Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Alanine Aminotransferase (ALT) Activity During Early Acetaminophen Therapy in Patients with Osteoarthritis
Kuffner, Edwin, Cooper, Kimberly, Baggish, Jeffrey, Lynch, Joseph M., Zimmerman, Brenda, Temple, Anthony
Acetaminophen (APAP) is a first-line analgesic for the management of OA pain, recommended in the OA Guidelines of the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR). Over-the-counter (OTC) analgesic labels instruct patients not to use these medications for pain for more than 10 days without consulting a doctor.
Some healthy volunteers given APAP 4000 mg/d for up to 2 wks were reported to have ALT elevations [cir]3 times upper limit of reference range (ULRR) which continued for several days after stopping therapy but then decreased. To determine whether this phenomenon was transient or persistent with the continued use of APAP, we retrospectively analyzed ALT data collected within approximately 2 wks of initiating therapy with the maximum recommended daily dose (MRDD) of APAP (39004000 mg/d) and determined elevated ALT and rates of resolution while the patients remained on APAP therapy.
3 McNeil-sponsored, controlled OA trials included ALT measurements within approximately 2 wks of initiating APAP monotherapy. Patients with elevated ALT at screening or baseline were excluded from the analysis. Maximum ALT for each patient was stratified by degree of elevation: >ULRR, >1.5X ULRR, >3X ULRR, >5X ULRR, or ALT >3X ULRR and bilirubin >=2X ULRR. Resolution of ALT elevation was defined as an ALT <=ULRR after the last dose of study drug. If ALT at study completion was lower than the maximum ALT observed during the trial but >ULRR, the ALT elevation was considered to be decreasing.
All trials had double-blind study designs and were at least 12 wks in duration. Patients in 2 placebo-controlled trials received extended-release APAP 3900mg/d; patients in the active-controlled trial received extra-strength APAP 4000mg/d. ALT remained within the normal range throughout the 2 wk analysis period for 376 (80.7%) of 466 patients. At some point during the 2 wk analysis period, 90 (19.3%) patients had an ALT >ULRR; 21 (4.5%) patients had an ALT >1.5X ULRR; and 4 (0.9%) patients had an ALT >3X ULRR. No patient had ALT >5X ULRR, or >3X ULRR with bilirubin >=2X ULRR. No patient exhibited signs or symptoms of hepatotoxicity or hepatic failure. ALT resolution was observed for 62 (68.9%) of 90 patients with elevations and decreasing ALT was observed for 19 (21.1%) patients. Incidence of adverse events possibly of hepatic origin was similar between patients without and with elevated ALT during the 2 wk analysis period.
Fewer than 5% of OA patients taking the MRDD of APAP for 2 wks had elevated ALT (>1.5X ULRR). These elevated values resolved or were decreasing during continued APAP therapy in >95% of patients and were not accompanied by signs or symptoms suggestive of liver toxicity. These data show that while some individuals who take APAP may experience increased ALT during treatment that is consistent with OTC labeling, nearly all of these elevations resolved with continued APAP use.
To cite this abstract, please use the following information:
Kuffner, Edwin, Cooper, Kimberly, Baggish, Jeffrey, Lynch, Joseph M., Zimmerman, Brenda, Temple, Anthony; Alanine Aminotransferase (ALT) Activity During Early Acetaminophen Therapy in Patients with Osteoarthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :834