Valdecoxib drug data and news

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Glenmark: Study in contrast  17 May 2006
API prices. Also, the discontinuation of Valdecoxib (medication for osteoarthritis) earlier this year affected top line. However ... - Business Standard,

How safe is your painkiller?  May 13, 2006
While valdecoxib and rofecoxib have been voluntarily withdrawn from the US market by the manufacturers, mandatory celecoxib labelling is required to contain ... - Hindustan Times,

Vioxx's risk high in first two weeks, study finds  May 3, 2006
Research has shown that Celebrex does not appear to increase cardiovascular risk in the same way as Vioxx and Bextra (valdecoxib), which was pulled from the ... - Globe and Mail,

Use of First- and Second-Generation Cyclooxygenase-2-Selective ...  Apr 19, 2006
Whether the newer second-generation COX-2 inhibitors (etoricoxib, valdecoxib) also increase the cardiovascular risk is unknown. ... - HeartZine,

Despite Conflicts, Drug Judges Continue to Vote Yea or Nay  Apr 26, 2006
They noted that at a 2005 advisory committee meeting to evaluate the risks of the COX-2 inhibitors Bextra (valdecoxib), Celebrex (celecoxib) and Vioxx ... - MedPage Today,

Selective inhibitors of mPGES-1, a new class of anti-inflammatory ...  Apr 17, 2006
Ever since the association of selective inhibitors of COX-2 – Vioxx ( Rofecoxib ), Bextra ( Valdecoxib ), and Celebrex ( Celecoxib ) - with an increased ... - Xagena.it,

Cardiovascular outcomes in new users of coxibs and nonsteroidal ...  Apr 29, 2006
Predefined exposure groups included the 3 coxibs available in the US during the study period (celecoxib, rofecoxib, and valdecoxib), as well as oral ... - HeartZine,

Pfizer profits soar despite slipping revenues  Apr 20, 2006
...the first quarter of 2005 had been impacted by charges related to the withdrawal from the marketplace of COX-2 inhibitor Bextra (valdecoxib) and repatriation ... - Pharma Times (subscription),

The drug interaction studies with valdecoxib were performed both with valdecoxib and a rapidly hydrolyzed intravenous prodrug form. The results from trials using the intravenous prodrug are reported in this section as they relate to the role of valdecoxib in drug interactions.

General: In humans, valdecoxib metabolism is predominantly mediated via CYP 3A4 and 2C9 with glucuronidation being a further (20%) route of metabolism. In vitro studies indicate that valdecoxib is a moderate inhibitor of CYP 2C19 (IC50 = 6 µg/mL or 19 µM) and 2C9 (IC50 = 13 µg/mL or 41 µM), and a weak inhibitor of CYP 2D6 (IC50 = 31 µg/mL or 100 µM) and 3A4 (IC50 = 44 µg/mL or 141 µM )..

Aspirin: Concomitant administration of aspirin with valdecoxib may result in an increased risk of GI ulceration and complications compared to valdecoxib alone. Because of its lack of anti-platelet effect valdecoxib is not a substitute for aspirin for cardiovascular prophylaxis. In a parallel group drug interaction study comparing the intravenous prodrug form of valdecoxib at 40 mg BID (n=10) vs placebo (n=9), valdecoxib had no effect on in vitro aspirin-mediated inhibition of arachidonate- or collagen-stimulated platelet aggregation.

Methotrexate: Valdecoxib 10 mg BID did not show a significant effect on the plasma exposure or renal clearance of methotrexate.

ACE-inhibitors:Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking BEXTRA concomitantly with ACE-inhibitors.

Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

Anticonvulsants (Phenytoin): Steady state plasma exposure (AUC) of valdecoxib (40 mg BID for 12 days) was decreased by 27% when co-administered with multiple doses (300 mg QD for 12 days) of phenytoin (a CYP 3A4 inducer). Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration. Valdecoxib did not have a statistically significant effect on the pharmacokinetics of phenytoin (a CYP 2C9 and CYP 2C19 substrate).

Drug interaction studies with other anticonvulsants have not been conducted. Routine monitoring should be performed when therapy with BEXTRA is either initiated or discontinued in patients on anticonvulsant therapy.

Dextromethorphan: Dextromethorphan is primarily metabolized by CYP 2D6 and to a lesser extent by 3A4. Coadministration with valdecoxib (40 mg BID for 7 days) resulted in a significant increase in dextromethorphan plasma levels suggesting that, at these doses, valdecoxib is a weak inhibitor of 2D6. Even so dextromethorphan plasma concentrations in the presence of high doses of valdecoxib were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers suggesting that dose adjustment is not necessary.

Lithium: Valdecoxib 40 mg BID 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 therapy with BEXTRA in patients receiving lithium. Lithium carbonate (450 mg BID for 7 days) had no effect on valdecoxib pharmacokinetics.

Warfarin: The effect of valdecoxib on the anticoagulant effect of warfarin (1 - 8 mg/day) was studied in healthy subjects by coadministration of BEXTRA 40 mg BID for 7 days. Valdecoxib caused a statistically significant increase in plasma exposures 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 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 weeks, after initiating therapy with BEXTRA in patients receiving warfarin or similar agents.

Fluconazole and Ketoconazole: Ketoconazole and fluconazole are predominantly CYP 3A4 and 2C9 inhibitors, respectively. Concomitant single dose administration of valdecoxib 20 mg with multiple doses of ketoconazole and fluconazole produced a significant increase in exposure of valdecoxib. Plasma exposure (AUC) to valdecoxib was increased 62% when coadministered with fluconazole and 38% when coadministered with ketoconazole.

Glyburide: Glyburide is a CYP 2C9 substrate. Coadministration of valdecoxib (10 mg BID for 7 days) with glyburide (5 mg QD or 10 mg BID) did not affect the pharmacokinetics (exposure) of glyburide. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2-7)) with glyburide (5 mg QD) did not affect either the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glyburide. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2-7)) with glyburide (10 mg glyburide BID) resulted in 21% increase in glyburide AUC_0-12 and a 16% increase in glyburide C_max leading to a 16% decrease in glucose AUC_0-24. Insulin parameters were not affected.

Because changes in glucose concentrations with valdecoxib coadministration were within the normal variability and individual glucose concentrations were above or near 70 mg/dL, dose adjustment for glyburide (5 mg QD and 10 mg BID) with valdecoxib coadministration (up to 40 mg QD) is not indicated. Coadministration of glyburide with doses higher than 40 mg valdecoxib (e.g., 40 mg BID) have not been studied.

Omeprazole: Omeprazole is a CYP 3A4 substrate and CYP 2C19 substrate and inhibitor. Valdecoxib steady state plasma concentrations (40 mg BID) were not affected significantly with multiple doses of omeprazole (40 mg QD). Coadministration with valdecoxib increased exposure of omeprazole (AUC) by 46%. Drugs whose absorption is sensitive to pH may be negatively impacted by concomitant administration of omeprazole and valdecoxib. However, because higher doses (up to 360 mg QD) of omeprazole are tolerated in Zollinger-Ellison (ZE) patients, no dose adjustment for omeprazole is recommended at current doses. Coadministration of valdecoxib with doses higher than 40 mg QD omeprazole has not been studied.

Oral Contraceptives: Valdecoxib (40 mg BID) did not induce the metabolism of the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg /35 mcg combination, Ortho-Novum 1/35^®). Coadministration of valdecoxib and Ortho-Novum 1/35^® increased the exposure of norethindrone and ethinyl estradiol by 20% and 34%, respectively. Although there is little risk for loss of contraceptive efficacy, the clinical significance of these increased exposures in terms of safety is not known. These increased exposures of norethindrone and ethinyl estradiol should be taken into consideration when selecting an oral contraceptive for women taking valdecoxib.

Diazepam: Diazepam (Valium) is a CYP 3A4 and CYP 2C19 substrate. Plasma exposure of diazepam (10 mg BID) was increased by 28% following administration of valdecoxib (40 mg BID) for 12 days, while plasma exposure of valdecoxib (40 mg BID) was not substantially increased following administration of diazepam (10 mg BID) for 12 days.

Although the magnitude of changes in diazepam plasma exposure when coadministered with valdecoxib were not sufficient to warrant dosage adjustments, patients may experience enhanced sedative side effects caused by increased exposure of diazepam under this circumstance. Patients should be cautioned against engaging in hazardous activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.