Olicoxib Drug Interactions

General: In vitro studies with human hepatic microsomal systems showed no significant inhibitory effects on CYP3A4, 2D6, 2E1, and 1A2 isoforms by parecoxib and Valdecoxib (active moiety). Weak inhibitory activity was found for 2C9 and 2C19 isozymes.
In humans, studies have demonstrated that valdecoxib metabolism is predominantly mediated via CYP450 3A4 and 2C9 isozymes.
Glucuronidation is a further route of metabolism. Due to CYP450-mediated and non-CYP450-mediated metabolic pathways, genetic polymorphisms leading to substantially higher plasma concentrations resulting from impaired metabolism are not expected.
Aspirin: Parecoxib sodium Injection had no effect on aspirin-mediated inhibition of platelet aggregation or bleeding times. Clinical trials indicate that Parecoxib sodium Injection can be given with low dose aspirin. Because of its lack of platelet effects, OLICOXIB Injection is not a substitute for aspirin for cardiovascular prophylaxis.
Methotrexate: In interaction studies in rheumatoid arthritis patients receiving weekly methotrexate (5-20 mg IM), valdecoxib (10 mg BD and 40 mg BD) did not have a clinically significant effect on the plasma exposure to methotrexate. However, caution is advised when methotrexate is administered concurrently with NSAIDs, because NSAID administration may result in increased plasma levels of methotrexate.
Anti-hypertensives including ACE-inhibitors, Angiotensin Receptor Antagonists, Beta Blockers and Diuretics: Reports suggest that NSAIDs may diminish the antihypertensive effects of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, beta blockers and diuretics. It is unclear, at the present time, how this may apply to OLICOXIB Injection. This potential interaction should be given consideration in patients taking OLICOXIB Injection concomitantly with ACE-inhibitors, angiotensin receptor antagonists, beta blockers and diuretics.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors and/or angiotensin receptor antagonists, may result in deterioration of renal function, including possible acute renal failure.
Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.
Cyclosporin: Because of their effect on renal prostaglandins, NSAIDs may increase the risk of nephrotoxicity with cyclosporin.
Injectable Anaesthetics: Propofol is metabolised by CYP2C9. Coadministration of parecoxib sodium with propofol did not affect either the pharmacokinetics (metabolism and exposure) or the pharmacodynamics of IV propofol.
Midazolam is metabolised primarily by CYP3A4. Coadministration of parecoxib sodium IV, or valdecoxib orally, with IV midazolam did not affect the pharmacokinetics (metabolism and exposure) or the pharmacodynamics of midazolam.
Fentanyl and Alfentanil are extensively metabolised by CYP3A4. Coadministration with parecoxib sodium had no significant effect on the pharmacokinetics of either IV fentanyl or IV alfentanil.
Inhalation Anaesthetics: No formal interaction studies have been conducted. In the general surgery studies, no evidence of pharmacodynamic medicine interaction was observed between parecoxib sodium administered preoperatively and the inhalation anaesthetic agents; nitrous oxide and isoflurane.
Glibenclamide: Glibenclamide is a CYP3A4 substrate. Coadministration of valdecoxib (10 mg BD for 7 days) with glibenclamide (5 mg or 10 mg OD) did not affect the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glibenclamide.
Anticonvulsants: Potential interactions with phenytoin (2C9/19 substrate) and carbamazepine (3A4 substrate) have not been studied. However, as mentioned previously (see General), no interactions were noted using prototype 3A4 and 2C9 substrates of these isozymes.
Ketoconazole and Fluconazole: AUC and C_max of valdecoxib was increased (62%) when coadministered with fluconazole, indicating that the dose of parecoxib sodium should be reduced in those patients who are receiving fluconazole therapy. AUC and C_max of valdecoxib was increased (38%) when coadministered with ketoconazole.
Dextromethorphan: Valdecoxib 40 mg BD for 7 days did not produce clinically relevant inhibition in the metabolism by the CYP 2D6-mediated pathway involved in the conversion of dextromethorphan to dextrorphan.
Lithium: Valdecoxib 40 mg BD for 7 days produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone. Lithium serum concentrations should be monitored closely when initiating or changing parecoxib sodium therapy in patients receiving lithium.
Anticoagulants: The effect of valdecoxib on the anticoagulant effect of warfarin (1-8 mg/day) was studied in healthy subjects by IV coadministration of 10 mg parecoxib sodium BD for 7 days. There was a slight increase in the plasma concentration of R-warfarin, but not S-warfarin, as a result of parecoxib sodium coadministration. The effect of oral valdecoxib (40 mg BD) on the anticoagulant effect of warfarin (1-8 mg/day) was studied in healthy subjects by coadministration for 7 days. Valdecoxib caused a statistically significant increase in plasma exposure of R-warfarin and S-warfarin (12% and 15% respectively), and in the pharmacodynamic effects (prothrombin time, measured as INR of warfarin). While mean INR values were only slightly increased (≤8%) with coadministration of valdecoxib, the day-to-day variability in individual INR values was increased.
Anticoagulant therapy should be monitored, particularly during the first few days, after initiating OLICOXIB Injection therapy in patients receiving warfarin or similar agents, since these patients are at increased risk of bleeding complications.