Fenofibrate

Publication Details

OVERVIEW

Introduction

Fenofibrate is a fibric acid derivative used in the therapy of hypertriglyceridemia and dyslipidemia. Fenofibrate therapy is associated with mild and transient serum aminotransferase elevations and with rare instances of acute liver injury, which can be severe and prolonged and lead to significant hepatic fibrosis.

Background

Fenofibrate (fen" oh fye' brate) is a fibric acid derivative. Its lipid lowering activity is probably mediated by its interactions with the peroxisome proliferator activated receptor alpha (PPARα), which regulates gene expression of enzymes involved in fatty acid oxidation. These fenofibrate induced changes cause an increase in lipoprotein lipase levels which enhance clearance of triglyceride-rich lipoproteins. Fenofibrate is recommended for therapy of hypertriglyceridemia (Fredrickson types IV and V hyperlipidemia) and hypercholesterolemia (Fredrickson types IIa and IIb). Fenofibrate was approved for use in Europe in 1975 and in the United States in 1993. Fenofibrate is available in multiple generic forms and under the brand names of Antara, Lipofen, Lofibra, TriCor and Triglide as capsules and tablets of multiple concentrations, ranging from 43 to 200 mg each. The recommended initial dosage in adults is 43 to 130 mg daily with adjustment to as high as 200 mg daily (depending upon the formulation). Common side effects of fenofibrate include nausea, gastrointestinal upset, headache, muscle cramps and rash. Fibrates have multiple drug interactions requiring careful review and use.

Hepatotoxicity

Mild, transient serum aminotransferase elevations develop in up to 20% of patients receiving fenofibrate, but values above 3 times normal in only 3% to 5%. These abnormalities are usually asymptomatic and transient, resolving even with continuation of fenofibrate, but they occasionally may require drug discontinuation. Monitoring of aminotransferase levels is recommended for patients receiving fenofibrate and discontinuation if enzymes persist above 3 times the upper limit of normal (ULN).

There have also been multiple reports of clinically apparent liver injury in patients on fenofibrate. Onset of injury is variable; cases resembling acute hepatitis usually arise within a few weeks or months of starting therapy (Case 2), whereas cases resembling chronic hepatitis and cirrhosis typically arise after more than 6 months or even years of treatment (Case 1). The pattern of serum enzyme elevations is typically hepatocellular, but both mixed and cholestatic patterns have also been described. Some instances of acute injury with a short latency (2 to 8 weeks) are associated with fever, rash and eosinophilia, suggesting immunoallergic hepatitis. Cases with a longer latency typically present with nonspecific symptoms of weakness and fatigue, have autoimmune features with hyperglobulinemia, smooth muscle or antinuclear antibody, and a chronic hepatitis-like clinical and histological picture that is sometimes prolonged and associated with significant fibrosis or cirrhosis.

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

Mechanism of Injury

The mechanism of hepatotoxicity of fenofibrate is not known but appears to be immunologic. Cases of autoimmune-like hepatitis due to fenofibrate suggest that there is induction of immune reactivity to altered metabolites or fenofibrate-protein haptens in the liver.

Outcome and Management

Several instances of chronic liver injury and fibrosis have been reported with fenofibrate use, typically in patients who were continued on therapy despite evidence of liver injury. However, in most cases, serum aminotransferase levels eventually fall to normal within 2 to as long as 12 months after stopping. Rechallenge is usually followed by recurrence of liver injury and should be avoided. While many cases of fenofibrate associated liver injury have been prolonged and severe, there have been no instances of acute liver failure due to the fibrates. Chronic injury with vanishing bile duct syndrome may underlie many of the instances of chronic liver disease due to fenofibrate. In other instances, features of autoimmune hepatitis are present (ANA, SMA or high immunoglobulin levels). Corticosteroids have been used with apparent effect on serum enzyme levels, but their efficacy in altering the outcome of injury is less clear. If corticosteroids are used, the dose and duration of therapy should be kept to a minimum. Although not proven, there may be some degree of cross reactivity to hepatic injury among the different fibrates.

Drug Class: Antilipemic Agents, Fibrates

CASE REPORTS

Case 1. Acute hepatitis due to fenofibrate therapy.

[Modified from: Rigal J, Furet Y, Autret E, Breteau M. [Severe mixed hepatitis caused by fenofibrate? A review of the literature apropos of a case]. Rev Med Interne 1989; 10: 65-7. PubMed Citation]

A 74 year old woman developed jaundice having been on oral therapy with fenofibrate (200 mg daily) for two years. She was not taking other medications and had no history of liver disease, alcohol use, or exposures to hepatitis. On hospital admission, physical examination revealed jaundice but no fever or rash. Laboratory findings included marked elevations in serum aminotransferase levels (Table) and bilirubin of 4.7 mg/dL. Tests for hepatitis A and B were negative, as were autoantibodies. Abdominal ultrasound and endoscopic retrograde cholangiopancreatography showed no evidence of biliary obstruction. During the first week in the hospital, serum bilirubin rose to 13.3 mg/dL and prothrombin time decreased to 46% of normal. At this point, fenofibrate was stopped and she then began to improve, with rapid regression of jaundice, allowing her to be discharged after 25 days in the hospital. In follow up over the next year, all abnormal liver tests returned to normal.

Key Points

Laboratory Values

Comment

This elderly woman developed a moderately severe, acute hepatocellular injury years after starting fenofibrate therapy, a distinctly unusual latency for drug-induced liver injury, but not inconsistent with other reports of fenofibrate hepatotoxicity. The hepatic injury was severe and associated with prolongation of prothrombin time and worsening liver function tests. Liver biopsy was not performed, but most cases of fenofibrate induced liver injury with a prolonged time to onset have been associated with hepatic fibrosis and, in some cases, cirrhosis. Ultimate recovery and return of serum enzyme levels into the normal range is typical even in cases with chronic hepatitis and cirrhosis.

Case 2. Acute hepatitis due to fenofibrate.

[Modified from: Ho CY, Kuo TH, Chen TS, Tsay SH, Chang FY, Lee SD. Fenofibrate-induced acute cholestatic hepatitis. J Chin Med Assoc 2004; 67: 245-7. PubMed Citation]

A 61 year old man with diabetes, hyperlipidemia and hypertension was started on fenofibrate (300 mg daily) and developed dark urine and fatigue two weeks later. After another two weeks, he presented to his physician and was found to be jaundiced. Fenofibrate was stopped, and he was admitted for evaluation. Serum aminotransferase and alkaline phosphatase levels were elevated, and total bilirubin was 9.3 mg/dL (Table). Tests for markers of acute hepatitis A, B and C were negative. Serum autoantibodies were not detected. An abdominal ultrasound and endoscopic retrograde cholangiography showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis, mild degrees of steatosis, and inflammatory cells and mild fibrosis in portal areas. His liver tests improved slowly and were normal two months later.

Key Points

Laboratory Values

* Estimated from Figure 1.

Comment

This patient developed symptoms of acute hepatitis within 2 weeks of starting fenofibrate and was found to be jaundice when seen two weeks later. The serum enzyme elevations were initially "mixed" but then evolved into a cholestatic pattern. Testing closer to the time of onset (2 weeks before presentation) may have shown a more hepatocellular pattern. Recovery is usually prompt and complete in cases of acute injury due to fenofibrate with a short latency period. This patient was treated with ursodiol which is frequently used in cholestatic liver disease, although its efficacy has not been proven.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Fenofibrate – Antara®, Lipofen®, Lofibra®, Tricor®, Triglide®

DRUG CLASS

Antilipemic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 24 January 2017

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    (74 year old developed jaundice 2 years after starting fenofibrate [bilirubin 4.7 mg/dL, ALT 1430 U/L, Alk P 315 U/L], with worsening [bilirubin 8.2 mg/dL] until fenofibrate stopped, and then resolving in 2 months).
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    (59 year old woman developed jaundice 14 months after starting fenofibrate [bilirubin 19.5 mg/mL, ALT 34 times and Alk P 1.5 times ULN, IgG high, ANA negative], resolution over 9 months after stopping; biopsy showed chronic hepatitis and fibrosis).
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    (60 year old woman developed asymptomatic rises in ALT [10.9 times ULN], with normal Alk P and bilirubin 22 months after starting fenofibrate; ANA 1:32,000 and biopsy showing chronic active hepatitis and bridging fibrosis, resolution in 2 months with slow and incomplete decline in ANA).
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    (56 year old woman had asymptomatic rise in GGT [16 times ULN], Alk P [1.5 times ULN], ALT [4.5 times ULN] 5 months after starting fenofibrate, with persistent GGT elevations and biopsy showing mild loss of bile ducts).
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    (53 year old female developed severe abdominal pain 36 hours after restarting fenofibrate; rechallenge caused the same pain with elevations in ALT [8 times ULN], Alk P [1.5 times ULN], normal bilirubin levels; rapid resolution; persistent ANA of 1:500).
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    (Retrospective analysis of 5 patients [4 men, 1 woman] with chronic hepatitis due to fibrates identified between 1989-1996; ages 56-73 years, on fenofibrate [n=3] or ciprofibrate [n=2] for 5-36 months; 2 asymptomatic; none with immunoallergic features or eosinophilia, with bilirubin 0.6-36 mg/dL, ALT 4-26 times ULN; all had ANA 1:200-1:2560; liver biopsy showed active cirrhosis in 3 and chronic hepatitis with fibrosis in 2; hepatitis resolved spontaneously in 2, and 3 required corticosteroid therapy in 2 of whom they could be stopped without relapse).
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    (72 year old woman developed fatigue after 3 weeks of ciprofibrate [bilirubin 2.9 mg/dL, ALT 25 times ULN, Alk P 2 times ULN, ANA 1:40]; no improvement after 2 months, liver biopsy showed chronic active hepatitis with fibrosis; corticosteroids caused decrease in ALT, but repeat biopsy showed cirrhosis, slow but ultimate resolution).
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    (Controlled trial of 4 doses of micronized fenofibrate vs placebo for 3 months in 340 patients; decreased triglycerides by 27-41%, ALT elevations above 3 times ULN occurred in 3% on fenofibrate vs 1% on placebo).
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    (43 year old man developed jaundice, rash and fever 2 weeks after starting fenofibrate [300 mg/day] [bilirubin 7.7 mg/dL, ALT 3.2 times ULN, Alk P 2.6 times ULN, atypical lymphocytes without eosinophilia], with rapid recovery and desquamation after stopping fenofibrate).
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    (63 year old woman developed mild fatigue and abnormal ALT [443 U/L]) 2 years after starting fenofibrate, having been on statins and having normal enzymes for years [Ig G 2.2 g/dL, ANA 1:40, SMA negative], biopsy showed chronic hepatitis and bridging fibrosis; resolved within 2 months of stopping, IgG and ANA falling to normal).
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    eech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, et al.; FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366 (9500): 1849-61. PubMed Citation (Among 9795 patients with diabetes treated with fenofibrate or placebo for an average of 5 years, ALT levels >3 times ULN occurred in 0.4% on fenofibrate vs 0.8% on placebo; clinically apparent hepatitis in 6 [0.1%] of both groups).
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    (66 year old woman with primary biliary cirrhosis developed fever and rise in ALT [40 to 216 U/L] and Alk P [367 to 537 U/L] with eosinophilia [14%], 11 days after starting fenofibrate, liver enzymes falling to baseline 2 weeks after stopping).
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    (60 year old woman developed dark urine 2 weeks after starting fenofibrate [bilirubin 9.6 mg/dL, ALT 241 U/L, Alk P 174 U/L], developing rash and prolonged jaundice [4 months] and persistence of Alk P elevations, with biopsy showing decrease in bile ducts; concurrent therapy with estrogen receptor modulator may have altered course).
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    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 1 case was attributed to fenofibrate, but none to clofibrate or gemfibrozil).
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    (50 year old woman developed jaundice 2 weeks after adding fenofibrate to a chronic regimen of atorvastatin and citalopram [bilirubin 31.2 mg/dL, ALT 156 U/L, Alk P 525 U/L, ANA and SMA negative], resolving within one month of stopping fenofibrate).
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    (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, none of which were attributed to fibrates).
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    (Retrospective analysis of 261 cases of autoimmune hepatitis, 24 [9%] of which were due to a medication; 11 nitrofurantoin, 11 minocylcine, but none attributed to fibrates).
  • Liberopoulos EN, Florentin M, Elisaf MS, Mikhailidis DP, Tsianos E. Fenofibrate in primary biliary cirrhosis: a pilot study. Open Cardiovasc Med J 2010; 4: 120-6. [PMC free article: PMC2885597] [PubMed: 20556204]
    (10 patients with primary biliary cirrhosis were treated either with fenofibrate [n=6] or continued on ursodiol [n=4] for 8 weeks; serum ALT and Alk P improved with fenofibrate therapy and no patient had worsening of disease).
  • Roth EM, McKenney JM, Kelly MT, Setze CM, Carlson DM, Gold A, Stolzenbach JC, et al. Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study. Am J Cardiovasc Drugs 2010; 10: 175-86. (Controlled trial. [PubMed: 20524719]
    of several doses of fenofibrate combined with rosuvastatin vs simvastatin alone in 474 patients with hypercholesterolemia; 1% of fenofibrate/rosuvastatin vs 0% of simvastatin treated patients had an ALT elevation >5 times ULN, but none had clinically apparent liver injury).
  • Levy C, Peter JA, Nelson DR, Keach J, Petz J, Cabrera R, Clark V, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther 2011; 33: 235-42. [PubMed: 21083674]
    (20 patients with primary biliary cirrhosis with an incomplete response to ursodiol were treated with fenofibrate for 48 weeks; none had worsening of liver disease and mean serum AST and Alk P levels improved).
  • Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci 2011; 56: 958-76. [PubMed: 21327704]
    (Review of drug induced autoimmune hepatitis, the principal causes being minocycline and nitrofurantoin; other caues being methyldopa, hydralazine, statins, fibrates, diclofenac, anti-TNF agents, interferons, propylthiouracil and isoniazid).
  • 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: 22350498]
    (Pooled analysis of 5 large trials of fenofibrate vs a statin vs the combination for 12-64 weeks found ALT >3 times ULN in 1.6% of subjects on fenofibrate and 0.4% on the combination; one patient had "hepatic insufficiency of moderate intensity", but the event was considered "non-serious" because it did not lead to "patient withdrawal").
  • Geng Q, Ren J, Chen H, Lee C, Liang W. Adverse events following statin-fenofibrate therapy versus statin alone: a meta-analysis of randomized controlled trials. Clin Exp Pharmacol Physiol 2013; 40: 219-26. [PubMed: 23324122]
    (Systematic review of the safety of the combination of fenofibrate and statins found higher rates of ALT and AST elevations with the combination than with statins alone).
  • 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: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, of which 2 were attributed to atorvastatin and 1 to simvastatin, but none to fibrates).
  • 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: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, but none were attributed to a fibrates).
  • 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. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 4 cases [0.5%] were attributed to fenofibrate).