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DRUG RECORD

 

PRAVASTATIN

OVERVIEW
Pravastatin

 

Introduction

Pravastatin 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

Pravastatin (pra" 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”), pravastatin lowers total serum cholesterol and low densitylipoprotein (LDL) concentrations, thereby reducing the risk of atherosclerosis and its complications – myocardial infarction and stroke.  Pravastatin was approved for use in the United States in 1991 and continues to be widely used with more than 9 million prescriptions filled yearly.   Current indications are for treatment of hypercholesterolemia in persons at high risk for coronary, cerebrovascular and peripheral artery disease.  Pravastatin is available in tablets of 10, 20, 40 and 80 mg in several generic forms and under the brand name of Pravachol.  The recommended dose in adults is 40 to 80 mg once daily.  Common side effects include muscle cramps, joint aches, headache and weakness.

Hepatotoxicity

Pravastatin 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 15% of patients; but levels above 3 times the upper limit of normal (ULN) occurred in only 0.7% of pravastatin treated compared to 0.3% of placebo recipients.  These elevations were more common with higher doses of pravastatin, being 2.3% with 80 mg daily.  Most of these elevations were self-limited and did not require dose modification.  Pravastatin has been only rarely associated with clinically apparent hepatic injury with symptoms or jaundice at a rate estimated to be 1 per 100,000 users.  In the case reports, latency varied from 2 to 9 months and the pattern of serum enzyme elevations from cholestatic to hepatocellular.  Recovery was complete within a few months.  Rash, fever and eosinophilia were uncommon as were autoantibodies, but few cases have been reported and the full clinical syndrome not well defined.  Pravastatin appears to be less likely to cause clinically apparent liver injury than atorvastatin, simvastatin and rosuvastatin.

Mechanism of Injury

The cause of hepatic injury from pravastatin is unknown.  Pravastatin has only minimal hepatic metabolism and most is excreted unchanged in the urine.  The mild, self-limited ALT elevations may be due to production of a minor toxic intermediate of metabolism and the reversal of these elevations due to adaptation.  The idiosyncratic, clinically apparent liver injury associated with pravastatin may be due to failure of adaptation.

Outcome and Management

The mild ALT elevations associated with pravastatin therapy are usually self-limited and do not require dose modification, although pravastatin should be stopped if ALT levels rise above 10-fold the ULN, or persist in being above 5-fold elevated or are associated with symptoms.  In the clinically apparent liver injury attributed to pravastatin, recovery is usually complete within 1 to 2 months.  In view of the wide scale use of pravastatin, 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 pravastatin induced injury can lead to recurrence and should be done with careful monitoring.

Drug Class:  Antilipemic Agents, Statins. 

 

 

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CASE REPORT
Pravastatin

 

Case 1.  Acute cholestatic hepatitis attributed to pravastatin therapy.
[Modified from:  Hartleb M, Rymarczyk G, Januszewski K. Acute cholestatic hepatitis associated with pravastatin. Am J Gastroenterol 1999; 94:1388-90. PubMed Citation]


A 57 year old man developed abdominal pain and nausea followed by fever and jaundice 6 weeks after starting pravastatin (20 mg daily) for long standing hypercholesterolemia.  He had a history of coronary artery disease and had been treated with beta blockers and various cholesterol lowering drugs, including fenofibrate and simvastatin in the past.  At the time of presentation, he was taking only pravastatin and metoprolol, both of which were discontinued promptly.  He denied alcohol use and had no risk factors for viral hepatitis.  Physical examination showed jaundice and hepatic tenderness but no rash, fever or signs of chronic liver disease.  Laboratory results showed a cholestatic pattern of serum enzyme elevations and hyperbilirubinemia (Table).  Tests for hepatitis A, B and C were negative as were autoantibodies.  Ultrasound and CT of the abdomen showed no evidence of biliary obstruction and ERCP was normal.  A liver biopsy showed intrahepatic cholestasis compatible with drug induced liver injury.  He was treated with ursodiol (750 mg daily).  Once pravastatin was stopped, symptoms and liver test abnormalities improved rapidly and were completely normal 7 weeks later.


Key Points

Medication:Pravastatin (20 mg daily)
Pattern: Mixed (R=2.8)
Severity: 3+ (jaundice, hospitalization)
Latency: 6 weeks
Recovery: ~7 weeks
Other medications:Metoprolol

Laboratory Values

Time After Starting Time After Stopping ALT* (U/L) Alk P* (U/L) Bilirubin (mg/dL) Other
6 weeks 0 421 482 13.6 Admission
2 days 260 11.8
8 weeks 2 weeks 151 3.7
9 weeks 3 weeks 255 3.0 Liver biopsy
10 weeks 4 weeks 210 1.9 Discharge
3 months 7 weeks 40 Normal 0.5 Outpatient follow up
Normal Values <40 <130 <1.2

* Some values estimated from Figure 1.


Comment

The onset of injury within 2 months of starting pravastatin and resolution within 2 months of stopping is supportive evidence that this represented drug-induced liver disease due to pravastatin. All other causes of acute liver injury were satisfactorily excluded. Metoprolol had been used for a longer period and, like other beta-blockers, is a rare cause of drug induced liver injury. The pattern of serum enzyme elevations was considered “mixed” but the clinical presentation, symptoms and liver histology were more cholestatic.  This patient had previously tolerated simvastatin without obvious liver injury.  Cross susceptibility to cholestatic hepatitis from the statins is frequent but not invariable. 

 

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PRODUCT INFORMATION
Pravastatin

 

REPRESENTATIVE TRADE NAMES
Pravastatin – Generic, Pravachol®


DRUG CLASS
Antilipemic Agents


COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH


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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Pravastatin 81093-37-0 C23-H36-O7 Image of Chemical Structure

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REFERENCES
Pravastatin

 

References Last Updated: 22 January 2014

  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 states that the statins are the most effective and best-tolerated agents for treating dyslipidemia and that the act by inhibition of the rate limiting step in hepatic cholesterol synthesis).

  4. Ballarè M, Campanini M, Airoldi G, Zaccala G, Bertoncelli MC, Cornaglia G, Porzio M, et al. Hepatotoxicity of hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors. Minerva Gastroenterol Dietol 1992; 38: 41-4. PubMed Citation  (Prospective monitoring identified ALT elevations in 5% of 100 patients on simvastatin and 4.5% of 90 on pravastatin).

  5. 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).

  6. Morris R, Robinson G, Tilyard M, Gurr E. Pravastatin and risk factor modification in patients with moderate primary hypercholesterolaemia. NZ Med J 1996; 109: 319-22. PubMed Citation  (In a prospective controlled trial in 78 patients, transient liver test abnormalities occurred in 3 patients on pravastatin [18%] and 7 [18%] on placebo; none led to discontinuation and none had symptoms or jaundice).

  7. Hartleb M, Rymarczyk G, Januszewski K. Acute cholestatic hepatitis associated with pravastatin. Am J Gastroenterol 1999; 94:1388-90. PubMed Citation  (57 year old man developed jaundice, 2 months after starting pravastatin [bilirubin 13.6 mg/dL, ALT 421 U/L, Alk P 482 U/L], resolving within 8 weeks of stopping: Case 1).

  8. Heuer T, Gerards H, Pauw M, Gabbert HE, Reis HE. [Toxic liver damage caused by HMG-CoA reductase inhibitor]. Med Klin(Munich) 2000; 95: 642-4. German. PubMed Citation  (4 patients with liver injury due to statins: 3 simvastatin and 1 pravastatin with jaundice arising 8-24 months after starting [bilirubin 1.9 to 7.4 mg/dL, ALT 39 to 841 U/L, Alk P 266 to 353], resolving within 3 months of stopping).

  9. Punthakee Z, Scully LJ, Guindi MM, Ooi TC. Liver fibrosis attributed to lipid lowering medications: two cases. J Intern Med 2001; 250: 249-54. PubMed Citation  (39 year old man developed fever and weakness 9 months after starting pravastatin [ALT ~500 U/L, but no jaundice], resolving rapidly with stopping and then recurring after 22 months of simvastatin therapy [ALT ~2800 U/L, ANA negative], biopsy showing chronic hepatitis whereas his enzymes remained normal over the next 6 years on no-statin therapy).

  10. Hartleb M, Biernat L, Kochel A. Drug-induced liver damage--a three-year study of patients from one gastroenterological department. Med Sci Monit 2002; 8: CR292-6. PubMed Citation  (14 patients with drug induced liver injury seen in one hospital [Silesian Medical University] over 3 year period; due to amoxicillin/clavulanate in 3, antituberculosis agents 2, pravastatin 2, fluvastatin 1, and 6 other agents in 1 each; 2 pravastatin cases in 62 and 57 year olds with onset after 4 and 7 weeks [bilirubin 1.0 and 13.6 mg/dL, ALT 3.4 and 10.5 times ULN, Alk P 1.0 and 4.4 times ULN], one case with rapid recovery upon stopping and the other [with jaundice] protracted).

  11. Batey RG, Harvey M. Cholestasis associated with the use of pravastatin sodium. Med J Aust 2002; 176: 561. PubMed Citation  (64 year old woman developed abnormal liver tests 4 months after starting pravastatin [bilirubin 0.8 mg/dL, ALT 85 U/L, Alk P 362 U/L], improving on stopping and rising again with restarting, decreasing upon stopping but not to normal; never jaundiced or symptomatic).

  12. Pfeffer MA, Keech A, Sacks FM, Cobbe SM, Tonkin A, Byington RP, Davis BR, et al. Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling(PPP) Project. Circulation 2002; 105: 2341-6. PubMed Citation  (Controlled trial of pravastatin vs placebo for 5 years in ~18,000 patients with hypercholesterolemia; no differences in rates of adverse events, gallstones in 1.9% vs 2.1 % [pravastatin vs placebo], any abnormal ALT in 8.8% vs 8.2% and ALT >3 times ULN in 1.4% vs 1.3%).

  13. Rosenson RS, Bays HE. Results of two clinical trials on the safety and efficacy of pravastatin 80 and 160 mg per day. Am J Cardiol 2003; 91: 878-81. PubMed Citation  (Two placebo controlled trials of higher doses of pravastatin [40 and 160 mg/day for 6 weeks]; no ALT or AST elevations above 3 times the ULN in either study).

  14. Parra JL, Reddy KR. Hepatotoxicity of hypolipidemic drugs. Clin Liver Dis 2003; 7: 415-33. PubMed Citation  (Review and discussion of individual agents; rate of serum ALT elevations with pravastatin has been similar to that with placebo; mentions that single case report of cholestatic hepatitis due to pravastatin has appeared in the literature).

  15. 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).

  16. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004; 174: 193-6. PubMed Citation  (5 patients with nonalcoholic steatohepatitis were treated with pravastatin [20 mg daily for 6 months], ALT levels became normal in all five patients and histology improved in some, but not fibrosis scores).

  17. Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004; 94: 1140-6. PubMed Citation  (Pharmacokinetic studies that demonstrate that drugs that inhibit CYP 3A4, the major P450 drug metabolizing enzyme [itraconazole, clarithromycin, verapamil], cause increases in blood levels of simvastatin and atorvastatin, but have little effect on pravastatin levels).

  18. Nissen SE. Effect of intensive lipid lowering on progression of coronary atherosclerosis: evidence for an early benefit from the Reversal of Atherosclerosis with Aggressive Lipid Lowering(REVERSAL) trial. Am J Cardiol 2005; 96(5A): 61F-68F. PubMed Citation  (Controlled trial comparing pravastatin [40 mg] to atorvastatin [80 mg] daily for 18 months in 654 patients; ALT elevations >3 times ULN occurred in 1.6% on pravastatin vs 2.3% on atorvastatin, but no instances of clinically apparent hepatitis).

  19. 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 attributed to statins, but no specific agent caused more than 4 cases).

  20. Alsheikh-Ali AA, Karas RH. Adverse events with concomitant amiodarone and statin therapy. Prev Cardiol 2005; 8: 95-7. PubMed Citation  (Review of MedWatch adverse event reports for proportion that included combination with amiodarone; 1.0% for simvastatin, 0.7% atorvastatin and 0.4% pravastatin; 77% had muscle and 30% liver involvement).

  21. Conforti A, Magro L, Moretti U, Scotto S, Motola D, Salvo F, Ros B, et al. Fluvastatin and hepatic reactions: a ignal from spontaneous reporting in Italy. Drug Safety 2006; 29:1163-72. PubMed Citation  (Italian Pharmacovigilance Group review of 35,757 adverse reaction reports: 1260 due to statins of which 178 were hepatic; 69 [36%] fluvastatin, 37 [10%] atorvastatin, 50 [11%] simvastatin, 16 [9%] pravastatin, 6 [13%] rosuvastatin; proportion reporting rate based on number of prescriptions was highest for fluvastatin [~9] compared to other agents [~2-3]; 26 fluvastatin cases described as “hepatitis”, but no details given except that most cases occurred within 90 days of starting).

  22. 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 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).

  23. 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 statin [6.6% vs 1.2%]).

  24. 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).

  25. 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 9 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]).

  26. 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 rely upon spontaneous reporting).

  27. Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R; Pravastatin in Chronic Liver Disease Study Investigators. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007; 46: 1453-63. PubMed Citation  (Controlled trial of pravastatin [80 mg daily] vs placebo for 36 weeks in 326 patients with chronic liver disease and hypercholesterolemia [64% nonalcoholic steatohepatitis and 25% chronic hepatitis C]; cumulative incidence of ALT levels >twice baseline or ULN was 7.5% for pravastatin and 12.5% for placebo, and none had exacerbation of underlying liver disease or jaundice).

  28. Contreras AM, Monteón FJ, Flores MR, Mendoza-Sánchez F, Ruiz I. Drug-related hepatotoxicity in a renal transplant recipient with long-term survival and hepatitis C. Ann Hepatol 2007; 6: 70-3. PubMed Citation  (26 year old man with a renal transplant had ALT elevations [peak 151 U/L] without jaundice after several years of pravastatin therapy, which did not improve with stopping pravastatin or azathioprine, and later found to be due to chronic hepatitis C).

  29. 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%. Abnormalities are usually asymptomatic, individual case reports of autoimmune hepatitis have been published).

  30. 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).

  31. 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, but most cases were mild or not clearly attributable to the statin therapy).

  32. 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).

  33. 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).

  34. Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009; 29: 412-22. PubMed Citation  (Case reports and review of literature; 52 year old woman who developed fatigue 12 weeks after starting fluvastatin [bilirubin 1.2 mg/dL, ALT 850 U/L, Alk P 215 U/L, ANA negative], resolving on stopping fluvastatin, but recurring within 11 weeks of starting atorvastatin [bilirubin 1.0 rising to 12.5 mg/dL, ALT 1750 U/L, Alk P 285 U/L, ANA 1:160], responding to prednisone and azathioprine therapy).

  35. Liu Y, Cheng Z, Ding L, Fang F, Cheng KA, Fang Q, Shi GP. Atorvastatin-induced acute elevation of hepatic enzymes and the absence of cross-toxicity of pravastatin. Int J Clin Pharmacol Ther 2010; 48: 798-802. PubMed Citation  (Two men, ages 53 and 58, developed ALT elevations [peak 120 and 278 U/L] within a day of starting atorvastatin, resolving within 7 days of stopping and not recurring in either when pravastatin was started).

  36. 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]).

  37. 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 were attributed to drug induced liver injury including 2 due to atorvastatin, 2 simvastatin and 2 cerivastatin, but none to pravastatin).

  38. 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; atorvastatin injury was more likely to be cholestatic and was estimated to occur in 2.9 per 100,000 person years).

  39. Farnier M, Marcereuil D, De Niet S, Ducobu J, Steinmetz A, Retterstøl K, Bryniarski L, et al. Safety of a fixed-dose combination of fenofibrate/pravastatin 160 mg/40 mg in patients with mixed hyperlipidaemia: a pooled analysis from a database of clinical trials. Clin Drug Investig 2012; 32: 281-91. PubMed Citation  (Analysis of fixed combination of pravastatin with fenofibrate vs each alone in 5 large trials found no case of drug induced liver injury or rhabdomyosis; elevations in ALT >3 times ULN occured in 1.6% [2/122] on fenofibrate, 0.2% [1/519] on statins and 1.0% [16/1566] on the fixed combination, but all were transient and not accompanied by jaundice).

  40. Sirtori CR, Mombelli G, Triolo M, Laaksonen R. Clinical response to statins: mechanism(s) of variable activity and adverse effects. Ann Med 2012; 44: 419-32. PubMed Citation  (Review of the possible mechanisms for the beneficial and adverse effects of statins, including genetic variations in CYP enzymes, ABC transporters and HLA genes in causing adverse events, focused mostly upon myopathy and myalgias).

  41. 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 attributed to atorvastatin and 1 to simvastatin, but none to pravastatin).

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Pravastatin
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