title: The hepatic safety and tolerability of the cyclooxygenase-2 selective NSAID celecoxib: pooled analysis of 41 randomized controlled trials.
abstract: OBJECTIVE
  To assess the hepatic safety and tolerability of celecoxib versus placebo and three commonly prescribed nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).
  
  
  METHODS
  This was a retrospective, pooled analysis of a 41-study dataset involving patients with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, chronic low back pain, and Alzheimer's disease. Criteria for selection of studies were: (1) Randomized, parallel-group design and planned treatment duration of > or =2 weeks (2) > or =1 placebo or NSAID comparator (3) > or =1 arm with celecoxib at total daily dose of > or =200 mg (4) Data available as of October 31, 2004 Data were pooled by treatment and subject from the safety analysis population of included studies. Treatment-emergent hepatobiliary adverse events (AEs) were compared for celecoxib <200 mg/day (943 patients), 200 mg/day (12 008 patients), 400 mg/day (7380 patients), and 800 mg/day (4602 patients); placebo (4057 patients); diclofenac 100-150 mg/day (7639 patients); naproxen 1000 mg/day (2953 patients); and ibuprofen 2400 mg/day (2484 patients). Hepatobiliary laboratory abnormalities were also analyzed.
  
  
  RESULTS
  There were no cases of liver failure, treatment-related liver transplant, or treatment-related hepatobiliary death. Incidence of serious hepatic AEs was low, with 13 (0.05%) serious hepatic AEs among 24 933 celecoxib-treated patients, and 16 (0.21%) among 7639 diclofenac-treated patients. No patients receiving celecoxib or any nonselective NSAID met criteria for Hy's rule (alanine aminotransferase [ALT] > or =3 x upper limit of normal [ULN] with bilirubin > or =2 x ULN). The incidence of notable (> or =5 x ULN) and severe (> or =10 x ULN) ALT elevations was similar for all treatment groups except diclofenac. Significantly fewer hepatobiliary AEs were reported for celecoxib (any dose; 1.11%) than for diclofenac (vs. 4.24%, p < 0.0001); for ibuprofen (vs. 1.53%, p = 0.06) and placebo (vs. 0.89%, p = 0.21) the incidence of AEs was comparable to celecoxib.
  
  
  CONCLUSIONS
  A number of limitations should be considered when evaluating the results: findings were limited by the quality and reporting of the studies selected; difficulty in estimating the incidence of AEs due to the low frequency of events; acetaminophen not included as an active comparator.
  
  
  CONCLUSIONS
  In this pooled analysis, the incidence of hepatic AEs in patients treated with celecoxib was similar to that for both placebo-treated patients and patients treated with ibuprofen or naproxen, but lower than for diclofenac.
authors.affiliation: Pfizer Inc, New York, NY 10017, USA.
authors.forename: Paresh
authors.initials: P
authors.lastname: Soni
authors.forename: Briton
authors.initials: B
authors.lastname: Shell
authors.forename: Gail
authors.initials: G
authors.lastname: Cawkwell
authors.forename: Chunming
authors.initials: C
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009140:Musculoskeletal Diseases / Q000188:drug therapy; D011720:Pyrazoles / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D013449:Sulfonamides / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib