認為是冠狀動脈疾病的主因而對腦中風而言則意義不大。相反地,高血壓被認為是中風的一個主要危險因子,但對冠狀動脈粥樣硬化的影響而言則較不重要。高膽固醇血症和高血壓皆非冠狀動脈疾病和中風的絕對危險因子,但分別地在冠狀動脈和腦血管系統有不同的相對重要性。

  大部份的缺血性腦中風(小洞梗塞除外)是由顱外的頸動脈、aortic arch (動脈弓)或是心臟粥狀動脈硬化疾病產生的血栓、栓塞所引起的,高膽固醇血症是發展成冠狀動脈硬化的一個重要危險因子。進一步而言,冠狀動脈心臟病會增加腦中風的危險性。因此以降低膽固醇治療方式來預防心肌梗塞也應該可以減少缺血性中風的發生率。

  雖然statins可以降低顱外動脈和腦血管硬化程度,statin治療對不同類型的缺血性中風是否具有不同的預防效果,則有待探討。目前並不知statin治療是否對腦部小動脈疾病有效而因此可預防小洞梗塞(lacunes)。許多臨床的 lacunes 並非導因於lipohyalinosis,而是因動脈至動脈的栓塞。進一步而言,既然高血壓和糖尿病皆和高膽固醇血症有關,statin治療可能有改進小血管硬化之效果。

  臨床試驗結果顯示,statin治療高膽固醇血症可減少心肌梗塞的發生率達30%。除心臟血管外的益處,中風發生率也降低30%左右。事後分析Scandinavian Simvastatin Survival Study (4S)以每天20~40mg Simvastatin治療冠狀動脈疾病病人,也可以有效地降低缺血性腦中風發生率,但並不增加腦出血之機會。巨量分析顯示statin治療可降低病人有血管疾病後的腦中風危險性是可以和Aspirin的效果相比美的。

  Statins降膽固醇的效果和劑量有關,適當劑量可降低總膽固醇及LDL膽固醇達25-35%,另外可適當增加血中HDL濃度。Statins穩定粥狀動脈硬化斑塊的機轉是多方面的,其中包含降低巨噬細胞活化,減少foam cell的形成,降低tissue factors的表現,降低cytokine及免疫性活化,以及抑制平滑肌細胞增生和活化等作用。除了減少動脈硬化斑塊之大小外,尚可減緩其破裂、出血、及血栓之機會。Statins的抗增生作用可能來自於降低氧化的LDL濃度和減少膽固醇代謝合成的中間產物(isoprenoids)高膽固醇血症所導致的血管內膜功能異常也會因statins治療而改善,其中包括使血管張力正常化及減少血液流變異常。Statins也有抗血小板凝集和促進血栓溶解等作用,因此可降低血栓之傾向。

參考資料: Delanty N, Vaughan CJ: Vascular effects of statins in stroke. Stoke. 1997; 28: 2315-20


Lipitor 10mg/tab.  40mg/Tab.(Atorvastatin 10mg/40mg per Tablets)

品名規格 Atorva  10mg / Tab. Lipitor 40mg/Tab.
廠        商

 生達製藥

輝瑞大藥廠股份有限公司
代        號 OLIP OLIP40
成  份  名 Atorvastatin 10mg/Tab. Atorvastatin 40mg/Tab.
中文名稱 律脂 膜衣錠10公絲  立普妥 膜衣錠40公絲 
藥理分類

Dyslipidemia

外        觀

衛教單張

說明書

 

 

藥理作用:
為還原脢3-hydroxy-3-methylglutary coenzyme A(HMG-COa)
的抑制劑,此脢對肝的產生膽固醇是不可缺少的。

藥物動力學:
吸收:迅速由胃腸道吸收
蛋白結合率:98%以上
半衰期:14小時
作用起始時間:2週
代謝:肝
排泄:主要由膽汁,2%以下由尿
治療項目:
降低高膽固醇血症及混合不良脂血症患者
之低密度脂蛋白膽固醇及三酸甘油脂。
用法用量:
口服:由每天一次每次10mg開始可增至一天80mg。
副作用:
1全身:背痛,虛弱,過敏反應,肌痛,橫紋肌溶解。
2中樞神經:頭痛。
3胃腸:腹痛,便秘,下痢,消化不良,氣脹,肝功能試驗上昇。
4呼吸:竇炎,咽炎。
5皮膚:發疹。
注意事項:
1本劑之投與不必顧慮餐食。
2由密度蛋白質降低顯現治療效益。
3在開始治療後2∼4週內或劑量改變時監測脂質量;
 在開始治療後6和12週或增加劑量時監測肝功能,此後定期做。
4評估肌肉痛、觸痛或無力;如出現時監測肌酸酐磷酸激脢值,
 如顯著的上昇或懷疑肌病變時應停用本劑。
5與 digoxin 併用時應仔細監測 digoxin 毒性。
6如有下列症狀時立即報告:無法解釋的肌肉痛、觸痛或無力,
 尤其是帶有發燒或不適時;皮膚或眼睛黃;
 胃痛帶有噁心、嘔吐或食慾喪失;皮膚發疹或蕁麻疹。
7有下列任何藥物併用時應通知醫師;
 紅黴素、niacin、抗黴菌劑、避孕藥。
8服用本劑時,酒精的攝食應減到最小。
使用禁忌:
對本劑過敏,肌病,活動性肝疾病,
無法解釋的持續性轉胺基脢昇高,懷孕,授乳。
交互作用:
1本劑會增加 digoxin 濃度 20%,
 增加 norethindrone 與 ethinyl estradiol 口服避孕藥的濃度。
2紅徽素會增加本劑的濃度40%。
3macrolide抗生素、cycolsporine、niacin、
 clofibrate、azole抗黴素(ketoconazole、itraconazole)
 會增加本劑之危險性。

 

 



Caduet 5mg/10mg per Tablets. (Amlodipine 5mg/Atorvastatin 10mg)

 

 

品名規格 Caduet 5mg/10mg tablet 
廠        商 輝瑞大藥廠股份有限公司
代        號 OCAD
成  份  名 Amlodipine 5mg / Atrovastatin 10mg  per Tablets
中文名稱 脂脈優5毫克/10毫克 
藥理分類  
孕婦用藥分級 X 級:
不論是動物或人體的研究試驗中均顯示該藥物對胚胎有不良影響,且此藥物對懷孕婦女所產生的效益很低,則此藥對妊娠婦女或可能懷孕的婦女為禁忌使用。
外        觀

說明書


 
適應症:

因有高血壓和血脂異常這兩種可矯正的危險因子併存,而使心血管危險增加的患者;或因有心絞痛為表現之冠心病(CHD)併有可矯正的血脂異常危險因子,而使心血管危險增加的患者。

用法用量:

劑量範圍由amlodipine/atrovastain 5 mg/10 mg至10 mg/80 mg之最高劑量,每天一次。起始劑量和維持劑量應依每個成分對高血壓/心絞痛和高脂血症的效果和耐受性而個別決定。本品可在一天任何時間服用空腹、飯後服用不拘。

禁忌:

對dilhydropyridine類化合物、amlodipine 、atrovastain或本品任何成分過敏之患者。有活動性肝病或不明原因的血清氨基轉移酵素持續上升超過正常值上限3倍以上之患者。孕婦、授乳婦女。

警語:

atrovastain 可能會造成氨基轉移酵素的濃度上升,atorvastain治療前應做肝功能檢查,並定期監測。如果AST或ALT超過正常上限值3倍以上,應當降低劑量或停藥。

藥品保存方式:

藥品應置於攝氏 15 ~ 25 度乾燥處所;如發生變質或過期,不可再食用。

 


 

Crestor 5mg/Tab. (Rosuvastatin 5mg/Tab.)

 

 

品名規格 CRESTOR 5MG FILM-COATED TABLETS 
廠        商 臺灣阿斯特捷利康股份有限公司
代        號 OCRE5
成  份  名 Rosuvastatin 5mg/Tab.
中文名稱 冠脂妥膜衣錠  5公絲
藥理分類 Lipid modifying agents, plain / HMG CoA reductase inhibitors
孕婦用藥等級  
外        觀

 

 

中文說明書

製造商 AstraZeneca
代理/經銷商 AstraZeneca
成份 Rosuvastatin Ca
適應症 Adjunctive therapy to diet to reduce elevated total-C, LDL-C, Apo B, non-HDL-C and triglycerides and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate.

Adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

Adjunctive therapy to other lipid-lowering treatments (eg, LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, total-C and Apo B in adult patients with homozygous familial hypercholesterolemia.

Limitations of Use: The effect of Crestor on cardiovascular morbidity and mortality has not been determined.

Crestor has not been studied in Fredrickson type I, III and V dyslipidemias.

用量 Dose Range: 5-20 mg orally once daily.

Crestor can be administered as a single dose at any time of day, with or without food.

When initiating Crestor therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate Crestor starting dose should first be utilized and only then titrated according to the patient's response and individualized goal of therapy.

Hyperlipidemia, Mixed Dyslipidemia and Hypertriglyceridemia: Dose Range: 5-20 mg once daily. Therapy with Crestor should be individualized according to goal of therapy and response. Usual Recommended Starting Dose: 10 mg once daily. However, initiation of therapy with 5 mg once daily should be considered for patients requiring less aggressive LDL-C reductions, who have predisposing factors for myopathy and as noted as follows for special populations eg, patients taking cyclosporine, Asian patients and patients with severe renal insufficiency (see Pharmacokinetics and Drug-Drug Interactions under Pharmacology). For patients with marked hypercholesterolemia (LDL-C >190 mg/dL) and aggressive lipid targets, a 20-mg starting dose may be considered. After initiation and/or upon titration of Crestor, lipid levels should be analyzed within 2-4 weeks and dosage adjusted accordingly.

When initiating statin therapy or switching from another statin therapy, the appropriate Crestor starting dose should first be utilized and only then titrated according to the patient's individualized goal of therapy.

Homozygous Familial Hypercholesterolemia: Recommended Starting Dose: 20 mg once daily. Response to therapy should be estimated from pre-apheresis LDL-C levels.

Asian Patients: Initiation of Crestor therapy with 5 mg once daily should be considered for Asian patients (see Asian Patients under Precautions and Pharmacology under Actions).

Use with Cyclosporine or Lopinavir/Ritonavir: In patients taking cyclosporine, dose of Crestor should be limited to 5 mg once daily (see Precautions and Interactions). In patients taking a combination of lopinavir and ritonavir, the dose of Crestor should be limited to 10 mg once daily (see Precautions and Interactions).

Concomitant Lipid-Lowering Therapy: The risk of skeletal muscle effects may be enhanced when Crestor is used in combination with niacin or fenofibrate; a reduction in Crestor dosage should be considered in this setting (see Precautions and Interactions).

Combination therapy with gemfibrozil should be avoided because of an increase in Crestor exposure with concomitant use; if Crestor is used in combination with gemfibrozil, the dose of Crestor should be limited to 10 mg once daily (see Precautions and Interactions ).

Patients with Severe Renal Impairment: For patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2) not on hemodialysis, dosing of Crestor should be started at 5 mg once daily and not exceed 10 mg once daily (see Precautions and Pharmacology under Actions).

過量 There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.
用法 May be taken with or without food
美國食品藥物管理局之懷孕等級 Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
禁忌 Hypersensitivity to rosuvastatin or any component of Crestor. Hypersensitivity reactions including rash, pruritus, urticaria and angioedema have been reported with Crestor (see Adverse Reactions).

Active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels (see Precautions).

Use in pregnancy & lactation: Teratogenic Effects: Pregnancy Category X: Crestor is contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy.

There are no adequate and well-controlled studies of Crestor in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the 1st trimester when pregnancy was identified.

Rosuvastatin crosses the placenta in rats and rabbits. In rats, Crestor was not teratogenic at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10-12 times the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight among female pups and delayed ossification. In rabbits, pup viability decreased and maternal mortality increased at doses equivalent to the human dose of 40 mg/day. (See Nonclinical Toxicology under Actions.)

Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Crestor may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy and safety in pregnant women has not been established. If the patient becomes pregnant while taking Crestor, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy (see Toxicology under Actions).

It is not known whether rosuvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of rosuvastatin are 3 times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require Crestor treatment should be advised not to breastfeed their infants.

注意事項 Skeletal Muscle Effects: Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Crestor. These risks can occur at any dose level, but are increased at the highest dose (40 mg).

Crestor should be prescribed with caution in patients with predisposing factors for myopathy (eg, ≥65 years, inadequately treated hypothyroidism, renal impairment).

The risk of myopathy during treatment with Crestor may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine or lopinavir/ritonavir. (See Dosage & Administration and Interactions.)

Crestor therapy should be discontinued if markedly elevated creatinine kinase levels occur or myopathy is diagnosed or suspected. Crestor therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (eg, sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

Liver Enzyme Abnormalities and Monitoring: It is recommended that liver enzyme tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose and periodically (eg, semiannually) thereafter.

Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including Crestor. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were 2 cases of jaundice, for which a relationship to Crestor therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking Crestor versus 0.5% of patients treated with placebo.

Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of Crestor is recommended.

Crestor should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease (see Pharmacology under Actions). Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of Crestor. (See Contraindications.)

Concomitant Coumarin Anticoagulants: Caution should be exercised when anticoagulants are given in conjunction with Crestor because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and Crestor concomitantly, INR should be determined before starting Crestor and frequently enough during early therapy to ensure that no significant alteration of INR occurs (see Interactions).

Proteinuria and Hematuria: In the Crestor clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among Crestor-treated patients. This finding was more frequent in patients taking Crestor 40 mg, when compared to lower doses of Crestor or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on Crestor therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

Endocrine Effects: Although clinical studies have shown that Crestor alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if Crestor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones eg, ketoconazole, spironolactone and cimetidine.

Renal Impairment: Rosuvastatin exposure is not influenced by mild to moderate renal impairment (creatinine clearance ≥30 mL/min/1.73 m2); however, exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment who are not receiving hemodialysis. Crestor dosing should be adjusted in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2) not requiring hemodialysis (see Dosage & Administration and Pharmacology under Actions).

Hepatic Impairment: Crestor is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; Crestor should be used with caution in these patients (see Contraindications and Pharmacology under Actions).

Asian Patients: Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. Crestor dosage should be adjusted in Asian patients (see Dosage & Administration and Pharmacology under Actions).

Use in children: The safety and effectiveness of Crestor in pediatric patients have not been established.

Treatment experience with Crestor in a pediatric population is limited to 8 patients with homozygous FH. None of these patients was <8 years.

In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10-17 years with heterozygous FH received single and multiple oral doses of Crestor. Both Cmax and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses.

Use in the elderly: Of the 10,275 patients in clinical studies with Crestor, 3159 (31%) were ≥65 years and 698 (6.8%) were ≥75 years. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients are at higher risk of myopathy and Crestor should be prescribed with caution in the elderly (see Pharmacology under Actions).

不良反應 The following serious adverse reactions are discussed in greater detail under Precautions: Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis); liver enzyme abnormalities.

 

In the Crestor controlled clinical trials database (placebo or active-controlled) of 5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: Myalgia, abdominal pain, nausea.

 

The most commonly reported adverse reactions (incidence ≥2%) in the Crestor controlled clinical trial database of 5394 patients were: Headache, myalgia, abdominal pain, asthenia, nausea.

 

Clinical Studies Experience: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

 

Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 7. These studies had a treatment duration of up to 12 weeks.

Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: Dipstick-positive proteinuria and microscopic hematuria (see Precautions); elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase and bilirubin; and thyroid function abnormalities.

 

In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of Crestor-treated subjects versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: Myalgia, increased hepatic enzyme, headache and nausea (see Clinical Studies under Actions).

 

Adverse reactions reported in ≥2% of patients and at a rate greater than or equal to placebo are shown in Table 8.

Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of Crestor: Arthralgia, hepatitis, jaundice and memory loss. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
View ADR Monitoring Website[參閱藥物不良反應監測表格]

交互作用 Cyclosporine: Cyclosporine significantly increased rosuvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to Crestor 5 mg once daily (see Dosage & Administration, Precautions and Pharmacology under Actions).

Gemfibrozil: Gemfibrozil significantly increased rosuvastatin exposure. Therefore, combination therapy with Crestor and gemfibrozil should be avoided. If used, do not exceed Crestor 10 mg once daily (see Dosage & Administration and Pharmacology under Actions).

Lopinavir/Ritonavir: The combination of lopinavir and ritonavir significantly increased rosuvastatin exposure. Therefore, in patients taking a combination of lopinavir and ritonavir, the dose of Crestor should be limited to 10 mg once daily. The effect of other protease inhibitors on rosuvastatin pharmacokinetics has not been examined (see Dosage & Administration, Precautions and Pharmacology under Actions).

Coumarin Anticoagulants: Crestor significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with Crestor. In patients taking coumarin anticoagulants and Crestor concomitantly, INR should be determined before starting Crestor and frequently enough during early therapy to ensure that no significant alteration of INR occurs (see Precautions and Pharmacology under Actions).

Niacin: The risk of skeletal muscle effects may be enhanced when Crestor is used in combination with niacin; a reduction in Crestor dosage should be considered in this setting (see Precautions).

Fenofibrate: When Crestor was co-administered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. The benefit of further alterations in lipid levels by the combined use of Crestor with fibrates should be carefully weighed against the potential risks of this combination (see Precautions and Pharmacology under Actions).
View more drug interactions with Crestor[冠脂妥]

儲存 Do not store above 30°C. Store in the original package.
描述 Each tablet also contains the following excipients: Microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide and red ferric oxide NF.

Rosuvastatin calcium is a synthetic lipid-lowering agent for oral administration. It is bis [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt. Its empirical formula is (C22H27FN3O6S)2Ca and the molecular weight is 1001.14.

Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol and slightly soluble in ethanol. It is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.

作用 Pharmacology: Mechanism of Action: Crestor is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl co-enzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in 2 ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

 

Clinical Studies: Hyperlipidemia and Mixed Dyslipidemia: Crestor reduces total-C, LDL-C, Apo B, non-HDL-C and TG and increases HDL-C, in adult patients with hyperlipidemia and mixed dyslipidemia.

 

Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with hyperlipidemia, Crestor given as a single daily dose for 6 weeks significantly reduced total-C, LDL-C, non-HDL-C and Apo B, across the dose range (see Table 1).

Active-Controlled Study: Crestor was compared with the HMG-CoA reductase inhibitors atorvastatin, simvastatin and pravastatin in a multicenter, open-label, dose-ranging study of 2240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either Crestor, atorvastatin, simvastatin or pravastatin (see figure and Table 2).

Heterozygous Familial Hypercholesterolemia (Heterozygous FH): Active-Controlled Study: In a study of patients with heterozygous FH (baseline mean LDL of 291), patients were randomized to Crestor 20 mg or atorvastatin 20 mg. The dose was increased by 6-week intervals. Significant LDL-C reductions from baseline were seen at each dose in both treatment groups (see Table 3).

Hypertriglyceridemia: Dose-Response Study: In a double-blind, placebo-controlled, dose-response study in patients with baseline TG levels from 273-817 mg/dL, Crestor given as a single daily dose (5-40 mg) over 6 weeks significantly reduced serum TG levels (see Table 4).

Homozygous Familial Hypercholesterolemia (Homozygous FH): Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8-63 years) were evaluated for their response to Crestor 20-40 mg titrated at a 6-week interval. In the overall population, the mean LDL-C reduction from baseline was 22%. About 1/3 of the patients benefited from increasing their dose from 20-40 mg with further LDL lowering of >6%. In the 27 patients with at least a 15% reduction in LDL-C, the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL-C reduction of <15%, 3 had no change or an increase in LDL-C. Reductions in LDL-C of ≥15% were observed in 3 of 5 patients with known receptor-negative status.

Results of the METEOR Study: In the Measuring Effects on Intima Media Thickness: An Evaluation of Rosuvastatin 40 mg (METEOR) study, the effect of therapy with Crestor on carotid atherosclerosis was assessed by B-mode ultrasonography in patients with elevated LDL-C, at low risk (Framingham risk <10% over 10 years) for symptomatic coronary artery disease and with subclinical atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind, placebo-controlled clinical study, 984 patients were randomized (of whom 876 were analyzed) in a 5:2 ratio to Crestor 40 mg or placebo once daily. Ultrasonograms of the carotid walls were used to determine the annualized rate of change per patient from baseline to 2 years in mean maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the maximum cIMT analyzed over all 12 carotid artery sites between Crestor-treated patients and placebo-treated patients was -0.0145 mm/year (95% CI -0.0196, -0.0093; p<0.0001).

The annualized rate of change from baseline for the placebo group was +0.0131 mm/year (p<0.0001). The annualized rate of change from baseline for the Crestor group was -0.0014 mm/year (p=0.32).

At an individual patient level in the Crestor group, 52.1% of patients demonstrated an absence of disease progression (defined as a negative annualized rate of change), compared to 37.7% of patients in the placebo group.

Pharmacokinetics: Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3-5 hrs following oral dosing. Both Cmax and AUC increased in approximate proportion to Crestor dose. The absolute bioavailability of rosuvastatin is approximately 20%.

Administration of Crestor with food did not affect the AUC of rosuvastatin.

The AUC of rosuvastatin does not differ following evening or morning drug administration.

Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 L. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P-450 2C9 and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately 1/6-½ the HMG-CoA reductase inhibitory activity of the parent compound. Overall, >90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.

Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination t½ of rosuvastatin is approximately 19 hrs.

After an IV dose, approximately 28% of total body clearance was via the renal route and 72% by the hepatic route.

Race: A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including 1 conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group.

Gender: There were no differences in plasma concentrations of rosuvastatin between men and women.

Geriatric: There were no differences in plasma concentrations of rosuvastatin between the non-elderly and elderly populations (≥65 years).

Renal Impairment: Mild to moderate renal impairment (creatinine clearance ≥30 mL/min/1.73 m2) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects (creatinine clearance >80 mL/min/1.73 m2).

Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased.

In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

Drug-Drug Interactions: Cytochrome P-450 3A4: Rosuvastatin clearance is not dependent on metabolism by cytochrome P-450 3A4 to a clinically significant extent. (See Tables 5 and 6.)

Toxicology: Nonclinical Toxicology: Carcinogenicity, Mutagenicity, Impairment of Fertility: In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60 or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.

In a 107-week carcinogenicity study in mice given 10, 60, 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.

Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for 1 month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.

Animal Toxicology and/or Pharmacology: Embryo-Fetal Development: Rosuvastatin crosses the placenta and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.

In female rats given oral gavage doses of 5, 15, 50 mg/kg/day rosuvastatin before mating and continuing through day 7 postcoitus results in decreased fetal body weight (female pups) and delayed ossification at the high dose (systemic exposures 10 times the human exposure at 40 mg/day based on AUC).

In pregnant rats given oral gavage doses of 2, 10, 50 mg/kg/day from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred in groups given 50 mg/kg/day, systemic exposures ≥12 times the human exposure at 40 mg/day based on body surface area.

In pregnant rabbits given oral gavage doses of 0.3, 1, 3 mg/kg/day from gestation day 6 to lactation day 18 (weaning), exposures equivalent to the human exposure at 40 mg/day based on body surface area, decreased fetal viability and maternal mortality was observed.

Rosuvastatin was not teratogenic in rats at ≤25 mg/kg/day or in rabbits ≤3 mg/kg/day (systemic exposures equivalent to the human exposure at 40 mg/day based on AUC or body surface area, respectively).

Central Nervous System Toxicity: CNS vascular lesions, characterized by perivascular hemorrhages, edema and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to 1 year.

 

Sivasin Film coated Tab. ( Simvastatin20mg/Tab.)

 

品名規格 Sivasin Film Coated Tablets 20mg 
廠        商 永信藥品工業股份有限公司 
代        號 OSIM
成  份  名 Simvastatin 20mg/Tab.
中文名稱 律脂 膜衣錠20毫克
藥理分類 Lipid modifying agents, plain / HMG CoA reductase inhibitors
孕婦用藥等級  
外        觀

說明書

藥名(學名) SIMVASTATIN
商品名【廠商】 ZOCOR(MSD)
SIMVAHEXAL(SALUTAS/盛益)
SIMVATIN(順生/道斯)
ZOLOTIN(健亞/萬菱)
 
成分:
每錠含20mg。
藥理作用:
3-Hydroxy-3methylglutary1 輔脢A(HMG-CoA)還原酵素抑制劑,
作用類似lovastatin但較強。
HMG-CoA還原酵素抑制劑增加高密度脂蛋白膽固醇,
並降低低密度脂蛋白膽固醇及總膽固醇之合成。

藥物動力學:
吸收:迅速由胃腸道吸收;蛋白結合率:95%;
作用起始時間:2週;到達最大作用時間:4∼6週;
代謝:肝;排泄:13%由尿,60%由膽汁及糞便。
治療項目:
高膽固醇血症,家族性高膽固醇血症。
用法用量:
口服 成人:一天5∼40mg。
副作用:
(1)心血管:絞痛病。
(2)中樞神經系統:眩暈,頭痛,虛弱,疲倦,失眠。
(3)胃腸:噁心,下痢,嘔吐,腹痛,便秘,脹氣,
   胃灼熱,肝轉胺基鋂脢暫時昇高。
(4)其他:鼻炎,咳嗽,CPK暫時昇高。
注意事項:
(1)本劑之投與不必顧慮餐食在傍晚給藥。
(2)整個療程中應監測膽固醇值。
(3)肝功能試驗在治療的前3個月每4∼6週一次,
   以後的12個月每6∼8週一次,之後定期做。
(4)同時接受warfarin治療的患者應監測凝固試驗,
   凝血脢元時間會延長。
(5)建議患者有無法解釋的肌肉痛、觸痛、虛弱、
   尤其是如伴有身體不適或發燒時立即報告。
(6)告訴患者在warfarin治療期間有出血的徵兆立即報告。
(7)使用本劑併服葡萄柚或葡萄柚汁時,應注意可產生藥品相互作用。
使用禁忌:
對本劑過敏,懷孕,授乳婦,現有肝病之患者。
交互作用:
與warfarin併用會增加凝血時間。

 

Fenogal 200mg/Cap. ( Fenofibrate 200mg/Cap.)

 

品名規格 FENOGAL 200MG LIDOSE 
廠        商 天義企業股份有限公司 
代        號 OFEN
成  份  名 Fenofibrate 200mg/Cap.
中文名稱 芬諾克膠囊200公絲
藥理分類 Lipid modifying agents, plain / Fibrates
孕婦用藥等級  
外        觀

 

衛生署許可適應症:高脂質血症

作用:冠狀動脈功能不全、伴有糖尿病之高血脂症、動脈粥狀硬化、高脂質血症、混合型高血脂症、

動脈性高血壓、末梢血管疾病、血三酸甘油酯過多症、腦血管功能不合、伴有高尿酸症之高血脂症、

血膽固醇過多症

副作用:肝功能異常、皮疹、肌肉痛、便秘、禿頭、腹瀉、噁心

使用禁忌:高度肝、腎機能障礙患者不宜服用,懷孕

注意事項:可能造成肌肉損傷,包括罕見的橫紋肌溶解症曾被報告與fibrates有關。若係低白蛋白症患

者,則此不適發生率增加。造成肌肉損傷是指在患者的身上產生瀰漫性的肌痛,疼痛肌肉敏感和/

肌肉來源的CPK顯著增加(數值超過正常的五倍)。在這情況下應停止治療。

如有下列副作用發生,請立即 通知 醫師:

1、肌肉疼痛或壓痛、無力、嚴重腹痛、噁心、嘔吐。

2、不明原因的發燒。

3、過敏反應(搔癢或蕁痲疹、臉部或手部水腫、嘴部或喉嚨水腫、胸悶或呼吸困難)

4、水泡、脫皮及皮膚紅疹 。

5、眼睛或皮膚變黃,尿液變深或糞便顏色變白 。

 交互作用:

1、併用HMG-CoA還原脢抑制劑(lovastatin, simvastatin, pravastatin, atorvastatin)時,可能增加發生橫

紋肌溶解現象,應留意肌肉病變的產生。

2使用抗凝血劑之病人服用本品時應小心。病人之抗凝血劑劑量應減低至可保持一定的Prothrombin 

Time, 以防止流血之併發症,並定期作Prothrombin Time檢查,以保持Prothrombin Time之穩定。

3 Cholestyramine會降低fenofibratebezafibrate 的吸收,因此兩者併用時,fenofibrate 應於

cholestyramine之前1小時或之後 4-6小時投予。而bezafibrate應於cholestyramine之後 2小時投予。

 健保給付規定:

2.6.降血脂藥物Drugs used for dyslipidemia
HMG Co-A Reductase Inhibitor (simvastatin "Zocor"; pravastatin "Mevalotin"; fluvastatin "Lescol"; lovastatin

 "Delipic 20mg/tab"; atorvastatin"Lipitor 10mg/tab"; Rosuvastatin "Crestor 10mg/tab",其他降血酯藥物

(bezafibrate "Bezalip 200mg/tab"; gemfibrozil "Lopid 300mg/cap, Gem-S, Gemd 600mg/tab"; fenofibrate 

"Lipanthyl" ; acipimox "Olbetam 250mg/cap"; cholestyramine "Questran 4g/pack")

 

血脂異常之起步治療準則

血脂濃度

2個危險因子(如附註二)

TC/HDL-C>5 HDL-C<35mg/dL

治療目標

處方規定

無心血管疾病患者(如附註一)

有下列情況之一時,應給予三至六個月非藥物治療

TC

200mg/dL

ˇ

×

<200mg/dL

如非藥物治療未達治療目標,得使用降血脂藥物(請附三個月前及本次血脂檢查數據),接受藥物治療後,應每三至六個月抽血檢查一次,同時請注意副作用產生,如肝功能異常或橫紋肌溶解症等,如已達治療目標,請考慮減量,並持續治療之。

240mg/dL

×

×

<240 mg/dL

LDL

130mg/dL

ˇ

×

<130mg/dL

160mg/dL

×

×

<160mg/dL

TG 200mg/dL (需同時合併有TC/HDL-C>5 或是HDL-C<40mg/dL)

×

ˇ

<200mg/dL (87/4/1)

有心血管疾病或糖尿病患者

同時予以非藥物治療(87/7/1)

TC 200mg/dL

×

×

<160mg/dL (87/7/1)

接受藥物治療後,接受藥物治療後,應每三至六個月抽血檢查一次,同時請注意副作用產生,如肝功能異常或橫紋肌溶解症等

LDL 130mg/dL

×

×

100mg/dL (87/7/1)

TG 200mg/dL (需同時合併有TC/HDL-C>5或是HDL-C<40mg/dL)

×

ˇ

<150mg/dL (87/7/1)

血中三酸甘油酯高於500 mg/dL,具有罹患急性胰臟炎危險者,得使用降血脂藥物。(87/4/1)

附註一:心血管疾病:                            (ˇ)需符合此項條件  (×)不需符合此項條件

()冠狀動脈粥狀硬化患者                            

1.有心導管檢查證實(附檢查報告、醫院名稱及日期)

 2.曾患心肌梗塞有心電圖(附心電圖)或住院證實(附檢查醫院名稱及日期)

3.心絞痛病患,有缺氧性心電圖變化或運動試驗陽性反應者(附檢查報告)

()腦血管病變患者

1.腦梗塞。

2.腦內出血(不含其他顱內出血)

3.陣發性腦缺血患者(TIA)其頸動脈超音波證實有粥腫樣變化併有70%以上阻塞者。

()周邊血管粥狀硬化有缺血性症狀且經血管都卜勒超音波或血管攝影證實者。

附註二:危險因子:

1.高血壓  2.糖尿病  3.男性45  4.有早發性冠心病家族史  5.女性55歲或停經沒有雌激素療法者 

6.吸菸(因吸菸而符合起步治療準則之個案,如要求藥物治療,應以自費治療)


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