Characteristics of the Various Statins

Transcription

1 PL Detail-Document # This Detail-Document accompanies the related article published in PHARMACIST S LETTER / PRESCRIBER S LETTER May 2012 Characteristics of the Various Statins Based on U.S. product labeling and relevant studies. Canadian product information given if differs significantly (e.g., more conservative) from U.S. Drug a Atorvastatin (Lipitor, generics) Fluvastatin (Lescol, generics [U.S.]; Lescol XL) Potency (average decrease in LDL) 1,2 10 mg: 35-39% 20 mg: 43% 40 mg: 50% 80 mg: 55-60% 20 mg: 22% 40 mg: 25% 80 mg: 35% (as XL product) View our helpful PL Chart, Non-Statin Lipid-Lowering Agents Renal Liver Function Selected Drug Interactions c Considerations Monitoring d No dose adjustment necessary for reduced renal function. (Use 10 mg daily in patients with renal disease per Canadian labelling.) In severe renal impairment, use daily doses over 40 mg with caution. (Canadian labelling recommends not using if CrCl <30 ml/min.) periodically, per Canadian labelling) and 8 weeks after initiation or dosage increase, per Canadian labelling) and Metabolized by CYP3A4, but less than lovastatin and simvastatin. Some drugs that significantly inhibit its metabolism through CYP3A4 inhibition include erythromycin, clarithromycin, telithromycin, itraconazole, verapamil, nefazodone, protease inhibitors, cyclosporine, and grapefruit juice; atorvastatin dose reduction or discontinuation may be recommended. Consider cautious dosing with niacin or fibrates (avoid gemfibrozil). Rifampin may increase or decrease levels, depending on timing. Metabolized primarily by CYP2C9. Few significant interactions with 2C9 inhibitors. 3 May be less likely to be involved in drug interactions. Use with phenytoin or glyburide can increase levels of both drugs. Consider dose reduction with niacin. Caution with fibrates (avoid gemfibrozil). Do not exceed 20 mg twice daily with cyclosporine. Rifampin decreases levels. Cost/month (U.S./ Canada) b 10 mg: $91.99 (generic)/ $18.85 (generic) 80 mg XL: $141.98/ $47.87

2 (PL Detail-Document #280502: Page 2 of 9) Drug a Lovastatin (Mevacor, generics) Potency (average decrease in LDL) 1,2 10 mg: 21% 20 mg: 24-27% 40 mg: 30-31% 80 mg: 40-42% (as 40 mg BID) Renal Considerations If CrCl <30 ml/min, use daily doses over 20 mg with caution. Liver Function Monitoring d periodically, per Canadian labelling [more frequent with 40 mg or more]) and Selected Drug Interactions c Metabolized by CYP3A4. Some drugs that significantly inhibit its metabolism through CYP3A4 inhibition include amiodarone, erythromycin, clarithromycin, telithromycin, itraconazole, ketoconazole, posaconazole, verapamil, diltiazem, nefazodone, cyclosporine, and grapefruit juice; lovastatin dose reduction or discontinuation may be recommended. Do not exceed 40 mg daily with amiodarone. Do not exceed 20 mg daily with diltiazem, verapamil, or niacin >1000 mg/day (Canada), or 40 mg daily with extended-release niacin (Niaspan). Caution with fibrates (avoid gemfibrozil; do not exceed 20 mg daily with fibrates [Canada]); avoid gemfibrozil. Do not use with protease inhibitors. Cost/month (U.S./ Canada) b 40 mg: $33 (generic)/ $40.76 (generic) Pitavastatin (Livalo) (U.S. only) 1 mg: 31-32% 2 mg: 36-39% 4 mg: 41-45% For glomerular filtration rate (GFR) ml/min/1.73m 2, including hemodialysis, initial daily dose is 1 mg, max daily dose is 2 mg. tests at baseline and Not significantly metabolized by cytochrome P450 and may be less likely to be involved in drug interactions. Contraindicated with cyclosporine. Limit dose to 1 mg daily with erythromycin or 2 mg daily with rifampin. Consider dosage reduction with niacin. Caution with fibrates (avoid gemfibrozil). 2 mg: $117.32

3 (PL Detail-Document #280502: Page 3 of 9) Drug a Pravastatin (Pravachol, generics) Potency (average decrease in LDL) 1,2 10 mg: 22% 20 mg: 32% 40 mg: 34% 80 mg: 37% Renal Considerations In significant renal impairment, start with 10 mg daily. (Canadian labelling advises caution with daily doses of 40 mg or more in renal impairment.) Liver Function Monitoring d 12 weeks after initiation or dosage increase, per Canadian labelling), and when clinically Selected Drug Interactions c Not significantly metabolized by cytochrome P450 and may be less likely to be involved in drug interactions. Do not exceed 20 mg once daily with cyclosporine. Caution with fibrates (avoid gemfibrozil). Consider dose reduction with niacin >1000 mg/day. Cost/month (U.S./ Canada) b 40 mg: $16.66 (generic)/ $26.11 (generic) Rosuvastatin (Crestor) 5 mg: 45% 10 mg: 46-52% 20 mg: 47-55% 40 mg: 55-63% If CrCl <30 ml/min/1.73 m 2 (but not on hemodialysis), starting dose is 5 mg daily, maximum 10 mg daily. Rosuvastatin levels in hemodialysis patients are about 50% higher than levels in normal renal function. 12 weeks after initiation or titration to 40 mg, per Canadian labelling), and when clinically Not significantly metabolized by cytochrome P450 and may be less likely to be involved in drug interactions. Caution with niacin. Limit to 10 mg with lopinavir/ritonavir or atazanavir/ritonavir. Use lowest necessary dose with indinavir (not recommended, per Canadian labelling) or saquinavir/ritonavir (not recommended, per Canadian labelling). Canada: cyclosporine contraindicated. Rosuvastatin 40 mg contraindicated with fibrate or niacin. U.S.: max rosuvastatin dose 5 mg with cyclosporine, and 10 mg with gemfibrozil (avoid gemfibrozil preferred); caution with fenofibrate. 5 mg: $142.32/ $41.80

4 (PL Detail-Document #280502: Page 4 of 9) Drug a Simvastatin (Zocor, generics) Potency (average decrease in LDL) 1,2 5 mg: 26% 10 mg: 30% 20 mg: 38% 40 mg: 29-41% 80 mg: 36-47% Renal Considerations In severe renal impairment, starting dose is 5 mg daily with close monitoring. (Per Canadian labelling, caution with doses >10 mg daily with severe renal impairment [CrCl <30 ml/min].) Liver Function Monitoring d tests at baseline and (Per Canadian labelling, for patients to be titrated to 80 mg, check prior to dosage increase, three months later, then periodically [e.g., semiannually] for the first year.) Selected Drug Interactions c Metabolized by CYP3A4. Some drugs that significantly inhibit its metabolism through CYP3A4 inhibition include amiodarone, erythromycin, clarithromycin, telithromycin, itraconazole, ketoconazole, posaconazole, verapamil, diltiazem, nefazodone, cyclosporine, and grapefruit juice; simvastatin dose reduction or discontinuation may be recommended. Do not exceed 20 mg daily with amiodarone and amlodipine. Do not exceed 10 mg daily with diltiazem or verapamil, or 40 mg daily with extendedrelease niacin (Niaspan). Caution with fibrates; contraindicated with gemfibrozil. Do not use with protease inhibitors. Cost/month (U.S./ Canada) b 20 mg: $24.66 (generic)/ $28.35 (generic) a. The following product labeling was used for the above chart: Lipitor (February 2012), Lescol/Lescol XL (February 2012), Mevacor (February 2012), Livalo (February 2012), Pravachol (February 2012), Crestor (February 2012), Zocor (February 2012), Lipitor Canada (March 2011), Lescol/Lescol XL Canada (March 2012), Mevacor Canada (March 2011), Pravachol Canada (October 2010), Crestor Canada (October 2010), Zocor Canada (October 2011). b. U.S. cost is from drugstore.com at time of writing. Cost is for generic if available. c. From labeling and PL Chart, Clinically Significant Statin Drug Interactions. d. Tell statin users to stop the statin and report symptoms of liver injury (e.g., jaundice, abdominal pain, etc) right away. Stop the statin in the event of evidence of liver injury (e.g., elevated direct bilirubin level, hepatomegaly, jaundice, increased prothrombin time). 5,6 If the statin cannot be excluded as a cause of liver injury, do not restart a statin. 5 But if elevated transaminase levels are the only problem, experts recommend continuing the statin. 5 There s no proof that dose reduction is necessary. 5 If transaminases exceed three times the upper limit of normal, repeat the test. 6 In asymptomatic patients with transaminases less than five times normal and no evidence of liver injury, the repeat test can be deferred for six months. In the meantime, stop alcohol and hepatotoxic medications, encourage weight loss, and control diabetes. 7 If still elevated, rule out other causes and consider decreasing the dose or stopping the statin. 6

5 (PL Detail-Document #280502: Page 5 of 9) Abbreviations: ACS = acute coronary syndrome; CHD = coronary heart disease; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; MACE = major adverse cardiac event (cardiac death, non-fatal MI, or revascularization); MI = myocardial infarction; PCI = percutaneous coronary intervention; TIA = transient ischemic attack. Evidence is Level A for all studies except CARDS, FLORIDA, TREADMILL [Level A/B] and GREACE and L-CAD [Level B]. Clinical Benefit of Statins (Study acronym in parentheses; FDA-labeled indications are underlined.) Atorvastatin (Lipitor) Primary prevention of CHD: Reduces non-fatal MI and fatal CHD, and stroke in patients with hypertension and total cholesterol <250 mg/dl (ASCOT). Primary prevention of CHD in diabetes: Reduces stroke and MI in patients with type 2 diabetes, an additional CHD risk factor, and LDL <160 mg/dl (CARDS). Secondary prevention of CHD: 80 mg/day reduced risk of major cardiovascular events in patients with CHD and LDL<130 mg/dl vs 10 mg. No overall mortality difference (TNT). Secondary prevention of CHD: 80 mg/day reduced risk of non-fatal cardiovascular events vs simvastatin mg/day in patients with CHD and previous MI (mean LDL mg/dl) (IDEAL). Secondary prevention of CHD:* Reduced risk of coronary morbidity and mortality, and stroke in open-label comparison with usual care of patients with LDL >100 mg/dl (GREACE). (*Note: GREACE not used to support this indication.) 80 mg/day begun within 1 to 4 days after ACS reduced recurrent ischemic events and stroke over 4 months (MIRACL). In ACS, intense lipid lowering (median LDL 62 mg/dl) lowers risk of death/major cardio events more than moderate lipid lowering (median LDL 95 mg/dl) (PROVE-IT). Regresses/slows progression of atherosclerosis (ASAP, ARBITER, REVERSAL). Unclear benefit in peripheral arterial disease (TREADMILL).

6 (PL Detail-Document #280502: Page 6 of 9) Fluvastatin (Lescol) Slows progression of atherosclerosis in patients with CHD and mild to moderate hypercholesterolemia (LCAS). Secondary prevention of CHD: Reduces need for revascularization. Dose of 40 mg twice daily reduced risk of MACE when begun within days after PCI in patients with average cholesterol levels (LIPS). Did not reduce MACE in renal transplant recipients, but secondary endpoints of cardiac death and MI were reduced (ALERT). No benefit for early treatment of ACS with 80 mg/day (FLORIDA). Lovastatin (Mevacor) Primary prevention of CHD: Reduces first acute coronary event, MI, unstable angina, and revascularization in patients with average LDL (AFCAPS/ TexCAPS). Slows progression of coronary atherosclerosis in CHD (CCAIT, FATS, MARS). Improvement also in carotid arteries (ACAPS). Pitavastatin (Livalo) Pitavastatin 4 mg and atorvastatin 20 mg similarly reduce nonculprit coronary plaque volume post-acs (JAPAN-ACS). Pravastatin (Pravachol) Primary prevention of CHD: Reduces cardiovascular death, MI, and revascularization in patients with high LDL and multiple risk factors (WOSCOPS). Secondary prevention of CHD: Reduces recurrent MI, coronary death, revascularization, and stroke/tia across range of cholesterol levels (CARE, LIPID). Slows progression of coronary atherosclerosis in CHD; improvement also in carotid arteries (REGRESS, PLAC I, PLAC II, KAPS). Failed to show benefit in hypertensive patients (ALLHAT-LLT), but result probably due to high non-study statin use in usual care group. Preliminary study found lower risk of MACE with early therapy of ACS (L-CAD). Reduced composite of coronary death, non-fatal MI, and stroke in high-risk patients >70 years old, but no benefit for stroke alone; result attributed to short study duration (PROSPER).

7 (PL Detail-Document #280502: Page 7 of 9) Rosuvastatin (Crestor) Regression of atherosclerosis with intensive statin therapy in patients with angiographic coronary disease. 40 mg/day reduced LDL (mean 60.8 mg/dl), raised HDL (mean 49.0 mg/dl), and reduced percent mean atheroma volume by 0.98% (ASTEROID). Slows progression of atherosclerosis (METEOR). Primary prevention of CAD: Reduces MI, stroke, and cardiovascular death in patients with LDL <130 mg/dl and hs-crp >2 mg/l (JUPITER). Simvastatin (Zocor) Primary and secondary prevention of CHD: Reduces risk of total mortality, non-fatal MI, stroke, and revascularization in patients at high risk of coronary events c, but with normal cholesterol (including LDL <100 mg/dl, women, diabetes, and peripheral arterial disease) (HPS). Secondary prevention of CHD: Reduces recurrent MI, coronary and total mortality, revascularization, and stroke in patients with high LDL (4S). Slows progression of atherosclerosis in patients with CHD and normal to high cholesterol (MAAS, SCAT). Combined with niacin reduces major coronary events in patients with CHD and HDL <35 mg/dl (HATS). Reduces vascular events (HPS) and development/progression of intermittent claudication (4S) in peripheral arterial disease. c. In patients with CHD or CHD risk-equivalent (diabetes, peripheral arterial disease, history of stroke or other cerebrovascular disease). Statin Clinical Trials 4S - Scandinavian Simvastatin Survival Study: Lancet 1994;344: Am J Cardiol 1998;81: ACAPS - Asymptomatic Carotid Artery Progression Study: Circulation 1994;90: AFCAPS/TEXCAPS - Air Force/Texas Coronary Atherosclerosis Prevention Study: JAMA 1998;279: ALERT - Assessment of Lescol in Renal Transplantation Study: Lancet 2003;361: ALLHAT-LLT - Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: JAMA 2002;288: ARBITER - Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: Circulation 2002;106: ASAP - Atorvastatin versus Simvastatin on Atherosclerosis Prevention: Lancet 2001;357: ASCOT - Anglo-Scandinavian Cardiac Outcomes Trial: Lancet 2003;361: ASTEROID - A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden: JAMA 2006;295: CARDS - Collaborative Atorvastatin Diabetes Study. Lancet 2004;364: CARE - Cholesterol and Recurrent Events Trial: N Engl J Med 1996;335: CCAIT - Canadian Coronary Atherosclerosis Intervention Trial: Circulation 1994;89: Circulation 1995;92:

8 (PL Detail-Document #280502: Page 8 of 9) FATS - Familial Atherosclerosis Treatment Study: N Engl J Med 1990;323: FLORIDA - Fluvastatin on Risk Diminishing after Acute Myocardial Infarction: [Abstract] Circulation 2000;102:2672d. GREACE - GREek Atorvastatin and Coronary-heart-disease Evaluation study: Curr Med Res Opin 2002;18: HATS - HDL Atherosclerosis Treatment Study: N Engl J Med 2001;345: HPS - Heart Protection Study: Lancet 2002;360:7-22. Lancet 2003;361: IDEAL - Incremental Decrease in End points through Aggressive Lipid lowering. JAMA 2005;294: JAPAN-ACS - Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study. J Am Coll Cardiol 2009;54: JUPITER - Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. N Engl J Med 2008;359: KAPS - Kuopio Atherosclerosis Prevention Study: Circulation 1995;92: LCAS - Lipoprotein and Coronary Atherosclerosis Study: Am J Cardiol 1997;80: L-CAD - Lipid-Coronary Artery Disease Study: Am J Cardiol 2000;86: LIPID - Long-term Intervention with Pravastatin in Ischaemic Disease: N Engl J Med 1998;339: LIPS - Lescol Intervention Prevention Study: JAMA 2002; MAAS - Multicentre Anti-Atheroma Study: Lancet 1994;344: MARS - Monitored Atherosclerosis Regression Study: Ann Intern Med 1993;119: METEOR - Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin: JAMA 2007;297: MIRACL - Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering: JAMA 2001;285: PLAC-I - Pravastatin Limitation of Atherosclerosis in the Coronary arteries (PLAC-I): J Am Coll Cardiol 1995;26: PLAC-II - Pravastatin Limitation of Atherosclerosis in the Carotid arteries. Am J Cardiol 1995;75: PROSPER - Prevention of First Stroke: Lancet 2002;360: PROVE-IT - Pravastatin or Atorvastatin Evaluation and Infection Therapy: New Engl J Med 2004;350 (early release). REGRESS - Regression Growth Evaluation Study: Circulation 1995;91: REVERSAL - Reversal of Atherosclerosis with Aggressive Lipid Lowering. JAMA 2004;291: SCAT - Simvastatin/Enalapril Coronary Atherosclerosis Trial: Circulation 2000;102: TNT - Treating to New Targets. N Engl J Med 2005;352: TREADMILL - Treatment of Peripheral Atherosclerotic Disease with Moderate or Intensive Lipid Lowering: Creager MA, et al [Abstract]. Presented at the 14th International Symposium on Drugs Affecting Lipid Metabolism, New York, September 9-13, Mohler E, et al. [Abstract]. Presented at the 75th Scientific Sessions of the American Heart Association, Chicago, November 17-20, WOSCOPS - West of Scotland Coronary Prevention Study: N Engl J Med 1995;333: Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and Internet links in this article were current as of the date of publication.

9 (Detail-Document #280502: Page 9 of 9) Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65: Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 2006;112: FDA. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. February 28, m. (Accessed March 16, 2012). 5. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol 2006;97:77C-81C. 6. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C-94C. 7. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002;123: Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS References 1. PL Detail-Document, Statin Dose Comparison (U.S.). Pharmacist s Letter/Prescriber s Letter. August 2009 (Full update October 2011). 2. PL Detail-Document, Statin Dose Comparison (Canada). Pharmacist s Letter/Prescriber s Letter. August 2009 (Last modified November 2011). Cite this document as follows: PL Detail-Document, Characteristics of the Various Statins. Pharmacist s Letter/Prescriber s Letter. May Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA ~ TEL (209) ~ FAX (209) Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to or