Brands, Medical Use, Clinical Data
Drug Category
- Anti-inflammatory Agents
- Nonsteroidal Antiinflammatory Agents (NSAIDs)
Dosage Forms
Brands / Synonyms
Bextra; Valdecoxib [USAN]
Indications
For the treatment of osteoarthritis and dysmenorrhoea
Pharmacology
Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism.
Mechanism of Action
Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit platelet aggregation.
Absorption
Not Available
Toxicity
Not Available
Biotrnasformation / Drug Metabolism
Not Available
Contraindications
BEXTRA should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.
BEXTRA Tablets are contraindicated in patients with known hypersensitivity to valdecoxib. BEXTRA should not be given
to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or NSAIDs.
Severe, rarely fatal, anaphylactic-like reactions to NSAIDs are possible in such patients.
Drug Interactions
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 AUC0-12 and a 16% increase in glyburide Cmax leading to a
16% decrease in glucose AUC0-24. 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.
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