Fluconazole markedly raises celecoxib levels,whereas ketoconazole has no effect on celecoxib levels. Fluconazole and ketoconazole moderately increase levels of valdecoxib (the mainmetabolite of parecoxib). Ketoconazole moderately raises etoricoxib plasma levels,but this is unlikely to be of clinical relevance.Fluconazole has no clinically relevant effect on lumiracoxib pharmacokinetics.
The manufacturer notes that fluconazole 200mg daily increased AUC of a single 200mg dose of celecoxib by 130 % and increased maximum level by 60%. Conversely, ketoconazole had no effect on pharmacokinetics of celecoxib (See reference number 1).
The AUC of etoricoxib was increased by 43 % and maximum plasma levels was increased by 29 % (See reference number 2)
A placebo-controlled, crossover study in 13 healthy subjects(See reference number 3) found that fluconazole 400mg on day 1 and 200mg on days 2 to 4 had no clinically relevant effect on pharmacokinetics of a single 400mg dose of lumiracoxib given on day 4.
The manufacturer of parecoxib reports a study in which fluconazole increased plasma levels of valdecoxib (the main metabolite of parecoxib) by 19 % and raised its AUC by 62 % (See reference number 4). Ketoconazole had a similar, but more moderate effect on levels of valdecoxib (maximum plasma levels increased by 24%, AUC increased by 38%) (See reference number 4).
Fluconazole is a potent inhibitor of cytochrome P450 isoenzyme CYP2C9 and ketoconazole inhibits CYP3A4. Celecoxib is extensively metabolised by CYP2C9,and therefore shows marked rises in plasma levels when given with fluconazole but not ketoconazole. Etoricoxib is partially metabolised by CYP3A4,therefore shows moderate rises in plasma levels with ketoconazole. Valdecoxib is metabolised by both CYP2C9 and CYP3A4,therefore was modestly affected by both fluconazole and ketoconazole. Parecoxib is a valdecoxib prodrug,and interacts similarly. From study with lumiracoxib it appears that its pharmacokinetics are unlikely to be affected by inhibitors of CYP2C9, because, even though lumiracoxib is largely metabolised by CYP2C9, other pathways are also important (e.g. glucuronidation) (See reference number 3).
These pharmacokinetic interactions are established,although their effect in clinical practice has not been assessed. The marked rise in celecoxib levels with fluconazole could be important, and UK manufacturer recommends that dose of celecoxib should be halved in patients receiving fluconazole,(See reference number 1) whereas US manufacturer suggests starting with lowest recommended dose (See reference number 5). The rise in valdecoxib levels with fluconazole is less marked, nevertheless manufacturer recommends that for parecoxib dosage should be reduced (but they do not suggest by how much) (See reference number 4). No dosage adjustments are thought to be necessary if etoricoxib or parecoxib are given with ketoconazole,and if lumiracoxib is given with fluconazole.
Celebrex (Celecoxib). Pharmacia Ltd. UK Summary of product characteristics,February 2007.
Agrawal NGB,Matthews CZ, Mazenko RS, Woolf EJ, Porras AG, Chen X, Miller JL,Michiels N, Wehling M, Schultz A, Gottlieb AB, Kraft WK, Greenberg HE, Waldman SA,Curtis SP, Gottesdiener KM. The effects of modifying in vivo cytochrome P450 3A (CYP3A)activity on etoricoxib pharmacokinetics and of etoricoxib administration on CYP3A activity.J Clin Pharmacol (2004) 44, 1125–31.
Scott G,Yih L, Yeh C-M, Milosavljev S, Laurent A, Rordorf C. Lumiracoxib: pharmacokinetic and pharmacodynamic profile when coadministered with fluconazole in healthy subjects. J Clin Pharmacol (2004) 44, 193–9.
Dynastat Injection (Parecoxib sodium). Pfizer Ltd. UK Summary of product characteristics,April 2007.
Celebrex (Celecoxib). Pfizer Inc. US Prescribing information,February 2007.