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DRUG RECORD

 

LOVASTATIN

OVERVIEW
Lovastatin

 

Introduction

Lovastatin is a commonly used cholesterol lowering agent (statin) that is associated with mild, asymptomatic and self-limited serum aminotransferase elevations during therapy and rarely with clinically apparent acute liver injury.

Background

Lovastatin (loe" va stat' in) is an orally available inhibitor of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the major rate-limiting enzyme in cholesterol synthesis.  Like other members of its class (the “statins”), lovastatin lowers total serum cholesterol and low density lipoprotein (LDL) concentrations, thereby reducing the risk of atherosclerosis and its complications – myocardial infarction and stroke.  Lovastatin is indicated for treatment of hypercholesterolemia in persons at high risk for coronary, cerebrovascular and peripheral artery disease.  Lovastatin is available in tablets of 10, 20, 40 and 60 mg in generic forms and under the brand name Mevacor.  Extended release forms (Altoprev) and fixed combinations with niacin (Advicor) are also available.  The recommended adult dose is 10 to 80 mg daily in single or two divided doses based upon tolerability and lipid levels.  Lovastatin was approved for use in the United States in 1987, the first of this class of drugs to be commercially available.  Lovastatin is a widely prescribed drug with more than 7 million prescriptions filled yearly.  Common side effects include muscle cramps, joint aches, headache and weakness.

Hepatotoxicity

Lovastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations.  In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in 3 to 5% of patients, but were above 3 times the upper limit of normal (ULN) in only 0.4% compared to 0.1% of placebo recipients.  These elevations were more common with higher doses of lovastatin, being greater than 3 times ULN in 0.1% of patients receiving 20 mg daily, 0.9% with 40 mg and 1.5% with 80 mg daily.  Most of these elevations were self-limited and did not require dose modification, although discontinuation is recommended for any elevation above 10 times and for persistent elevations above 5 times the ULN.  Lovastatin is also associated with frank, clinically apparent hepatic injury, but cases are rare.  The onset of clinical injury ranges from a few weeks to several years.  The pattern of injury is typically cholestatic, but can be hepatocellular.  Rash, fever and eosinophilia are uncommon as are autoimmune features.  The injury usually resolves rapidly upon stopping lovastatin, but instances of prolonged cholestasis have been reported (Case 1).  

 

The traditional Chinese medication known as red yeast rice which is used to treat hyperlipidemia has been shown to contain monacolin K, a natural component that is chemically identical to lovastatin, perhaps explaining its efficacy in reducing cholesterol levels.  Red yeast rice has also been implicated in cases of acute liver injury and myopathies that are similar to those linked to lovastatin.  In some instances cross-sensitivity to hepatic injury has been shown between red yeast rice products and lovastatin.

 

Likelihood score: B (likely cause of clinically apparent liver injury). 

Mechanism of Injury

The cause of hepatic injury from lovastatin is unknown.  Lovastatin is largely metabolized in the liver (via CYP 3A4) and metabolites are excreted in bile.  The mild, self-limited ALT elevations are likely due to a toxic intermediate of drug metabolism and the reversal of these elevations due to adaptation.  The idiosyncratic, clinically apparent liver injury associated with lovastatin may be due to failure of adaptation.

Outcome and Management

The ALT elevations that occur with lovastatin therapy often resolve spontaneously within a few weeks without discontinuation.  The product label for lovastatin mentions rare cases of acute liver failure due to lovastatin, some of which were fatal.  There have not been fatal instances of acute liver injury attributable to lovastatin in the published literature.  In the average case, recovery is expected within 1 to 2 months of stopping lovastatin, but instances of prolonged cholestasis and some degree of vanishing bile duct syndrome have been reported.  In view of the wide scale use of lovastatin, clinically apparent and severe liver injury is extraordinarily rare.  Recurrence of injury with rechallenge has been reported and should be avoided.  Switching therapy to another statin after lovastatin induced injury is apparently safe, but few instances have been reported, and it should be done with careful monitoring for recurrence.

Drug Class:  Antilipemic Agents

 

Other Drugs in the Subclass, Statins:  Atorvastatin, Ezetimibe [used in combination], Fluvastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin

 

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CASE REPORT
Lovastatin

 

Case 1.  Cholestatic hepatitis due to lovastatin therapy.
[Modified from:  McQueen MJ. Cholestatic jaundice associated with lovastatin (Mevacor) therapy. Can Med Assoc J 1990; 142: 841-842.]

 

A 40 year old man developed fatigue, dark urine, jaundice and itching approximately 11 weeks after starting lovastatin (20 mg daily).  He had no previous history of liver disease and drank little alcohol.  He had a past history of kidney stones, hyperlipidemia and hypertension, and his other medications included allopurinol (100 mg daily) and the combination of hydrochlorothiazide and amiloride.  Liver tests had been normal in the past.  When he was finally seen and evaluated, 17 weeks after starting therapy, laboratory tests showed a mixed pattern of serum enzyme elevations.  Tests for hepatitis A and B and for autoantibodies were negative.  An ultrasound of the abdomen showed evidence suggestive of bile duct dilatation, but ERCP was normal.  Lovastatin was stopped and he improved symptomatically.  Liver tests had improved but were not completely normal six months later.

 

Key Points

Medication:Lovastatin (20 mg daily)
Pattern: Mixed (R=4.7)
Severity: 3+ (jaundice, hospitalization)
Latency: 11 weeks to symptoms
Recovery: 6 months
Other medications:Allopurinol, hydrochlorothiazide, amiloride

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
0 25 77 Lovastatin started
7 weeks 38 64
17 weeks 0 381 277 Lovastatin stopped
19 weeks 10 days 337 381
21 weeks 4 weeks 205 6.5
6 months 2 months 229 133 1.9
10 months 6 months 65 112
Normal Values <35 <120 <1.2

* Some values estimated from Figure 1.


Comment

The patient had symptoms of a cholestatic hepatitis with prominence of jaundice and itching.  There was a delay in stopping lovastatin and the cholestatic hepatitis was prolonged.  At the time of this report, lovastatin had been available for only approximately a year, and 3 cases of jaundice possibly related to lovastatin had already been reported to the Food and Drug Administration (MedWatch).

 

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Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review.  Most of these reference cases are from

the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case.  All cases have been reviewed and cleared

of personal identifiers and a brief comment added by the LiverTox editors.  Click on the following link to view the submitted case reports that have been made publically available.


Submitted Cases on Lovastatin

 

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PRODUCT INFORMATION
Lovastatin

 

REPRESENTATIVE TRADE NAMES
Lovastatin – Altoprev®, Mevacor®


DRUG CLASS
Antilipemic Agents


COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Lovastatin 75330-75-5 C24-H36-O5 Image of Chemical Structure

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REFERENCES
Lovastatin

 

References updated: 05 August 2017

  1. Zimmerman HJ. Drugs used in the treatment of hypercholesterolemia and hyperlipidemia. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 660-2.  (Expert review of hepatotoxicity published in 1999; the statins have dose related hepatic effects in guinea pigs and rabbits, and transient elevations in aminotransferases occur in 1-5% of humans treated; several cases of clinically apparent liver injury from lovastatin and simvastatin have been published).

  2. De Marzio DH, Navarro VJ.  Hepatotoxicity of cardiovascular and antidiabetic medications. Lipid lowering agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 519-40.  (Review of hepatotoxicity of lipid lowering agents; asymptomatic elevations in aminotransferases are common in patients receiving statins, but clinically significant hepatotoxicity is rare).

  3. Bersot TP. Drug therapy for hypercholesterolemia and dyslipidemia. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 877-908.  (Textbook of pharmacology and therapeutics: “the statins are the most effective and best-tolerated agents for treating dyslipidemia.” Act by inhibition of the rate limiting step in hepatic cholesterol synthesis).

  4. Stein EA, Lamkin GE, Bewley DZ. Lovastatin alone and in combination for treatment of primary hypercholesterolemia. Prog Clin Biol Res 1988; 255: 281-93. PubMed Citation  (Controlled trial comparing lovastatin to niacin in 80 patients, one lovastatin treated patient had transient ALT elevation >3 times ULN).

  5. The Lovastatin Study Group III. A multicenter comparison of lovastatin and cholestyramine therapy for severe primary hypercholesterolemia. JAMA 1988; 260: 359-66. PubMed Citation  (Controlled trial of lovastatin [20 or 40 mg/day] vs cholestyramine [16 g/day] for 12 weeks in 264 patients with hypercholesterolemia; ALT levels increased more frequently in cholestyramine treated patients, and ALT levels >2 times ULN occurred in 9% of cholestyramine vs 1% of lovastatin treated patients).

  6. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988; 63: 28J-34J. PubMed Citation  (Long term safety study of 744 patients receiving lovastatin, 9 [1.2%] developed raised serum enzymes).

  7. Mantell G, Burke MT, Staggers J. Extended clinical safety profile of lovastatin. Am J Cardiol. 1990; 66: 11B-15B. PubMed Citation  (Review of safety data on lovastatin from extensions of prelicensure clinical trials and the first year of postmarketing adverse event reporting; in clinical trials in 744 patients, rates of ALT elevations >3 times ULN were 0.1% on placebo vs 0.1% on 20 mg, 0.7% on 40 mg, and 1.5% on 80 mg of lovastatin daily; 49 cases of liver toxicity reported to MedWatch, but most could not be verified and most resolved spontaneously, but two positive rechallenges and two deaths from liver disease, although they were considered not drug related).

  8. Bilheimer DW. Long-term clinical tolerance of lovastatin and simvastatin. Cardiology 1990; 77 Suppl 4: 58-65. PubMed Citation  (Review; serum enzyme elevations occur in 1.3% of lovastatin treated patients, reversible upon discontinuation of drug).

  9. McQueen MJ. Cholestatic jaundice associated with lovastatin(Mevacor) therapy. Can Med Assoc J 1990; 142: 841-2. PubMed Citation  (40 year old man developed jaundice 11 weeks after starting lovastatin [peak bilirubin 6.5 mg/dL, ALT 381U/L, Alk P 381 U/L], resolving, but not completely, within 6 months of stopping: Case 1).

  10. Geddes JA. Cholestatic jaundice associated with lovastatin(Mevacor) therapy. Can Med Assoc J 1990; 143: 13-14. PubMed Citation  (72 year old woman developed jaundice 13 months after starting lovastatin [bilirubin 1.8 mg/dL, AST 177 U/L, Alk P 351 U/L], resolving within 4 weeks of stopping; but also exposed to cloxacillin 2 weeks before onset of jaundice).

  11. Spreckelsen U, Kirchoff R, Haake H. [Cholestatic jaundice during lovastatin medication](German). Dtsch Med Wochenschr 1991; 116: 739-40. PubMed Citation  (48 year old man developed jaundice 8 weeks after starting lovastatin [bilirubin 6.2 mg/dL, ALT 341 U/L, Alk P 389 U/L], resolving within 2 weeks of stopping).

  12. Bradford RH, Shear RL, Chremos AN, Dujovne C, Downton M, Franklin FA, Gould AL, et al. Expanded clinical evaluation of lovastatin(EXCEL) study results. I. Efficacy in modifying lipoproteins and adverse events profile of 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991; 151: 43-9. PubMed Citation  (Large, randomized controlled trial of 3 doses of lovastatin vs placebo in 8245 patients; serum ALT or AST elevations >3 times ULN occurred in 0.1% on placebo, 0.1% on 20 mg, 0.9% on 40 mg, and 1.5% on 80 mg of lovastatin daily).

  13. Raveh D, Arnon R, Israeli A, Eisenberg S. Lovastatin-induced hepatitis. Isr J Med Sci. 1992; 28: 101-2. PubMed Citation  (50 year old woman developed enzyme elevations and marked pruritus 7 months after starting lovastatin [bilirubin 0.7 mg/dL, ALT 296 U/L, Alk P 626 U/L], with prompt disappearance of symptoms, but slow improvement in abnormal liver tests upon stopping lovastatin).

  14. The Lovastatin Pravastatin Study Group. A multicenter comparative trial of lovastatin and pravastatin in the treatment of hypercholesterolemia. Am J Cardiol 1993; 71: 810-5. PubMed Citation  (Controlled trial of lovastatin [20 to 80 mg] vs pravastatin [10 to 40 mg] daily for 18 weeks in 672 hypercholesterolemic patients; ALT elevations >3 times ULN occurred in 1 lovastatin and 2 pravastatin treated patients; no clinically apparent liver injury mentioned).

  15. Grimbert S, Pessayre D, Degott C, Benhamou JP. Acute hepatitis induced by HMG-CoA reductase inhibitor, lovastatin. Dig Dis Sci. 1994; 39: 2032-3. PubMed Citation  (64 year old man developed jaundice 12 weeks after starting lovastatin [bilirubin 11.7 mg/dL, ALT 8 times and Alk P 1.5 times ULN], resolving within 2 months of stopping).

  16. LaRosa JC, Applegate W, Crouse JR 3rd, Hunninghake DB, Grimm R, Knopp R, Eckfeldt JH, et al. Cholesterol lowering in the elderly: results of the cholesterol reduction in seniors program (CRISP) pilot study. Arch Intern Med 1994; 154: 529-39. PubMed Citation  (Controlled trial of lovastatin vs placebo in 431 patients; average ALT levels were identical and constant in all 3 groups during treatment).

  17. Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic carotid artery progression study (ACAPS) research group. Circulation 1994; 90: 1679-87. PubMed Citation  (No comment on liver injury in this double blind randomized controlled clinical trial).

  18. Bradford RH, Shear RL, Chremos AN, Cujovne CA, Franklin FA, Grillo RB, Higgins J, et al. Expanded clinical evaluation of lovastatin(EXCEL) study results. Two year efficacy and safety follow up. Am J Cardiol 1994; 74: 667-73. PubMed Citation  (Controlled trial of lovastatin [20 mg daily] vs placebo in 8245 patients with hypercholesterolemia; confirmed ALT elevations >3 times ULN occurred in only 1 patient on lovastatin during year 2, and no episodes of clinically apparent liver disease; rates of ALT elevations >3 times ULN were 0.1% for placebo and 20 mg, 0.9% for 40 mg, and 1.9% for 80 mg daily).

  19. Huchzermeyer H, Munzenmaier R. [Lovastatin-induced acute cholestatic hepatitis] [German]. Dtsch Med Wochenschr. 1995;120:252-6. German. PubMed Citation  (58 year old man and 54 year old woman developed cholestatic hepatitis 3 years and 2 months after starting lovastatin [peak bilirubin 15.0 and 9.2 mg/dL, ALT 276 and 384 U/L, Alk P 1227 and 595 U/L], both cases resolving slowly after stopping).

  20. Gavilán Carrasco JC, Bermúdez Recio F, Salgado Ordóñez F, González Santos P. [Hepatitis due to lovastatin] Med Clin(Barc) 1996; 107: 557-8. PubMed Citation  (51 year old with epilepsy on long term phenytoin, phenobarbital and valproate therapy developed jaundice 6 weeks after starting lovastatin [bilirubin 15 mg/dL, ALT 4000 U/L, Alk P 662 U/L], resolving within 2 months of stopping; restarted on phenobarbital and carbamazepine without recurrence).

  21. Bruguera M, Joya P, Rodés J. [Hepatitis associated with treatment with lovastatin. Presentation of 2 cases] Gastroenterol Hepatol. 1998; 21: 127-8. PubMed Citation  (Two women, ages 57 and 59 years, developed symptomatic but anicteric hepatitis 9 months and 3 years after starting lovastatin [bilirubin 0.8 and 1.3 mg/dL, ALT 244 and 273 U/L, Alk P 845 and 306 U/L], resolving rapidly on stopping).

  22. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA 1998; 279: 1615-22. PubMed Citation  (Controlled trialof lovastatin in 9905 patients; AST or ALT elevations >3 times ULN occurred in 0.7% on 20 mg and 0.4% on 40 mg of lovastatin, and 0.3% on placebo).

  23. de Denus S, Spinler SA, Miller K, Peterson AM. Statins and liver toxicity: a meta-analysis. Pharmacotherapy 2004; 24: 584-91. PubMed Citation  (Systematic review of 13 large controlled trials of statins with at least 48 weeks of therapy in 43,390 patients; overall odds ratio for liver test abnormalities with statins versus placebo was 1.26; lovastatin 1.78; simvastatin 1.06; pravastatin 1.00, and fluvastatin, 3.54).

  24. Charles EC, Olson KL, Sandhoff BG, McClure DL, Merenich JA. Evaluation of cases of severe statin-induced transaminitis within a large health maintenance organization. Am J Med 2005; 118: 618-24. PubMed Citation  (Among 23,000 patients on statins in a health plan, 17 had ALT elevation >10 times ULN attributable to statin use; 10 on simvastatin, 5 lovastatin, and 2 atorvastatin; onset 2 days to 4 years after starting; 10 symptomatic; all resolved within 2-8 weeks, except one death; 3 of 7 recurred on rechallenge, 5 of 6 tolerated switching to another statin).

  25. Tolman KG. The liver and lovastatin. Am J Cardiol 2002; 89: 1374-80. PubMed Citation  (In premarketing controlled trials of lovastatin, 21% of patients had ALT elevations, but only 1.9% had ALT >3 times ULN and rates were similar to comparator statins).

  26. Parra JL, Reddy KR. Hepatotoxicity of hypolipidemic drugs. Clin Liver Dis 2003; 7: 415-33. PubMed Citation  (Review and discussion of individual agents; lovastatin available since 1990 and linked to several case reports of hepatotoxicity).

  27. Bays HE, Dujovne CA, McGovern ME, White TE, Kashyap ML, Hutcheson AG, Crouse JR; Advicor Versus Other Cholesterol-Modulating Agents Trial Evaluation. Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin(the Advicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol 2003; 91: 667-72. PubMed Citation  (Controlled trial comparing lovastatin combined with niacin to atorvastatin or simvastatin alone in 315 patients for 16 weeks; no patient had confirmed ALT elevation >3 times ULN).

  28. Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129: 512-21. PubMed Citation  (Analysis of 461 cases of drug induced liver disease 1984 to 2004 in Spanish Registry; 11 cases [2%] were attributed to “statins”, but no specific agent caused more than 4 cases).

  29. Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol 2006; 4: 902-7. PubMed Citation  (Electronic record review of rate of ALT elevations in patients with hepatitis C with or without statin therapy and controls on statin therapy found no differences between the three groups [20%, 24% and 17%]; severe abnormalities most frequent in patients with chronic hepatitis C not on statins [6.6% vs 1.2%]).

  30. Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: a meta-analysis. Clin Ther 2006; 28: 26-35. PubMed Citation  (Meta analysis of adverse event rates in 18 placebo controlled trials of six statins in 71,108 patients; ALT elevations >3 times ULN in 1.7% of statin vs 1.4% placebo recipients; event rates highest with atorvastatin, lowest with fluvastatin).

  31. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006; 97(8A): 52C-60C. PubMed Citation  (Review of safety of statins; 38 cases of acute liver failure attributed to statins were submitted to MedWatch by end of 1999, which gives an estimated rate of 1 per million person years of use; rate of confirmed ALT elevations >3 times ULN is 0.1% with statins and 0.04% with placebo).

  32. Dale KM, White CM, Henyan NN, Kluger J, Coleman CI. Impact of statin dosing intensity on transaminase and creatine kinase. Am J Med 2007; 120: 706-12. PubMed Citation  (Meta analysis of rates of ALT and CPK elevations in nine controlled studies comparing low vs high doses of statins; ALT elevations >3 times ULN occurred in 1.5% of high- and 0.4% of low-intensity statin groups, effect particularly seen with hydrophilic [pravastatin and atorvastatin] compared to lipophilic agents [simvastatin and lovastatin]).

  33. Alsheikh-Ali AA, Karas RH. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system). Am J Cardiol 2007; 99: 379-81. PubMed Citation  (Analysis of MedWatch reports of adverse events found no excess in liver related adverse event reports per million prescription due to lovastatin alone [2.3] vs niacin alone [2.5] vs the combination [3.2], but slightly higher rates with atorvastatin [4.5], simvastatin [5.7] and pravastatin [4.9], but data relied upon spontaneous reporting).

  34. Bhardwah SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis 2007; 11: 597-613. PubMed Citation  (Review of hepatotoxicity of statins; reported rates of ALT or AST elevations >3 times ULN: atorvastatin 0.7%, fluvastatin 1.2%, lovastatin 0.6%, pravastatin 1.4%, rosuvastatin 0% and simvastatin 1.8%. Usually asymptomatic, individual case reports of autoimmune hepatitis).

  35. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol 2007; 50: 409-18. PubMed Citation  (Systematic review of relationship between LDL cholesterol lowering effects and adverse events in 23 statin treatment arms representing 309,506 person years of therapy; positive and graded relationship between statin dose [simvastatin, lovastatin and atorvastatin] and rates of ALT elevations, but no independent relationship to degree of LDL cholesterol decrease).

  36. Stein CA, Goel S, Ghavamian R. Hepatitis and rhabdomyolysis in a patient with hormone refractory prostate cancer on ketoconazole and concurrent lovastatin therapy. Invest New Drugs 2007; 25: 277-8. PubMed Citation  (84 year old man on long term lovastatin developed muscle weakness 4 weeks after starting ketoconazole [bilirubin and Alk P normal, ALT 829 U/L, CPK 47,250 U/L], suspected to be rhabdomyolysis caused by effects of ketoconazole on lovastatin pharmacokinetics, resolving in 3 weeks after stopping both).

  37. Alsheikh-Ali A, Karas RH. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone. Am J Cardiol 2007; 99: 379-81. PubMed Citation  (Review of Medwatch data base for serious adverse events: rates per million prescriptions were 11.2 for lovastatin/niacin ER; 11.6 niacin ER; 7.7 lovastatin; 19.6 atorvastatin; 22.6 simvastatin; 14.8 pravastatin. Hepatotoxicity [undefined] per million occurred in: 3.6 for lovastatin/ niacin ER; 2.4 niacin ER; 2.2 lovastatin; 4.2 atorvastatin; 5.9 simvastatin; 5.0 pravastatin).

  38. Martin JE, Cavanaugh TM, Trumbull L, Bass M, Weber F Jr, Aranda-Michel J, Hanaway M, et al. Incidence of adverse events with HMG-CoA reductase inhibitors in liver transplant patients. Clin Transplant 2008; 22: 113-9. PubMed Citation  (Retrospective review of adverse events associated with statin and fibrate use in 69 patients with liver transplants; myalgias problematic in 5, myopathy in 1, but none had significant ALT elevations or hepatitis related to medication).

  39. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug-Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 3 cases were attributed to atorvastatin, 3 to simvastatin/ezetimibe, and one each to pravastatin, fluvastatin, and simvastatin [none attributed to lovastatin], but most cases were mild or not clearly attributable to the statin therapy).

  40. Neuvonen PJ, Backman JT, Niemi M. Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clin Pharmacokinet 2008; 47: 463-74. PubMed Citation  (Review of literature on pharmacokinetics of statins; simvastatin and lovastatin are metabolized extensively by the P450 system and levels are affected by inhibitors or inducers of CYP 3A4 [itraconazole, erythromycin, verapamil, diltiazem, cyclosporine], whereas fluvastatin and pravastatin are minimally, if at all, affected).

  41. Avins AL, Manos MM, Ackerson L, Zhao W, Murphy R, Levin TR, Watson DJ, et al. Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study. Drug Saf 2008; 31: 325-34. PubMed Citation  (Analysis of electronic medical records on 93,106 patients, 14% of whom had received lovastatin; compared to controls, patients receiving lovastatin had lower rates of moderate ALT elevations and diagnosis of cirrhosis or liver failure compared to controls who did not receive lovastatin).

  42. Roselle H, Ekatan A, Tzeng J, Sapienza M, Kocher J. Symptomatic hepatitis associated with the use of herbal red yeast rice. Ann Intern Med 2008; 149: 516-7. PubMed Citation  (62 year old woman developed fever, nausea and fatigue 4 months after starting red yeast rice extract [ALT 211 U/L, bilirubin and Alk P not given], resolving within several months of stopping).

  43. Grieco A, Miele L, Pompili M, Biolato M, Vecchio FM, Grattagliano I, Gasbarrini G. Acute hepatitis caused by a natural lipid-lowering product: when "alternative" medicine is no "alternative" at all. J Hepatol 2009; 50: 1273-7. PubMed Citation  (63 year old woman with ALT elevations after 6 months of lovastatin use, developed fatigue 6 months after starting a cholesterol lowering herbal preparation containing red yeast rice extract [bilirubin 1.9 mg/dL, ALT 1760 U/L, Alk P 722 U/L], resolving over the next 6 months, but with persistence of ALT elevations).

  44. Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009; 29: 412-22. PubMed Citation  (Case reports linked to fluvastatin and atorvastatin and review of literature on statin related hepatotoxicity).

  45. Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med 2009; 150: 830-9. PubMed Citation  (Controlled trial of red yeast rice extract vs placebo in 62 patients who had stopped statin therapy because of myalgias, found similar rates of myalgias [7% vs 3%] and no change in ALT or AST levels in both groups).

  46. Halbert SC, French B, Gordon RY, Farrar JT, Schmitz K, Morris PB, Thompson PD, et al. Tolerability of red yeast rice  (2,400 mg twice daily) versus pravastatin  (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol 2010; 105: 198-204. PubMed Citation  (43 patients with myalgias due to statin use were treated with pravastatin or red rice extract for 24 weeks; discontinuation due to myalgias occurred in 5% on red yeast rice extract and 9% on pravastatin, and mean ALT levels were similar between the 2 groups).

  47. Gordon RY, Cooperman T, Obermeyer W, Becker DJ. Marked variability of monacolin levels in commercial red yeast rice products: buyer beware! Arch Intern Med 2010; 170: 1722-7. PubMed Citation  (Among 12 red yeast rice extracts commercially available in the US, total monacolin concentrations varied from 0.3-11.1 mg/capsule, monacolin K by 0.1-10.1 mg/capsule, and citrinin [which is nephrotoxic] was present in 4).

  48. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010; 340: c2197. PubMed Citation  (Among 225,922 new users of statins in a UK health care database, there was an increased risk of moderate or severe liver dysfunction [ALT >3 times ULN], usually within first 6 months and associated with higher doses of statins; relative risks were highest with fluvastatin [2.53 in women, 1.97 in men] and lowest with pravastatin [0.93 to 1.58]; there were too few persons treated with lovastatin for separate analysis).

  49. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury, of which 6 were attributed to statins: 2 atorvastatin, 2 simvastatin [one with ezetimibe] and 2 cerivastatin).

  50. Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012; 56:374-80. PubMed Citation  (Between 1988 and 2010, the Swedish registry received 217 adverse event reports possibly related to statins, 124 [57%] being liver related, 73 of which could be evaluated; 2 were fatal and one led to liver transplant; 3 had positive rechallenge; 43 [59%] were hepatocellular, 22 [30%] cholestatic and 8 [11%] mixed; 30 were due to atorvastatin, 28 simvastatin, 11 fluvastatin, 2 pravastatin, and 2 rosuvastatin, arising after 30-248 days; no mention of lovastatin).

  51. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation   (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, including 2 cases attributed to atorvastatin and 1 to simvastatin, but none to lovastatin).

  52. Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. PubMed Citation  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to statins or lipid lowering agents).

  53. Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, Chalasani N, et al. Spectrum of statin hepatotoxicity: Experience of the drug-induced liver injury network. Hepatology 2014; 60: 679-86. PubMed Citation  (Among 1,188 cases of drug induced liver disease collected in the US between 2004 to 2012, 22 [2%] were attributed to statins, including atorvastatin [8], simvastatin [5], rosuvastatin [4], fluvastatin [2], pravastatin [2] and lovastatin [1]; median age was 60 years and 68% were women; 9 cases were cholestatic and 12 hepatocellular [6 with autoimmune features]; the latency ranged widely, from 1 month to 10 years; only one case was fatal [a man with preexisting cirrhosis presenting with acute-on-chronic liver failure]).

  54. Bays H, Cohen DE, Chalasani N, Harrison SA. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol 2014; 8 (3 Suppl): S47-57. PubMed Citation  (Review of the safety of statins including their use in patients with liver disease recommending that liver tests be obtained before therapy, but that routine monitoring is not necessary and that statins can be safety used in patients with nonalcoholic liver disease, and are probably safe in other forms of chronic liver disease and after liver transplantation).

  55. Ooba N, Sato T, Wakana A, Orii T, Kitamura M, Kokan A, Kurata H, et al. A prospective stratified case-cohort study on statins and multiple adverse events in Japan. PLoS One 2014; 9: e96919. PubMed Citation  (Among 6877 patients started on statins between 2008 and 2010, 139 developed an increase in ALT or AST deemed likely due to the drug with no significant differences among those treated with pra-, ator-, flu-, pita- or rosu-vastatin).
  56. Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Med 2014; 12: 51. PubMed Citation  (Systematic review of 90 studies of 48 different "unintended effects" of statins with evidence of an increased risk of myopathy [Odds Ratio: OR=2.6] and raised liver enzymes [OR=1.5]).

  57. Drugs for lipids. Treat Guidel Med Lett 2014; 12 (137): 1-6. PubMed Citation  (Concise recommendations on management of hyperlipidemia mentions that 1-2% of patients on high doses of statins develop ALT elevations [above 3 times ULN], but that there is not always cross sensitivity to this side effect and that patients with mild-to-moderate ALT elevations can tolerate statins; no discussion of clinically apparent liver).

  58. Perdices EV, Medina-Cáliz I, Hernando S, Ortega A, Martín-Ocaña F, Navarro JM, Peláez G, et al. Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry. Rev Esp Enferm Dig 2014; 106: 246-54. PubMed Citation  (Among 858 cases of drug induced liver injury enrolled in a Spanish Registry between 1994 and 2012, 47 [5.5%] were attributed to statins [16 atorvastatin, 13 simvastatin, 12 fluvastatin, 4 lovastatin and 2 pravastatin], usually with a hepatocellular pattern of injury, 8.5% with autoimmune features, chronic injury in 19%, and no liver related deaths).

  59. Chen GL, Hsiao FY, Dong YH, Shen LJ, Wu FL. Statins and the risk of liver injury: a population-based case-control study. Pharmacoepidemiol Drug Saf 2014; 23: 719-25. PubMed Citation  (Among 2165 Taiwanese patients hospitalized for liver injury between 2002 and 2009, use of statins was not more frequent than among 16,600 hospitalized controls, except for use of high doses of rosuvastatin [adjusted odds ratio of 2.29]).

  60. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-1352.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 31 cases [3.4%] were attributed to statins, including 8 to atorvastatin,  8 simvastatin, 7 rosuvastatin, 4 pravastatin, 2 fluvastatin and 2 lovastatin).

  61. Chang CH, Chang YC, Lee YC, Liu YC, Chuang LM, Lin JW. Severe hepatic injury associated with different statins in patients with chronic liver disease: a nationwide population-based cohort study. J Gastroenterol Hepatol 2015; 30: 155-62. PubMed Citation  (Among 37,929 Taiwanese persons with chronic liver diesase started on statin therapy for hyperlipidemia between 2005 and 2009, there were 912 incident cases of hospitalization for liver injury, rates being similar for the 6 different statins used [1.94-2.95 per 100,000 person-days], but higher in those on high doses of atorvastatin [40 or 80 mg daily]).

  62. Kim HS, Lee SH, Kim H, Lee SH, Cho JH, Lee H, Yim HW, et al. Statin-related aminotransferase elevation according to baseline aminotransferases level in real practice in Korea. J Clin Pharm Ther 2016; 41: 266-72. PubMed Citation  (Among 21,233 Korean patients starting statin therapy between 2009 and 2013, abnormal ALT or AST values above 3 times ULN were more frequent among those with mild baseline elevations).

  63. Mazzanti G, Moro PA, Raschi E, Da Cas R, Menniti-Ippolito F. Adverse reactions to dietary supplements containing red yeast rice: assessment of cases from the Italian surveillance system. Br J Clin Pharmacol 2017; 83: 894-908. PubMed Citation  (Among 1261 spontaneous adverse event reports made to an Italian surveillance system for natural health products between 2002 and 2015, 55 were for red yeast rice, including 10 for liver injury of which 6 were described as "hepatitis" and required hospitalization, ALT elevations 315 to 3566 U/L, bilirubin normal or minimalllly elevated, all resolving upon stopping supplements).

  64. Björnsson ES. Hepatotoxicity of statins and other lipid-lowering agents. Liver
    Int 2017; 37: 173-8. PubMed Citation  (Review of the hepatotoxicity of statins mentions that 12 cases of lovastatin induced liver injury have been published, but none were fatal or had a positive rechallenge).

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