- Email: [email protected]
Are Statins Safe?
PHARMACY COLUMN Barbara J. Zarowitz
ARE STATINS SAFE? Barbara J. Zarowitz, PharmD, FCCP, BCPS, CGP, FASCP
Since the release of the revised National Cholesterol Education Panel Adult Treatment Panel (NCEP ATP III) guidelines, which expanded the population of patients suggested for treatment to include persons older than 65 years and those with metabolic syndrome, the question of statin safety has been revisited.1,2 In particular, given the more aggressive low-density lipoprotein (LDL) cholesterol goal of ⬍70 g/dL for patients at highest risk of coronary syndromes, statin drug therapy is more likely to be titrated to higher doses at which adverse drug events become more common.3 Although the statin safety profile on the whole is good, there are a number of statin-related events responsible for morbidity in older persons who are at increased risk of potential consequences.4 The benefit of drug therapy should always be balanced against the potential risks and the risks of adverse drug events minimized to the extent possible. In 2006, the National Lipid Association, a multidisciplinary, nonprofit association of health care providers and researchers convened a Safety Task Force to evaluate available information regarding statin safety and provide insight to practicing clinicians. The main areas of review are summarized here with general recommendations for optimizing statin safety in older Americans.
Drug Interactions Over 40 cytochrome P450 (CYP450) isoenzymes comprise the phase 1 pathways for drug metabolism.5 All statins except pravastatin undergo phase 1 metabolism through CYP450 isoenzymes. Approximately 80% of drugs require biotransformation to hydrophilic metabolites for renal elimination, with about 50% of these drugs undergoing metabolism by CYP3A4. CYP3A4 is the major liver microsomal (60%) and
212
intestinal wall (70%) isoenzyme of the CYP450 system.6 Pravastatin and rosuvastatin do not undergo significant metabolism. Many drug-drug interactions occur as a result of substrates competing for CYP3A4 metabolism.5 Common to older persons is the coadministration of the calcium channel blockers, such as verapamil and diltiazem, which inhibit CYP3A4 metabolism and can predispose patients to adverse statin effects. Dihydropyridines (i.e., amlodipine, nifedipine) do not affect CYP3A4. Most macrolide antibiotics are substrates of CYP3A4 and should be avoided during statin administration; conversely, statin therapy can be temporarily discontinued during a short course of a CYP3A4 inhibitor, such as erythromycin, ketoconazole, clarithromycin, or telithromycin (Ketek).5 Rätz Bravo et al. performed a cross-sectional study of 2742 ambulatory patients taking statins with electronic drug-drug interaction screening.7 They found that 190 patients (6.9%) exhibited a total of 198 potentially harmful interactions between simvastatin, atorvastatin, pravastatin, and fluvastatin and other agents; rosuvastatin and lovastatin were not studied. Fibrates or niacin accounted for 9.5%, CYP3A4 inhibitors accounted for 70%, and cyclosporine accounted for 1.6% of drug-statin interactions. In a separate analysis, drugs identified as most likely to increase statin serum concentrations were erythromycin, omeprazole, cimetidine, and clarithromycin.8 The risks associated with CYP3A4 inhibition and increased serum concentrations of statins affected by this metabolic pathway can include myopathy and rhabdomyolysis.5,9 Gemfibrozil is most notably associated with an increased incidence of rhabdomyolysis. The mechanism of the fibrate-statin interaction differs substantially be-
Geriatric Nursing, Volume 28, Number 4
Table 1 Effect of Cyclosporine on Statin Area under the Curve (AUC) and Recommended Dosing12,13 Recommended Daily Dose for Degree of Renal Impairment GFR (mL/min/m2) >30 or with Dialysis
Medication
>30
Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin
10–80 mg 20–80 mg 20–80 mg 20–40 mg 10–40mg 20–80 mg
10–80 10–40 10–40 20–40 10–40 10–40
tween gemfibrozil and fenofibrate. Gemfibrozil impairs glucuronidation of the hydroxyl statin acids, whereas fenofibrate does not. Gemfibrozil inhibits a hepatic uptake transporter, thereby increasing serum concentrations of simvastatin, atorvastatin, pravastatin, and rosuvastatin.10 Gemfibrozil can increase serum concentrations of pravastatin, simvastatin, lovastatin, and rosuvastatin by approximately twofold.10 Although not included in the Schneck et al. study, atorvastatin carries a label warning about adverse interactions with fibric acid derivatives as well.11 Analyses of the U.S. Food and Drug Administration Adverse Events Reporting System have suggested that the use of fenofibrate with statins results in fewer reports of rhabdomyolysis per million prescriptions than does gemfibrozil with statins.12 Higher doses of statins are associated with higher risk of adverse effects. Therefore, although fibrates as a drug class pose additional potential risk of myopathy and rhabdomyolysis in statin recipients, fenofibrate is considered safer than gemfibrozil. Some clinicians advise against the combination of fibrates and statins in older persons and particularly those with renal impairment.4 When therapeutic lifestyle changes alone fail to achieve goal triglyceride values, KDOQI recommends gemfibrozil 600 mg twice daily in persons with severe renal impairment who exhibit a hypertriglyceridemic predominance. However, in these instances, gemfibrozil monotherapy, not combined gemfibrozilstatin therapy, is recommended to minimize the potential for rhabdomyolysis.12
mg mg mg mg mg mg
With Cyclosporine
Increase in AUC with Cyclosporine
10–40 mg 10–40 mg 10–20 mg 10–20 mg 5 mg 10 mg
6 2 2–20 5 NA 3–8
Cyclosporine has been shown to increase statin serum concentrations and area under the serum concentration time curve (AUC) several fold, as seen in Table 1. Maximum recommended daily doses of all statins but pravastatin are reduced in persons receiving cyclosporine.
Simvastatin The maximum daily dose of simvastatin is 10 mg/day orally (PO) if taking gemfibrozil, danazol, or cyclosporine; 20 mg/day PO if taking amiodarone or verapamil.13
Lovastatin The maximum daily dose of lovasatin is 80 mg/day PO immediate-release tablets (e.g., Mevacor); 60 mg/day PO extended-release tablets (Altoprev); 20 mg/day PO immediate-release or extended-release lovastatin if taking fibrates, niacin, danazol, or cyclosporine; 40 mg/day PO immediate-release lovastatin if taking amiodarone or verapamil; and 20 mg/day PO extendedrelease lovastatin if taking amiodarone or verapamil.13
Rosuvastatin In adults not taking cyclosporin or gemfibrozil, the usual starting dose is 10 mg PO once daily. A lower starting dosage of 5 mg PO once daily may be initiated in patients requiring less aggressive LDL reductions, patients with CrCl ⬍30 ml/min, or patients at higher risk for myop-
Geriatric Nursing, Volume 28, Number 4
213
athy. For Asian patients, consider a lower starting dosage of 5 mg PO once daily. The overall dosage range is 5– 40 mg PO once daily. For patients with marked hypercholesterolemia (LDL ⬎190 mg/dl), a higher starting dosage of 20 mg/day may be considered. The 40 mg/day dosage is associated with a higher risk of myopathy and should be reserved for patients who require further LDL reduction after receiving the 20 mg/ day dosage. The manufacturer originally intended to seek approval for an 80-mg dose; however, 2 patients developed renal toxicity while receiving this dose. Adjust the initial dosage based on serum lipid measurements obtained at 2- to 4-week intervals to attain the target LDL and lipid goals (NCEP guidelines). Consider reducing initial dosage to 5 mg PO once daily in patients taking gemfibrozil if the combination is necessary. The maximum daily rosuvastatin dose in patients taking cyclosporine is 5 mg. Despite the lack of specific recommendations regarding concomitant cyclosporin or fibrate administration with atorvastatin and fluvastatin, caution is advised as rhabdomyolysis has been reported with both agents.12 Grapefruit juice contains 6=,7=-dihyroxybergamottin a fuanocoumarin compound that may inhibit CYP3A4 metabolism of drugs in the intestinal wall.14 The oral bioavailability of drugs metabolized by intestinal wall CYP3A4 (i.e., atorvastatin, simvastatin, and lovastatin) is thought to increase with grapefruit juice ingestion due to a loss of enzyme function. Ingestion of grapefruit juice should be avoided in patients receiving atorvastatin, simvastatin, and lovastatin because the effects are variable and last several hours after ingestion of grapefruit juice.
●
The aminotransferase elevations are a statin drug class effect. ● There are rare case reports of liver failure in patients receiving statin therapy. ● Although still recommended in product package inserts, the Liver Panel does not recommend liver enzymes and liver function tests in patients receiving long-term statin therapy. ● Statins are contraindicated in patients with decompensated cirrhosis or acute liver failure but not those with chronic liver disease or compensated cirrhosis. Dose-related aminotransferase elevations of ⬎3⫻ the upper limit of normal (ULN) generally occur in ⬍1% of statin recipients across the dose range for marketed statins; the exceptions are aminotransferase elevations of 2%–3% reported with atorvastatin 80-mg doses and in patients receiving a combination of ezetimibe with a statin.11,16,17 The overall incidence of aminotranferase elevation of ⬎3⫻ ULN is 300 per 100,000 person-years.18 These are generally transient and resolve spontaneously in 70% of cases even if the statin and dose are continued unchanged.18 Withdrawal of the statin or reduction in the statin dosage routinely results in a return of aminotransferases to within normal limits. In the absence of increased bilirubin values, isolated aminotransferase elevations have not been linked clinically or histologically to evidence of acute liver injury.15 In a meta-analysis of 49,275 patients, statins cannot be differentiated clinically by their effect on aminotransaminases, despite the fact that fluvastatin rates were statistically significantly higher than the other statins in the meta-analysis.15
Liver Dysfunction Myopathy and Rhabdomyolysis Recently the Liver Panel of the National Lipid Association reviewed the association between elevations in serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and liver dysfunction with the following specific findings15: ● With high confidence, the panel concluded that statins cause elevations in aminotransferase values. ● However, statin-induced elevations of aminotransaminases are not indicative of liver damage or dysfunction.
214
Statins are associated with muscle complaints ranging from muscle weakness and cramps to rhabdomyolysis. Statin-related muscle effects may include:9 ● myalgias—muscle ache, pain, or weakness with or without creatinine kinase (CK) elevation; ● myopathy— otherwise unexplained elevations in CK ⱖ10⫻ the upper limit of normal (ULN), associated with muscle symptoms (myalgias); and
Geriatric Nursing, Volume 28, Number 4
●
rhabdomyolysis—marked CK elevation, typically substantially ⬎10⫻ ULN and with creatinine elevation (usually brown urine and urinary myoglobin). Elevations in other muscle enzymes may also occur, as well as the following: hyperkalemia, hypocalcemia, hyperphosphatemia, hyperuricemia, metabolic acidosis, renal failure and death. Symptoms of muscle weakness may be present, but perhaps only 50% of the time. The Muscle Expert Panel of the National Lipid Association reviewed the relationship between statins and muscle disorders with the following findings19: ● Muscle complaints related to statins are a class effect. ● Myopathy and rhabdomyolysis associated with statin therapy are dependent on statin dose, serum concentrations, CYP450 metabolism, and glucuronidation half-life. ● The risk of myopathy and rhabdomyolysis is increased in older persons; those with impaired renal function (creatinine clearance [Clcr] ⬍30 ml/min), impaired liver function, and concurrent therapy with CYP3A4 inhibiting drugs or substrates. ● CK elevation in the absence of other evidence of muscle injury is indicative of statininduced muscle damage; muscle weakness or pain despite normal CK values is indicative of statin-induced muscle damage. ● The risk of myopathy or rhabdomyolysis in a statin recipient is increased with the addition of gemfibrozil or fenofibrate. ● The level of evidence is inadequate to conclude that the risk of myopathy or rhabdomyolysis in statin recipients is increase by niacin (crystalline, slow-release niacin, and extended-release niacin) or ezetimibe. Muscle side effects including myalgias, weakness, and cramps without CK elevation occur commonly in statin clinical trials at an incidence of 1.5%–3%. In data aggregated from 21 clinical studies of more than 180,000 person years of follow-up, statin-related myopathy occurs in 5 patients per 100,000 person-years and rhabdomyolysis in 1.6 patients per 100,000 personyears (placebo-corrected).20 Data from the Food and Drug Administration Adverse Reporting System (AERS) is consistent with 0.3–2.2 cases of myopathy and 0.3–13.5 cases of rhabdomyolysis per million statin prescriptions.18
The Muscle Expert Panel provided the following management recommendations18: ● Whenever muscle symptoms or an increased CK value occur in a patient receiving statin therapy, other etiologies should be ruled out because they are most likely to explain the findings; other causes of muscle symptoms include physical activity, trauma, falls, accidents, seizure, shaking chills, hypothyroidism, infections, carbon monoxide poisoning, polyositis, dermatomyositis, alcohol abuse, and drug abuse. ● It is unnecessary to obtain CK values in asymptomatic recipients of statins. ● CK values should be obtained in statin recipients with muscle symptoms to gauge the severity of the muscle damage and facilitate a decision about altering or continuing the dose. ● If other etiologies are ruled out but muscle symptoms are severe and persist, the statin should be discontinued. Once asymptomatic, the same or different statin can be restarted at an equivalent or lower dose to test the reproducibility of the symptoms. ● In patients who develop tolerable muscle complaints or are asymptomatic with a CK ⬍10⫻ ULN, statin therapy may be continued at the same or reduced dose, and symptoms may be used as the clinical guide to stop or continue therapy. ● In patients who develop rhabdomyolysis, statin therapy should be stopped. Intravenous hydration therapy should be instituted and the patient transferred to the hospital for more aggressive intervention and monitoring.
Renal Impairment Statins do not cause proteinuria, renal tubular damage, glomerular damage, hematuria, or chronic kidney disease and can be used safely in patients with chronic kidney disease whether or not they are treated by hemodialysis.21 The dose of simvastatin, lovastatin, and rosuvastatin should be reduced in persons with creatinine clearances less than 30 mL/min.13
Summary ➢
Review residents receiving statins to identify those not prescribed for evening administration and recommend administration at bedtime or with the evening meal.
Geriatric Nursing, Volume 28, Number 4
215
➢
➢
➢
➢
➢
➢
➢
➢
➢
➢
➢
➢
➢
Identify statin recipients receiving fibrate and statin therapy concomitantly. Question the need for both, and if appropriate, recommend fenofibrate unless the patient’s creatinine clearance is less than 30 ml/min.5 Gemfibrozil monotherapy or in combination with low-dose statin therapy may be appropriate in patients with end-stage renal disease.12 Caution against prescribing statin-fibrate combination therapy; when combination therapy is required, recommend clear documentation of the need for both medications and intensity the monitoring plan.5 Provide drug interaction and dosing guidance in situations when the patient may be at risk of drug-drug interactions. Double-check that the statin dose has been individualized appropriately for the degree of renal impairment, concomitant drugs, and desired lipid value targets.5 Verify that the lipid target values and goals of therapy have been documented in the patient’s medical record. Where appropriate, recommend dosage increases to attain the minimally effective tolerated dose needed to achieve target lipid values. Given that ALT and AST monitoring is still recommended in the products’ package inserts, provide advice on obtaining liver function tests when appropriate.5 Identify and counsel the multidisciplinary team if risk factors for statin-related myopathy or rhabdomyolysis are present.5,22 Work with facilities to adopt a policy for shortterm discontinuation of statin therapy during a short course of macrolide antibiotics and when residents become acutely ill or are admitted to the hospital. Caution against prescribing high-dose statin therapy for older persons or those with renal insufficiency and do not use in combination with fibrates or cyclosporin in high-risk patients.5,22 Suspect myopathy when a statin-treated patient complains of unexplained, generalized muscle pain, tenderness, or weakness. Joint pain, nocturnal leg cramps, and localized pain are not symptoms of myopathy.5,22 Consider the possibility of myopathy in older persons who report only weakness because these patients are less likely than younger patients to experience muscle pain. Recommend obtaining CK values when a patient reports symptoms of myopathy. If CK is elevated but ⬍5⫻ ULN, repeat the value in 1 week. If CK is elevated to 5⫻ ULN or greater, discontinue statin therapy and monitor serum CK values.5,22
When basic care planning steps are taken, statins can
216
be used safely to prolong life and decrease morbidity associated with progressive coronary heart disease.
References 1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final report. Circulation 2002;106:3143-3421. 2. Grundy SM. The issue of statin safety: where do we stand? Circulation 2005;111:3016-9. 3. Grundy SM, Cleeman JI, Bairey MN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39. 4. Gotto AM. Statins, cardiovascular disease, and drug safety. Am J Cardiol 2006;97(suppl):3C-5C. 5. Talbert RL. Safety issues with statin therapy. J Am Pharm Assoc 2006;46:479-90. 6. Wilkinson GR. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw Hill; 2001: 971-1002. 7. Rätz Bravo AE, Tchambaz L, Krähenbahl-Melcher A, et al. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Saf 2005;28:263-75. 8. Einarson TR, Metge CJ, Iskedjian M, Mukherjee J. An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme a reductase inhibitors on health care utilization: a Canadian population-based study. Clin Ther 2002;24: 2126-36. 9. Bays H. Statin safety: an overview and assessment of the data—2005. Am J Cardiol 2006;97(suppl):6C-26C. 10. Schneck DW, Birmingham BK, Zlikowski JA, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 2004;75:455-63. 11. Lipitor (atorvastatin) Product Information. New York: Pzifer, Inc., July 2004. 12. National Kidney Foundation. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI). Am J Transplant 2004;4(suppl 7):13-53. 13. Clinical Pharmacology On-line. Gold Standard Inc., 2007. Available at: http:www.clinicalpharmacology.com. 14. Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol 2006;97(suppl):27C-31C. 15. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol 2006; 97(suppl):77C-81C. 16. Vytorin (ezetimibe-simvastatin) Product Information. North Wales, PA: Merck/Schering-Plough Pharmaceuticals, 2005. 17. Zetia (ezetimibe) Product Information. North Wales, PA: Merck/Schering-Plough Pharmaceuticals, 2005.
Geriatric Nursing, Volume 28, Number 4
18. McKenney JM, Davison MH, Jacobson TA, et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97(suppl):89C-94C. 19. Thompson PD, Clarkson PM, Rosenson RS. An assessment of statin safety by muscle experts. Am J Cardiol 2006;97(suppl):69C-76C. 20. Law M, Rudnicka AR. Statin safety: evidence from the published literature. Am J Cardiol 2006;97(suppl 8): 52C-60C. 21. Kasiske BL, Wanner C, O’Neill C. An assessment of statin safety by nephrologists. Am J Cardiol 2006; 97(suppl):82C-85C.
22. Ballantyne CM, Corsini A, Davison MH, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003;163:553-64. BARBARA J. ZAROWITZ, Pharm.D., FCCP, BCPS, CGP, is the chief clinical officer and vice president of professional services at Omnicare, Inc., and an adjunct professor of pharmacy practice, College of Pharmacy and Allied Health Sciences, Wayne State University. 0197-4572/07/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.gerinurse.2007.06.005
Geriatric Nursing, Volume 28, Number 4
217
ARE STATINS SAFE? Barbara J. Zarowitz, PharmD, FCCP, BCPS, CGP, FASCP
Since the release of the revised National Cholesterol Education Panel Adult Treatment Panel (NCEP ATP III) guidelines, which expanded the population of patients suggested for treatment to include persons older than 65 years and those with metabolic syndrome, the question of statin safety has been revisited.1,2 In particular, given the more aggressive low-density lipoprotein (LDL) cholesterol goal of ⬍70 g/dL for patients at highest risk of coronary syndromes, statin drug therapy is more likely to be titrated to higher doses at which adverse drug events become more common.3 Although the statin safety profile on the whole is good, there are a number of statin-related events responsible for morbidity in older persons who are at increased risk of potential consequences.4 The benefit of drug therapy should always be balanced against the potential risks and the risks of adverse drug events minimized to the extent possible. In 2006, the National Lipid Association, a multidisciplinary, nonprofit association of health care providers and researchers convened a Safety Task Force to evaluate available information regarding statin safety and provide insight to practicing clinicians. The main areas of review are summarized here with general recommendations for optimizing statin safety in older Americans.
Drug Interactions Over 40 cytochrome P450 (CYP450) isoenzymes comprise the phase 1 pathways for drug metabolism.5 All statins except pravastatin undergo phase 1 metabolism through CYP450 isoenzymes. Approximately 80% of drugs require biotransformation to hydrophilic metabolites for renal elimination, with about 50% of these drugs undergoing metabolism by CYP3A4. CYP3A4 is the major liver microsomal (60%) and
212
intestinal wall (70%) isoenzyme of the CYP450 system.6 Pravastatin and rosuvastatin do not undergo significant metabolism. Many drug-drug interactions occur as a result of substrates competing for CYP3A4 metabolism.5 Common to older persons is the coadministration of the calcium channel blockers, such as verapamil and diltiazem, which inhibit CYP3A4 metabolism and can predispose patients to adverse statin effects. Dihydropyridines (i.e., amlodipine, nifedipine) do not affect CYP3A4. Most macrolide antibiotics are substrates of CYP3A4 and should be avoided during statin administration; conversely, statin therapy can be temporarily discontinued during a short course of a CYP3A4 inhibitor, such as erythromycin, ketoconazole, clarithromycin, or telithromycin (Ketek).5 Rätz Bravo et al. performed a cross-sectional study of 2742 ambulatory patients taking statins with electronic drug-drug interaction screening.7 They found that 190 patients (6.9%) exhibited a total of 198 potentially harmful interactions between simvastatin, atorvastatin, pravastatin, and fluvastatin and other agents; rosuvastatin and lovastatin were not studied. Fibrates or niacin accounted for 9.5%, CYP3A4 inhibitors accounted for 70%, and cyclosporine accounted for 1.6% of drug-statin interactions. In a separate analysis, drugs identified as most likely to increase statin serum concentrations were erythromycin, omeprazole, cimetidine, and clarithromycin.8 The risks associated with CYP3A4 inhibition and increased serum concentrations of statins affected by this metabolic pathway can include myopathy and rhabdomyolysis.5,9 Gemfibrozil is most notably associated with an increased incidence of rhabdomyolysis. The mechanism of the fibrate-statin interaction differs substantially be-
Geriatric Nursing, Volume 28, Number 4
Table 1 Effect of Cyclosporine on Statin Area under the Curve (AUC) and Recommended Dosing12,13 Recommended Daily Dose for Degree of Renal Impairment GFR (mL/min/m2) >30 or with Dialysis
Medication
>30
Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin
10–80 mg 20–80 mg 20–80 mg 20–40 mg 10–40mg 20–80 mg
10–80 10–40 10–40 20–40 10–40 10–40
tween gemfibrozil and fenofibrate. Gemfibrozil impairs glucuronidation of the hydroxyl statin acids, whereas fenofibrate does not. Gemfibrozil inhibits a hepatic uptake transporter, thereby increasing serum concentrations of simvastatin, atorvastatin, pravastatin, and rosuvastatin.10 Gemfibrozil can increase serum concentrations of pravastatin, simvastatin, lovastatin, and rosuvastatin by approximately twofold.10 Although not included in the Schneck et al. study, atorvastatin carries a label warning about adverse interactions with fibric acid derivatives as well.11 Analyses of the U.S. Food and Drug Administration Adverse Events Reporting System have suggested that the use of fenofibrate with statins results in fewer reports of rhabdomyolysis per million prescriptions than does gemfibrozil with statins.12 Higher doses of statins are associated with higher risk of adverse effects. Therefore, although fibrates as a drug class pose additional potential risk of myopathy and rhabdomyolysis in statin recipients, fenofibrate is considered safer than gemfibrozil. Some clinicians advise against the combination of fibrates and statins in older persons and particularly those with renal impairment.4 When therapeutic lifestyle changes alone fail to achieve goal triglyceride values, KDOQI recommends gemfibrozil 600 mg twice daily in persons with severe renal impairment who exhibit a hypertriglyceridemic predominance. However, in these instances, gemfibrozil monotherapy, not combined gemfibrozilstatin therapy, is recommended to minimize the potential for rhabdomyolysis.12
mg mg mg mg mg mg
With Cyclosporine
Increase in AUC with Cyclosporine
10–40 mg 10–40 mg 10–20 mg 10–20 mg 5 mg 10 mg
6 2 2–20 5 NA 3–8
Cyclosporine has been shown to increase statin serum concentrations and area under the serum concentration time curve (AUC) several fold, as seen in Table 1. Maximum recommended daily doses of all statins but pravastatin are reduced in persons receiving cyclosporine.
Simvastatin The maximum daily dose of simvastatin is 10 mg/day orally (PO) if taking gemfibrozil, danazol, or cyclosporine; 20 mg/day PO if taking amiodarone or verapamil.13
Lovastatin The maximum daily dose of lovasatin is 80 mg/day PO immediate-release tablets (e.g., Mevacor); 60 mg/day PO extended-release tablets (Altoprev); 20 mg/day PO immediate-release or extended-release lovastatin if taking fibrates, niacin, danazol, or cyclosporine; 40 mg/day PO immediate-release lovastatin if taking amiodarone or verapamil; and 20 mg/day PO extendedrelease lovastatin if taking amiodarone or verapamil.13
Rosuvastatin In adults not taking cyclosporin or gemfibrozil, the usual starting dose is 10 mg PO once daily. A lower starting dosage of 5 mg PO once daily may be initiated in patients requiring less aggressive LDL reductions, patients with CrCl ⬍30 ml/min, or patients at higher risk for myop-
Geriatric Nursing, Volume 28, Number 4
213
athy. For Asian patients, consider a lower starting dosage of 5 mg PO once daily. The overall dosage range is 5– 40 mg PO once daily. For patients with marked hypercholesterolemia (LDL ⬎190 mg/dl), a higher starting dosage of 20 mg/day may be considered. The 40 mg/day dosage is associated with a higher risk of myopathy and should be reserved for patients who require further LDL reduction after receiving the 20 mg/ day dosage. The manufacturer originally intended to seek approval for an 80-mg dose; however, 2 patients developed renal toxicity while receiving this dose. Adjust the initial dosage based on serum lipid measurements obtained at 2- to 4-week intervals to attain the target LDL and lipid goals (NCEP guidelines). Consider reducing initial dosage to 5 mg PO once daily in patients taking gemfibrozil if the combination is necessary. The maximum daily rosuvastatin dose in patients taking cyclosporine is 5 mg. Despite the lack of specific recommendations regarding concomitant cyclosporin or fibrate administration with atorvastatin and fluvastatin, caution is advised as rhabdomyolysis has been reported with both agents.12 Grapefruit juice contains 6=,7=-dihyroxybergamottin a fuanocoumarin compound that may inhibit CYP3A4 metabolism of drugs in the intestinal wall.14 The oral bioavailability of drugs metabolized by intestinal wall CYP3A4 (i.e., atorvastatin, simvastatin, and lovastatin) is thought to increase with grapefruit juice ingestion due to a loss of enzyme function. Ingestion of grapefruit juice should be avoided in patients receiving atorvastatin, simvastatin, and lovastatin because the effects are variable and last several hours after ingestion of grapefruit juice.
●
The aminotransferase elevations are a statin drug class effect. ● There are rare case reports of liver failure in patients receiving statin therapy. ● Although still recommended in product package inserts, the Liver Panel does not recommend liver enzymes and liver function tests in patients receiving long-term statin therapy. ● Statins are contraindicated in patients with decompensated cirrhosis or acute liver failure but not those with chronic liver disease or compensated cirrhosis. Dose-related aminotransferase elevations of ⬎3⫻ the upper limit of normal (ULN) generally occur in ⬍1% of statin recipients across the dose range for marketed statins; the exceptions are aminotransferase elevations of 2%–3% reported with atorvastatin 80-mg doses and in patients receiving a combination of ezetimibe with a statin.11,16,17 The overall incidence of aminotranferase elevation of ⬎3⫻ ULN is 300 per 100,000 person-years.18 These are generally transient and resolve spontaneously in 70% of cases even if the statin and dose are continued unchanged.18 Withdrawal of the statin or reduction in the statin dosage routinely results in a return of aminotransferases to within normal limits. In the absence of increased bilirubin values, isolated aminotransferase elevations have not been linked clinically or histologically to evidence of acute liver injury.15 In a meta-analysis of 49,275 patients, statins cannot be differentiated clinically by their effect on aminotransaminases, despite the fact that fluvastatin rates were statistically significantly higher than the other statins in the meta-analysis.15
Liver Dysfunction Myopathy and Rhabdomyolysis Recently the Liver Panel of the National Lipid Association reviewed the association between elevations in serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and liver dysfunction with the following specific findings15: ● With high confidence, the panel concluded that statins cause elevations in aminotransferase values. ● However, statin-induced elevations of aminotransaminases are not indicative of liver damage or dysfunction.
214
Statins are associated with muscle complaints ranging from muscle weakness and cramps to rhabdomyolysis. Statin-related muscle effects may include:9 ● myalgias—muscle ache, pain, or weakness with or without creatinine kinase (CK) elevation; ● myopathy— otherwise unexplained elevations in CK ⱖ10⫻ the upper limit of normal (ULN), associated with muscle symptoms (myalgias); and
Geriatric Nursing, Volume 28, Number 4
●
rhabdomyolysis—marked CK elevation, typically substantially ⬎10⫻ ULN and with creatinine elevation (usually brown urine and urinary myoglobin). Elevations in other muscle enzymes may also occur, as well as the following: hyperkalemia, hypocalcemia, hyperphosphatemia, hyperuricemia, metabolic acidosis, renal failure and death. Symptoms of muscle weakness may be present, but perhaps only 50% of the time. The Muscle Expert Panel of the National Lipid Association reviewed the relationship between statins and muscle disorders with the following findings19: ● Muscle complaints related to statins are a class effect. ● Myopathy and rhabdomyolysis associated with statin therapy are dependent on statin dose, serum concentrations, CYP450 metabolism, and glucuronidation half-life. ● The risk of myopathy and rhabdomyolysis is increased in older persons; those with impaired renal function (creatinine clearance [Clcr] ⬍30 ml/min), impaired liver function, and concurrent therapy with CYP3A4 inhibiting drugs or substrates. ● CK elevation in the absence of other evidence of muscle injury is indicative of statininduced muscle damage; muscle weakness or pain despite normal CK values is indicative of statin-induced muscle damage. ● The risk of myopathy or rhabdomyolysis in a statin recipient is increased with the addition of gemfibrozil or fenofibrate. ● The level of evidence is inadequate to conclude that the risk of myopathy or rhabdomyolysis in statin recipients is increase by niacin (crystalline, slow-release niacin, and extended-release niacin) or ezetimibe. Muscle side effects including myalgias, weakness, and cramps without CK elevation occur commonly in statin clinical trials at an incidence of 1.5%–3%. In data aggregated from 21 clinical studies of more than 180,000 person years of follow-up, statin-related myopathy occurs in 5 patients per 100,000 person-years and rhabdomyolysis in 1.6 patients per 100,000 personyears (placebo-corrected).20 Data from the Food and Drug Administration Adverse Reporting System (AERS) is consistent with 0.3–2.2 cases of myopathy and 0.3–13.5 cases of rhabdomyolysis per million statin prescriptions.18
The Muscle Expert Panel provided the following management recommendations18: ● Whenever muscle symptoms or an increased CK value occur in a patient receiving statin therapy, other etiologies should be ruled out because they are most likely to explain the findings; other causes of muscle symptoms include physical activity, trauma, falls, accidents, seizure, shaking chills, hypothyroidism, infections, carbon monoxide poisoning, polyositis, dermatomyositis, alcohol abuse, and drug abuse. ● It is unnecessary to obtain CK values in asymptomatic recipients of statins. ● CK values should be obtained in statin recipients with muscle symptoms to gauge the severity of the muscle damage and facilitate a decision about altering or continuing the dose. ● If other etiologies are ruled out but muscle symptoms are severe and persist, the statin should be discontinued. Once asymptomatic, the same or different statin can be restarted at an equivalent or lower dose to test the reproducibility of the symptoms. ● In patients who develop tolerable muscle complaints or are asymptomatic with a CK ⬍10⫻ ULN, statin therapy may be continued at the same or reduced dose, and symptoms may be used as the clinical guide to stop or continue therapy. ● In patients who develop rhabdomyolysis, statin therapy should be stopped. Intravenous hydration therapy should be instituted and the patient transferred to the hospital for more aggressive intervention and monitoring.
Renal Impairment Statins do not cause proteinuria, renal tubular damage, glomerular damage, hematuria, or chronic kidney disease and can be used safely in patients with chronic kidney disease whether or not they are treated by hemodialysis.21 The dose of simvastatin, lovastatin, and rosuvastatin should be reduced in persons with creatinine clearances less than 30 mL/min.13
Summary ➢
Review residents receiving statins to identify those not prescribed for evening administration and recommend administration at bedtime or with the evening meal.
Geriatric Nursing, Volume 28, Number 4
215
➢
➢
➢
➢
➢
➢
➢
➢
➢
➢
➢
➢
➢
Identify statin recipients receiving fibrate and statin therapy concomitantly. Question the need for both, and if appropriate, recommend fenofibrate unless the patient’s creatinine clearance is less than 30 ml/min.5 Gemfibrozil monotherapy or in combination with low-dose statin therapy may be appropriate in patients with end-stage renal disease.12 Caution against prescribing statin-fibrate combination therapy; when combination therapy is required, recommend clear documentation of the need for both medications and intensity the monitoring plan.5 Provide drug interaction and dosing guidance in situations when the patient may be at risk of drug-drug interactions. Double-check that the statin dose has been individualized appropriately for the degree of renal impairment, concomitant drugs, and desired lipid value targets.5 Verify that the lipid target values and goals of therapy have been documented in the patient’s medical record. Where appropriate, recommend dosage increases to attain the minimally effective tolerated dose needed to achieve target lipid values. Given that ALT and AST monitoring is still recommended in the products’ package inserts, provide advice on obtaining liver function tests when appropriate.5 Identify and counsel the multidisciplinary team if risk factors for statin-related myopathy or rhabdomyolysis are present.5,22 Work with facilities to adopt a policy for shortterm discontinuation of statin therapy during a short course of macrolide antibiotics and when residents become acutely ill or are admitted to the hospital. Caution against prescribing high-dose statin therapy for older persons or those with renal insufficiency and do not use in combination with fibrates or cyclosporin in high-risk patients.5,22 Suspect myopathy when a statin-treated patient complains of unexplained, generalized muscle pain, tenderness, or weakness. Joint pain, nocturnal leg cramps, and localized pain are not symptoms of myopathy.5,22 Consider the possibility of myopathy in older persons who report only weakness because these patients are less likely than younger patients to experience muscle pain. Recommend obtaining CK values when a patient reports symptoms of myopathy. If CK is elevated but ⬍5⫻ ULN, repeat the value in 1 week. If CK is elevated to 5⫻ ULN or greater, discontinue statin therapy and monitor serum CK values.5,22
When basic care planning steps are taken, statins can
216
be used safely to prolong life and decrease morbidity associated with progressive coronary heart disease.
References 1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final report. Circulation 2002;106:3143-3421. 2. Grundy SM. The issue of statin safety: where do we stand? Circulation 2005;111:3016-9. 3. Grundy SM, Cleeman JI, Bairey MN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39. 4. Gotto AM. Statins, cardiovascular disease, and drug safety. Am J Cardiol 2006;97(suppl):3C-5C. 5. Talbert RL. Safety issues with statin therapy. J Am Pharm Assoc 2006;46:479-90. 6. Wilkinson GR. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw Hill; 2001: 971-1002. 7. Rätz Bravo AE, Tchambaz L, Krähenbahl-Melcher A, et al. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Saf 2005;28:263-75. 8. Einarson TR, Metge CJ, Iskedjian M, Mukherjee J. An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme a reductase inhibitors on health care utilization: a Canadian population-based study. Clin Ther 2002;24: 2126-36. 9. Bays H. Statin safety: an overview and assessment of the data—2005. Am J Cardiol 2006;97(suppl):6C-26C. 10. Schneck DW, Birmingham BK, Zlikowski JA, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 2004;75:455-63. 11. Lipitor (atorvastatin) Product Information. New York: Pzifer, Inc., July 2004. 12. National Kidney Foundation. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI). Am J Transplant 2004;4(suppl 7):13-53. 13. Clinical Pharmacology On-line. Gold Standard Inc., 2007. Available at: http:www.clinicalpharmacology.com. 14. Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol 2006;97(suppl):27C-31C. 15. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol 2006; 97(suppl):77C-81C. 16. Vytorin (ezetimibe-simvastatin) Product Information. North Wales, PA: Merck/Schering-Plough Pharmaceuticals, 2005. 17. Zetia (ezetimibe) Product Information. North Wales, PA: Merck/Schering-Plough Pharmaceuticals, 2005.
Geriatric Nursing, Volume 28, Number 4
18. McKenney JM, Davison MH, Jacobson TA, et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97(suppl):89C-94C. 19. Thompson PD, Clarkson PM, Rosenson RS. An assessment of statin safety by muscle experts. Am J Cardiol 2006;97(suppl):69C-76C. 20. Law M, Rudnicka AR. Statin safety: evidence from the published literature. Am J Cardiol 2006;97(suppl 8): 52C-60C. 21. Kasiske BL, Wanner C, O’Neill C. An assessment of statin safety by nephrologists. Am J Cardiol 2006; 97(suppl):82C-85C.
22. Ballantyne CM, Corsini A, Davison MH, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003;163:553-64. BARBARA J. ZAROWITZ, Pharm.D., FCCP, BCPS, CGP, is the chief clinical officer and vice president of professional services at Omnicare, Inc., and an adjunct professor of pharmacy practice, College of Pharmacy and Allied Health Sciences, Wayne State University. 0197-4572/07/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.gerinurse.2007.06.005
Geriatric Nursing, Volume 28, Number 4
217