Valdecoxib: DRUG INTERACTIONS

8 Jul
2010

Valdecoxib is metabolized via the cytochrome P(CYP)-450 system, pre dominately 3A4 and 2C9, as well as non-P450 systems, including approximately 20% glucuronidation. Valdecoxib has one metabolite that is excreted in the urine, but it has not been shown to have significant activity or to contribute to the drug’s profile. Because valdecoxib is a substrate for the 3A4 enzyme, precaution should be taken when coadministering with inhibitors or inducers of this enzyme system. When potent inhibitors of the 3A4 system (i.e., fluconazole and ketocona-zole) where administered with a single dose of valdecoxib 20 mg, plasma concentrations increased to 62% with fluconazole and 38% with ketoconazole. Although they have not been fully established, similar effects can be seen with other 3A4 inhibitors such as ery-thromycin, itraconazole, and ritonavir. Despite the lack of clinical studies, this pharmacokinetic drug interaction should be taken into consideration when coad-ministering valdecoxib with 3A4 inducers such as carbamazepine, phenobarbital, phenytoin and rifampin as well. Patients taking valdecoxib with anticonvulsants should be monitored appropriately when initiating or discontinuing therapy.

Medications that induce or inhibit the 2C9 enzyme system might also have an effect on valdecoxib plasma concentrations. Although no published studies have been conducted with valdecoxib, when flucona-zole (a 2C9 inhibitor) was administered, plasma concentrations were increased. The same endpoint was seen when high-dose cimetidine, another 2C9 inhibitor, was coadministered with rofecox-ib. Theoretically, these same effects might be possible when taken with valde-coxib. When dextromethorphan (DM) was administered with valdecoxib for seven days, DM concentrations were shown to increase significantly, suggesting that valdecoxib is a weak inhibitor of the CYP-2D6 enzyme system.

As previously mentioned, although there are limited studies that have assessed all CYP-450 enzyme interactions, pharmacists and physicians have to theorize based on other coxib trials and their knowledge of pharmacokinetic interactions. Celecoxib, an inhibitor of 2D6, might increase the concentrations of 2D6 substrates, which include selective serotonin reuptake inhibitors, tricyclic antidepressants, antifungals, antipsy-chotics (i.e., haloperidol, thioridazine) and beta-blockers. Again, similar effects can be seen with other coxibs requiring appropriate monitoring. Regular monitoring of blood pressure should be performed when administering valdecoxib with ACE-inhibitors, furosemide, and thiazides. NSAIDs have been shown to diminish the antihypertensive effects of these medications by inhibiting the COX enzyme and causing a decrease in renal prostaglandins, which normally provide renal protection and maintain renal blood flow and fluid balance. The decrease in renal prostaglandin synthesis caused by the COX inhibition, might also have an effect on lithium concentrations, resulting in decreased lithium clearance and consequently increased lithium plasma levels. Post-marketing studies suggest these effects to be true of valdecoxib as well as the other coxibs.

Figure 2

As previously mentioned, the COX-1 enzyme is present in platelets and COX-1 inhibition can result in antiplatelet effects and an increased risk of bleeding. This effect is seen with all conventional NSAIDs, specifically with aspirin, which irreversibly inhibits platelet aggregation by binding to the COX-1 site. Because the COX-2 enzyme is not present in platelets, it would suggest that the coxibs would have no effect on platelet function or bleeding. Several small studies showed no effect on bleeding time or platelet aggregation when comparing high-dose coxibs to aspirin therapy. In a study by Leese et al., 65 healthy adults (aged 65-95 years) were randomized to receive either valdecoxib 40 mg twice daily (BID), ibuprofen 800 mg three times daily (TID), or placebo for 7.5 days. The overall study objective was to determine the effects of valdecoxib on platelet function. Serum concentrations of throm-boxane and arachidonate, bleeding times, and adverse events were assessed periodically on days one and eight of treatment. Overall, valdecoxib showed no effect on platelet markers (i.e., percent change in arachidonate concentration) when compared to placebo and ibuprofen (0.0 vs. -1.0 vs. -60.0, respectively, P<0.05). There were no effects seen on bleeding time in the valdecoxib treatment group. Despite limited studies with valdecoxib, it is recommended that patients on concomitant aspirin therapy be monitored for increased gastrointestinal adverse effects. There are currently no large-scale trials evaluating the concomitant use of valde-coxib and warfarin. One small study in healthy adults showed small increases in international normalized ratio (INR) as well as an increase in warfarin levels. It is recommended that patients receiving warfarin and valdecoxib be monitored regularly at the start of therapy and during the first few weeks, because variability in INR values can be seen.
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Table 5 Comparison of Adverse Effects

AdverseValdecoxib

Valdecoxib

Celecoxib

Rofecoxib

Event10 mg

20 mg

200 mg

2.5 or 25 mg

Abdominal pain7%

8.2%

4.1%

3.4%

Dizziness2.6%

2.7%

2%

3%

Diarrhea5.4%

6%

5.6%

6.5%

Nausea7%

6.3%

3.5%

5.2%

Dyspepsia7.9%

8.7%

8.8%

3.5%

Lower extremity edema   2.4%

3%

2.1%

3.7%

Upper respiratory
tract infection6.7%

5.7%

8.1%

8.5%

Side Effects and Precautions

Valdecoxib should be avoided in any patient who has experienced asthma, urticaria, or an allergic-type reaction after taking aspirin or an NSAID. Unlike rofe-coxib, which has a sulfone component, celecoxib canadian and valdecoxib both contain a sulfonamide moiety (Figure 2). Based on studies with celecoxib, patients who have a sulfonamide allergy should also avoid valdecoxib because of the possibility of a hypersensitivity reaction. Although there is limited information suggesting the same for valdecoxib, it does contain the same moiety as celecoxib and theoretically the sulfonamide sensitive patients could be affected as well. Overall, valde-coxib has shown side effects similar to the other COX-2 inhibitors (Table 5).

Table 6 COX-2 Inhibitor Price Comparison

Cox-2 InhibitorDosagePrice (quantity)
Valdecoxib (Bextra)10 mg, 20 mg$78.70 (30)
Celecoxib100 mg$84.95 (60)
200 mg$71.73 (30)
Rofecoxib (Vioxx)12.5 mg, 25 mg$73.29 (30)
50 mg$107.47 (30)
12.5 mg/5 ml, 25 mg/5 ml$112.71 (30 days)
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