liver microsomes, a process catalyzed in large part (~60%) by members of the hepatic cytochrome P450 (CYP) 3A subfamily with lesser contributions by multiple other CYP isoenzymes including CYP2C9, CYP2D6, CYP1A2, and possibly CYP2C19 (Kassahun et al 2001). Etoricoxib is a weak inhibitor of CYP3A and other CYP isoenzymes in vitro (IC50 > 100 µM) (Kassahun et al 2001), and has a minimal inhibitory effect on CYP3A activity in healthy volunteers (Agrawal et al 2004b). Coadministration of CYP3A inhibitors in healthy volunteers increased the etoricoxib area under the curve, but this effect was not considered to be clinically relevant (Agrawal et al 2004b). In contrast, agents that strongly induce CYP3A may reduce etoricoxib concentrations below therapeutic levels (Agrawal et al 2004b). Patients with mild to moderate hepatic insufficiency exhibit reduced clearance of etoricoxib. The etoricoxib dose should not exceed 60 mg once daily in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), and 60 mg every other day in patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9). No data are available for patients with severe hepatic impairment (Child-Pugh score ≥ 10), and etoricoxib is not recommended for use in this patient population (Agrawal, Rose, et al 2003). Renal insufficiency has little impact on etoricoxib pharmacokinetics and no dosage adjustment is required (Agrawal et al 2004a). However, etoricoxib, similar to other selective and traditional NSAIDs, appears to have dose-related renovascular effects (see renovascular tolerability section) (Curtis et al 2004), and use of etoricoxib in patients with a creatinine clearance < 30 ml/min is contraindicated (EMEA 2005a). Clinical studies Clinical studies have established the efficacy and tolerability of etoricoxib in arthritis and pain, and the drug is available in over 50 countries worldwide. Etoricoxib is approved in Europe for the symptomatic relief of OA, RA, and the pain and signs of inflammation associated with acute gouty arthritis (EMEA 2005a), whereas the US Food and Drug Administration (FDA) has requested additional efficacy and safety data prior to approval of etoricoxib. Some countries in Latin America and Asia have additional indications including LBP, ankylosing spondylitis, and primary dysmenorrhea Efficacy Etoricoxib in the treatment of osteoarthritis Clinical studies have shown that etoricoxib is more effective than placebo, and of similar efficacy to traditional NSAIDs, Therapeutics and Clinical Risk Management 2006:2(1) Etoricoxib for arthritis and pain in the treatment of OA. A dose-ranging study in 617 patients with knee OA established that etoricoxib 5 mg to 90 mg every day (QD) was more effective than placebo after 6 weeks as measured by the Western Ontario and McMaster’s University OA Index (WOMAC) pain subscale and patient and investigator global assessments (p < 0.05 each comparison), with maximal efficacy at a dosage of 60 mg QD (Gottesdiener et al 2002). The efficacy of etoricoxib 60 mg QD was comparable with that of diclofenac 50 mg three times daily (TID) in long-term extensions of this study for up to 52 weeks (Curtis et al 2005) and up to a total of 190 weeks (Fisher et al 2003) Etoricoxib 60 mg QD and diclofenac 50 mg TID also showed comparable efficacy in a 6-week, randomized study of 516 patients with hip or knee OA assessed using the WOMAC pain subscale (Zacher et al 2003), irrespective of baseline disease severity (Frizziero et al 2004). Interestingly, in this study etoricoxib had a more rapid effect with significantly more patients reporting a good or excellent response within 4 hours of the first dose compared with diclofenac (Figure 1) (Zacher et al 2003). The Etoricoxib versus Diclofenac sodium Gastro- intestinal tolerability and Effectiveness (EDGE) study which primarily evaluated gastrointestinal tolerability in 7111 14 23 31 * 30 2 Etoricoxib 60 mg (n = 187) Diclofenac 50 mg (n = 199) 15 24 42 18 1 0 10 20 30 70 80 90 100 40 50 60 Patients (%) PGART: None Poor Fair Good Excellent Figure 1 Osteoarthritis PGART 4 hours ± 15 minutes after the first dose of etoricoxib versus diclofenac. This randomized, double-blind, parallel-group study evaluated the efficacy and tolerability of etoricoxib 60 mg QD versus diclofenac 50 mg TID over 6 weeks in 516 patients with hip or knee osteoarthritis.The treatments were of comparable efficacy on all primary and secondary efficacy endpoints (data not shown), except for the analysis of early efficacy illustrated here in which a greater percentage of patients reported good or excellent PGART responses within 4 hours of receiving their first dose of etoricoxib compared with diclofenac. Copyright © 2003. Reproduced with permission from Zacher J, Feldman D, Gerli R, et al. 2003. A comparison of the therapeutic efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis. Curr Med Res Opin, 19:725–36. * p = 0.007 for good or excellent PGART with etoricoxib versus diclofenac. Abbreviations: QD, every day; PGART, Patient Global Assessment of Response to Therapy; TID, three times daily. 47