As parecoxib is rapidly metabolised to valdecoxib, interactions are usually considered to be due to effects of valdecoxib.The manufacturer of parecoxib cautions concurrent use withcarbamazepine, dexamethasone and rifampicin as their effects onparecoxib have not been studied. Valdecoxib increases levelsof dextromethorphan and omeprazole. Because of these interactions,caution is advised with drugs that are metabolised by thesame isoenzymes, namely flecainide, metoprolol, propafenone,omeprazole, diazepam, imipramine and phenytoin. No interaction appears to occur between parecoxib and midazolam.
Clinical evidence,mechanism, importance and management
Parecoxib is a parenteral drug that is rapidly metabolised in liver to active COX-2 inhibitor valdecoxib. Valdecoxib is predominantly metabolised by cytochrome P450 isoenzymes CYP3A4 and CYP2C9. The interactions therefore are usually considered to be due to effects of valdecoxib
The manufacturers have done several interaction studies to find out whether parecoxib or valdecoxib can inhibit or induce cytochrome P450 isoenzymes CYP2C9, CYP2D6, CYP2C19, and CYP3A4 and thereby determine their potential to interact with drugs metabolised by these isoenzymes.
CYP2C19. The manufacturers say that AUC of omeprazole 40mg was increased by 46 % by valdecoxib 40mg twice daily for a week. This indicates that valdecoxib is an inhibitor of CYP2C19 and although manufacturers consider it to be a weak inhibitor(See reference number 1)they suggest that caution should be observed with drugs that have a narrow therapeutic margin and are known to be metabolised by CYP2C19. They list diazepam,imipramine and phenytoin (See reference number 2). The implication is that serum levels of these drugs and their effects may possibly be increased by use of parecoxib.
CYP2D6. The manufacturers say that treatment with 40mg of valdecoxib twice daily for a week caused a threefold increase in serum levels of dextromethorphan. This indicates that valdecoxib is an inhibitor of CYP2D6, and therefore manufacturers(See reference number 1) suggest that caution should be observed with drugs that have a narrow therapeutic margin and are known to be predominantly metabolised by CYP2D6. They list flecainide, metoprolol and propafenone (See reference number 2). The implication is that serum levels of these
drugs and their effects may possibly be increased by use of parecoxib, but so far there appears to be no direct clinical reports of any problems with concurrent use.
A study in 12 healthy adults found no significant changes in pharmacokinetics of midazolam 70 micrograms/kg given an hour after a 40mg dose of intravenous parecoxib (See reference number 3). This suggests that parecoxib and valdecoxib are unlikely to inhibit or induce activity of CYP3A4
Enzyme inducers. The effects of enzyme inducers carbamazepine, dexamethasone, phenytoin and rifampicin have not been studied with parecoxib. Nevertheless, manufacturer of parecoxib warns that they may increase metabolism of valdecoxib (See reference number 2).
Pharmacia Ltd. Personal communication,May 2002.
Dynastat Injection (Parecoxib sodium). Pfizer Ltd. UK Summary of product characteristics,April 2007.
Ibrahim A,Karim A, Feldman J, Kharasch E. The influence of parecoxib, a parenteral cyclooxygenase-2 specific inhibitor, on the pharmacokinetics and clinical effects of midazolam. Anesth Analg (2002) 95, 667–73.