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DRUG RECORD

 

PITAVASTATIN

OVERVIEW
Pitavastatin

 

Introduction

Pitavastatin is a relatively newly developed cholesterol lowering agent (statin) that is associated with mild, asymptomatic and self-limited serum aminotransferase elevations during therapy, but has had limited use and has yet to be linked with clinically apparent acute liver injury.

Background

Pitavastatin (pi ta" va stat' in) is a potent, 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”), pitavastatin lowers total serum cholesterol and low density lipoprotein (LDL) concentrations, thereby reducing the risk of atherosclerosis and its complications – myocardial infarction and stroke.  Pitavastatin was approved for use in the United States in 2009 but experience with its use is limited.  Pitavastatin is indicated for treatment of hypercholesterolemia in persons at high risk for coronary, cerebrovascular and peripheral artery disease.  Pitavastatin is available in tablets of 1, 2 and 4 mg under the trade name Livalo.  Pitavastatin is one of the more potent statins and is typically used in a comparably lower dose.  The recommended dose is 2 to 4 mg once daily based upon tolerability and lipid levels.  Common side effects include muscle cramps, joint aches, headache and weakness.

Hepatotoxicity

Because pitavastatin is a relatively new agent, less information is available on its potential hepatotoxicity.  In large clinical trials, pitavastatin therapy was associated with mild, asymptomatic and usually transient serum aminotransferase elevations in approximately 1% of patients, but levels above 3 times the upper limit of normal (ULN) were infrequent and no cases of clinically apparent hepatitis were reported from the preregistration clinical trials.  Since marketing of pitavastatin, however, the sponsor has received reports of jaundice, hepatitis and hepatic failure including fatal cases.  There has been only a single published report of liver injury due to pitavastatin, so that the clinical signature of hepatic injury associated with its use has not been defined.  On the other hand, the other statins have all been implicated in cases of clinically apparent acute liver injury that typically arise after 1 to 6 months of therapy with either a cholestatic or hepatocellular pattern of serum enzyme elevations.  Rash, fever and eosinophilia are uncommon, but some cases have been marked by autoimmune features including autoantibodies, chronic hepatitis on liver biopsy and a clinical response to corticosteroid therapy.  This pattern has yet to be shown to apply to pitavastatin.

 

Likelihood score: D (possible rare cause of clinically apparent liver injury).

 

Mechanism of Injury

The cause of hepatic injury from pitavastatin is unknown.  Pitavastatin is minimally (~10%) metabolized in the liver (via CYP 2C9).  The mild, self-limited ALT elevations may be 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 many statins is often accompanied by autoimmune features and may, therefore, be caused by immune mechanisms.

Outcome and Management

The mild ALT elevations associated with pitavastatin therapy are usually self-limited and do not require dose modification.  Pitavastatin 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 statins, recovery is usually complete within 1 to 2 months.  Recurrence of injury with rechallenge has been reported and should be avoided.  Whether there is cross relativity to hepatic injury with other statins is unknown.

Drug Class:  Antilipemic Agents

 

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

 

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PRODUCT INFORMATION
Pitavastatin

 

REPRESENTATIVE TRADE NAMES
Pitavastatin – Livalo®

 

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
Pitavastatin 147511-69-1 C25-H24-F-N-O4 Image of Chemical Structure

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REFERENCES
Pitavastatin

 

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; no mention of pitavastatin).

  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 states that 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 they act by inhibition of the rate limiting step in hepatic cholesterol synthesis).

  4. Pitavastatin (Livalo) – the seventh statin. Med Lett Drugs Ther 2010; 52: 57-8. PubMed Citation  (Brief summary of the safety and efficacy of pitavastatin shortly after its approval in the United States; no mention of hepatotoxicity).

  5. Wensel TM, Waldrop BA, Wensel B. Pitavastatin: a new HMG-CoA reductase inhibitor. Ann Pharmacother 2010; 44: 507-14. PubMed Citation  (Literature review and summary of pharmacology, mechanism of action, clinical efficacy and side effects; ALT elevations reported in 1% of pitavastatin and 2% of atorvastatin recipients).

  6. Saku K, Zhang B, Noda K; The PATROL Trial Investigators. Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL). Circ J 2011; 75: 1493-1505. PubMed Citation  (Controlled trial comparing 3 potent statins in 302 patients for 16 weeks; ALT elevations above 3 times ULN occurred in 2% on atorvastatin, 2% on rosuvastatin and 1% on pitavastatin, and none developed clinically apparent liver injury). 

  7. 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 to 248 days; pitavastatin was not mentioned).

  8. 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; pitavastatin was not mentioned).

  9. Saito Y. Pitavastatin: an overview. Atheroscler Suppl 2011; 12: 271-6. PubMed Citation  (Review of the mechanisms of action, efficacy and tolerability of pitavastatin; no mention of ALT elevations or hepatotoxicity).

  10. Han KH, Rha SW, Kang HJ, Bae JW, Choi BJ, Choi SY, Gwon HC, et al. Evaluation of short-term safety and efficacy of HMG-CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage). J Clin Lipidol 2012; 6: 340-51. PubMed Citation  (Among 189 Korean patients with hypercholesterolemia and mild ALT elevations [not due to alcohol, HBV or HCV] treated with statins for 12 weeks, 5.2% on pitavastatin and 5.4% on atorvastatin had rises of ALT above 100 U/L [range 102-218 U/L], although average values decreased and hepatic steatosis was reduced [as assessed by computerized tomography).

  11. Berkelhammer C, Lerma EV. Statin treatment in patients with elevated liver enzymes: pitch to proceed. J Clin Lipidol 2012; 6: 310-1. PubMed Citation  (Editorial in response to article by Han [2012] suggesting that "the benefits of statin therapy outweigh the risk of transaminitis").

  12. Drugs for lipids. Treat Guidel Med Lett 2014; 12 (137): 1-6. PubMed Citation  (Concise recommendations for management of hyperlipidemia mentions that, unlike for other statins, there are no data on the effects of pitavastatin therapy on clinical outcomes such as coronary artery disease events, stroke and all cause mortality). 

  13. 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], but none due to pitavastatin).

  14. 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).

  15. 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; no mention of pitavastatin).

  16. 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: 1340-52.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; but none due to pitavastatin).

  17. Mora-Cuadrado N, Santana-Lora R, Fernández-Salazar L, González-Hernández JM. Pitavastatin: other statin to be used and monitored. Rev Esp Enferm Dig 2015; 107: 578-9. PubMed Citation  (48 year old man developed weakness, diarrhea and a "cholestatic pattern" of liver test abnormalities 4 months after starting pitavastatin [bilirubin and ALT not given, GGT 496 U/L, Alk P 382 U/L], which declined rapidly on switching to simvastatin).

  18. Gosho M, Tanahashi M, Hounslow N, Teramoto T. Pitavastatin therapy in polymedicated patients is associated with a low risk of drug-drug interactions: analysis of real-world and phase 3 clinical trial data. Int J Clin Pharmacol Ther 2015; 53: 635-46. PubMed Citation  (Analysis of postmarketing surveillance system on pitavastatin found no increase in adverse event reports in patients taking pitavastatin in combination with agents that interact with CYP 2C9).

  19. 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 statins represent 5% of cases of drug induced liver injury published in large case series or from registries and discusses atorvastatin, simvastatin, fluvasttin, lovastatin and pravastatin, but not pitavastatin).

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OTHER REFERENCE LINKS
Pitavastatin
  1. PubMed logoRecent References on Pitavastatin

  2. Clinical Trials logoTrials on Pitavastatin

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