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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Celecoxib

Last Update: January 23, 2017.

OVERVIEW

Introduction

Celecoxib is a nonsteroidal antiinflammatory drug (NSAID) with selectively for inhibition of cycloxgenase-2 (Cox-2), which is widely used in the therapy of arthritis. Celecoxib has been linked to rare instances of idiosyncratic drug induced liver disease.

Background

Celecoxib (sel" e kox' ib) is a commonly used NSAID with relative Cox-2 specificity. Like other NSAIDs, celecoxib acts by inhibition of prostaglandin synthesis and thereby decreasing the mediators of inflammation, fever and pain. The specificity for Cox-2 is believed to make celecoxib less likely to cause gastrointestinal mucosal injury compared to standard NSAIDs that inhibit both Cox-1 and Cox-2 enzymes. Celecoxib is indicated for therapy of chronic arthritis due to osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis and ankylosing spondylitis. It is also approved for use in acute pain from musculoskeletal conditions and trauma and for primary dysmenorrheal. Because of the role of the Cox-2 enzyme system in the growth of adenomatous polyps, celecoxib has also been used to prevent adenomatous polyps formation. Celecoxib was first approved for use in the United States in 2000 and became the only Cox-2 specific NSAID available when rofecoxib was withdrawn in 2006 because of increased rate of cardiovascular events associated with its long term use. Celecoxib is available by prescription as capsules of 50, 100, 200 and 400 mg under the commercial name Celebrex and is usually given in several week courses or long term. The recommended dose varies by indication, the usual adult dose in arthritis being 100 to 200 mg twice daily. Like most NSAIDs, celecoxib is generally well tolerated, but side effects can include dizziness, headache, somnolence, rash, nausea, diarrhea, abdominal discomfort, heartburn, peripheral edema and hypersensitivity reactions.

Hepatotoxicity

In clinical studies involving several thousand patients treated for at least 3 months, the rate of serum aminotransferase enzyme elevations above three times the upper limit of the normal range was 1.1% in celecoxib treated compared to 0.9% in placebo treated patients. The ALT elevations that occurred during celecoxib therapy were uncommon and usually benign, resolving even with continuation of the medication. It is unclear whether such elevations are due to the medication since similar rates of abnormalities are identified in patients with arthritis receiving placebo. In rare instances, celecoxib appears to be capable of causing clinical apparent, symptomatic and icteric drug induced liver injury. The pattern of liver enzyme elevations has ranged from hepatocellular (Case 1) to cholestatic (Case 2). Moreover, the resulting jaundice can be prolonged and accompanied by severe pruritus and chronic fatigue (Case 3). The latency to onset of liver injury is often short and the abruptness of onset resembles the hepatotoxicity caused by the sulfonamides. Indeed, in several instances, patients with celecoxib hepatotoxicity have a past history of sulfonamide hypersensitivity. Furthermore, celecoxib liver injury may occur in patients who have been treated with the drug without incident in the past, and reexposure after celecoxib liver injury usually results in reoccurrence with shortening of the latency period. Immunoallergic features are not uncommon in patients with clinically apparent liver injury due to celecoxib, but they are rarely prominent. Stevens Johnson syndrome has been described in patients on celecoxib. Autoimmune markers and features of autoimmunity are not common, although they may be present because of the underlying disease for which the celecoxib is prescribed.

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

Mechanism of Injury

The acute hepatic injury from celecoxib resembles that of the sulfonamides and a history of sulfa-allergy is common. These features of celecoxib hepatotoxicity suggest an immune and allergic-hypersensitivity etiology.

Outcome and Management

The idiosyncratic liver injury due to celecoxib can lead to prolonged jaundice and to a vanishing bile duct syndrome that can be severe and lead to hepatic failure and need for liver transplantation. Cases of acute liver failure with massive necrosis have not been specifically linked to celecoxib therapy in the published literature, although the possibility of liver failure is mentioned in the product labeling. In the few cases of self-limited liver injury that have been described, the time to recovery has varied greatly, from a few weeks to more than a year. Rechallenge should be avoided and patients should also be told to avoid sulfa-containing medications. Corticosteroids have been used to treat the immunoallergic features of celecoxib hypersensitivity, but their role in decreasing liver injury or improving outcome has not been shown (Cases 2 and 3).

Drug Class: Nonsteroidal Antiinflammatory Drugs

CASE REPORTS

Case 1. Acute hepatocellular injury with jaundice due to celecoxib.

[Modified from Nachimuthu S, Volfinzon L, Gopal L. Postgrad Med J 2001; 77: 548-50]

A 67 year old woman with osteoarthritis was treated with celecoxib (100 mg twice daily) for one week during which she developed abdominal pain and jaundice. She was hospitalized and celecoxib was stopped. She had multiple other medical problems including hypertension, diabetes, coronary artery disease, congestive heart failure, peptic ulcer disease and osteoarthritis and had been taking several medications in constant doses for some time. On admission, she had fever but no rash. Her jaundice deepened for a day, but then improved rapidly. Tests for hepatitis A, B and C and for autoantibodies were negative. Ultrasound of the abdomen was normal. A liver biopsy was not done.

Key Points

Medication:Celecoxib
Pattern:Hepatocellular (R=13.8)
Severity:3+ (symptoms, jaundice and hospitalization)
Latency:<1 week
Recovery:Complete within 2 weeks of onset
Other medications:Enalapril, metoprolol, isosorbide mononitrate, furosemide, iron, vitamin C

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin* (mg/dL)Other
Pre14760.7
Celecoxib Stopped after 7 Days
1 week06031504.9INR=1.02, albumin 3.4 g/dL
1 day3051617.5
2 weeks1 week231461.9
3 weeks2 weeks271000.9
Normal Values <35 <120 <1.2

*Converted from µmol/L.

Comment

The history and presentation of this case were typical of an immuno-allergic acute hepatitis from a medication and the only new medication that she was receiving was celecoxib. Once celecoxib was stopped, recovery was rapid. There was no mention of eosinophilia or history of allergy to sulfonamides.

Case 2. Severe cholestatic hepatitis and liver failure due to celecoxib.

[Modified from El Hajj, Malik SM, Alwakeel HR, Shaikh OS, Sasatomi E, Kandil HM. Celecoxib-induced cholestatic liver failure requiring orthotopic liver transplantation. World J Gastroenterol 2009; 15: 3937-9. PubMed Citation]

A 52 year old woman developed fatigue, pruritus and dark urine three days after starting celecoxib (200 mg, 2 to 3 times daily) for minor muscle aches. She stopped the medication (after 8 tablets), but had worsening symptoms and jaundice. One week after stopping she sought medical advice. She was a registered nurse, but had no previous history of liver disease and was known to have normal serum enzymes and to lack markers of hepatitis B, C and HIV infection. She did not drink alcohol, took no other medications or over-the-counter preparations, and denied exposures to viral hepatitis, history of drug-reactions, or specific risk factors other than nursing occupation. On examination, she was jaundiced and the liver was tender, but she had no fever or there was no mention of rash. Laboratory results showed eosinophilia (760 cells/uL) and elevated bilirubin and alkaline phosphatase levels (Table). Tests for hepatitis A, B and C were negative as were autoantibody markers. An abdominal CT scan showed no evidence of biliary tract obstruction. A liver biopsy showed cholestasis, loss of bile ducts ("ductopenia") and minimal periportal fibrosis. Over the next few weeks, her symptoms worsened and jaundice deepened. She was treated with ursodiol (500 mg twice daily) and then prednisone (40 mg daily), but bilirubin rose to 35 mg/dL and renal insufficiency developed. She had signs of progressive hepatic failure and underwent liver transplantation 54 days after the initial dose of celecoxib. The explant showed marked cholestasis and prominent ductopenia, but no cirrhosis. In follow up after transplant, her liver tests fell to normal.

Key Points

Medication:Celecoxib
Pattern:Cholestatic (R=0.6)
Severity:5+ (liver transplantation)
Latency:3 days to onset of symptoms
Recovery:None
Other medications:None

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)INR
Pre18780.41.0
Celecoxib taken for three days
10 days1 week25870010.81.0
24 days3 weeks29788915.01.0
2 months7 weeks167102438.02.6
Orthotopic Liver Transplantation on day 54 after starting celecoxib
6 months after transplant271000.91.1
Normal Values <72 <126

Comment

A dramatic example of severe immuno-allergic liver injury with acute cholestasis and rapid progression to vanishing bile duct syndrome and hepatic failure. Celecoxib has been linked to several instances of vanishing bile duct syndrome, but the course of injury is usually much more prolonged and can ultimately resolve.

Case 3. Prolonged mixed injury with cholestasis due to celecoxib.

[Modified from a case in the database of the Drug-Induced Liver Injury Network]

A 38 year old woman with chronic back pain after a motor vehicle accident was treated with celecoxib (100 mg twice daily) for several weeks without incident and again six months later for persistence of the pain. During the second course of celecoxib, she stopped the medication after 23 days when she developed nausea and right upper abdominal pain. During the next few days she developed jaundice and pruritus and was hospitalized. She reported no other medical problems and was taking no medications except for occasional aspirin and acetaminophen for her back pains. She had no history of alcohol abuse, allergies or drug reactions. On admission, she was mildly jaundiced, but had no rash or fever. There were moderate elevations in serum aminotransferase and alkaline phosphatase levels (Table). The white blood cell count was normal without eosinophilia. Tests for hepatitis A, B and C and for autoantibodies were negative. Ultrasound and MRI of the liver and abdomen were normal without evidence of biliary obstruction. She improved very slowly and because of persistence of jaundice, a liver biopsy was done that showed intrahepatic cholestasis compatible with acute drug induced liver injury. She was treated with a short course of prednisone with no little improvement in liver tests. Serum bilirubin eventually fell into the normal range, she continued to complain of nausea and fatigue and had persistence of cholestatic liver enzyme elevations more than six months after onset.

Key Points

Medication:Celecoxib
Pattern:Initially hepatocellular (R=8.4), later mixed (R=5.7→2.8)
Severity:3+ (symptoms, jaundice and hospitalization)
Latency:3 weeks
Recovery:Complete within 4 months of onset
Other medications:Rarely aspirin, acetaminophen

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
Celecoxib taken for 21 Days
27 days4 days6873043.7Albumin 4.6
28 days5 days4762433.9INR 1.0
31 days8 days3992644.2
5 weeks12 days3123694.9Liver biopsy
10 weeks47 days3104002.4
20 weeks17 weeks2607001.4
6 months5 months875181.0
9 months8 months1225881.0
Normal Values <35 <120

Comment

Despite the rarity of drug induced liver injury from celecoxib, this case was convincing in that there was a sudden onset of a cholestatic and prolonged hepatitis after 3 weeks of celecoxib. No other medications were being taken and no other cause for liver disease was identified. Serum enzyme elevations were initially in the hepatocellular range, but soon became distinctly cholestatic. Recovery was prolonged and incomplete. She likely has mild vanishing bile duct syndrome, not enough to cause jaundice, but enough to cause symptoms and persistent alkaline phosphatase elevations.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Celecoxib – Celebrex®

DRUG CLASS

Nonsteroidal Antiinflammatory Drugs

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Celecoxib 184007-95-2 C17-H14-F3-N3-O2-S
Celecoxib chemical structure

ANNOTATED BIBLIOGRAPHY

References updated: 23 January 2017

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    (Analysis of 42,389 spontaneous serious adverse event reports to the French Pharmacovigilance database on 8 NSAIDs between 2002 and 2006; liver adverse events were most frequent with nimesulide [0.15 per million daily doses] compared to diclofenac [0.09], ketoprofen [0.09] piroxicam [0.06], naproxen [0.04], meloxicam [0.03], and tenoxicam [0.03]; celecoxib not discussed).
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    (34 year old woman developed jaundice 3 weeks after starting celecoxib for menstral pain [bilirubin 3.4 mg/dL, ALT 458 U/L, Alk P 231 U/L], resolving within 1 month of stopping).
  • 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, including 6 attributed to diclofenac [ranking 2nd], but none due to celecoxib).
  • 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, the most common class of implicated agents being NSAIDS [n=62, 32%], but specific agents were nimesulide [n=53], piroxicam [5], diclofenac [2], gold salts [1], and naproxen [1]; celecoxib was not listed]).
  • 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. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 3 cases [0.3%] were attributed to celecoxib, with latencies of 16, 23 and 145 days, hepatocellular or mixed enzyme elevations and self-limited course in 2 and prolonged cholestasis in one).
  • Schmeltzer PA, Kosinski AS, Kleiner DE, Hoofnagle JH, Stolz A, Fontana RJ, Russo MW; Drug-Induced Liver Injury Network (DILIN).. Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int 2016; 36: 603-9. [PMC free article: PMC5035108] [PubMed: 26601797]
    (Among 1221 cases of drug induced liver injury enrolled in a prospective, US database between 2004 and 2014, 30 cases [2.5%] were attributed to NSAIDs, including 3 due to celecoxib: Case 3).

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