Pharmacology Update
Celebrex
By William T. Elliott, PhD, and James Chan, PharmD, PhD
To prerelease hype of near viagra proportions, the FDA approved Searle’s celecoxib (Celebrex) on the Dec. 31, 1998. Celecoxib is a NSAID, but, unlike current NSAIDs, it is a selective inhibitor of cyclooxygenase-2 (COX-2). Currently available NSAIDs generally inhibit both COX-1 as well as COX-2. Inhibition of COX-2 is believed to provide the therapeutic anti-inflammatory and analgesic benefit of traditional NSAIDs, while inhibition of COX-1 may contribute to upper gastrointestinal adverse effects, such as ulcers, and also mediates the anti-platelet aggregation effects of NSAIDS. At therapeutic concentrations, celecoxib does not inhibit COX-1. Thus, it is hoped that celecoxib, and other drugs of this class, will be "safer" NSAIDS. Several other COX-2 inhibitors are in the FDA pipeline including rofecoxib, valdecoxib, and parecoxib. Celecoxib is manufactured by Searle and co-marketed by Searle and Pfizer.
Indications
Celecoxib is indicated for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis in adults.
Dosage
For the relief of the signs and symptoms of osteoarthritis, the recommended dose is 200 mg daily administered as a single dose or as 100 mg twice daily.1
For the relief of the signs and symptoms of rheumatoid arthritis, the recommended dose is 100-200 mg twice a day.
In elderly patients (> 65 years of age), consideration should be given to start at a lower dose as higher peak plasma levels (40% greater) and greater total absorption (50% greater) have been reported.1
Celecoxib can be taken without regard to meals. However, a high-fat meal delays the absorption by about 1-2 hours, with an increase in total absorption of 10-20%. Coadministration with an aluminum and magnesium containing antacid reduces the peak plasma level by 37% and total absorption by 10%.1 Celecoxib is supplied as 100 mg and 200 mg capsules.
Potential Advantages
In comparative trials between celecoxib and ibuprofen or naproxen, celecoxib was associated with a statistically significantly lower incidence of endoscopic ulcers evaluated at 12 weeks.1 The incidences were 9.9%-17.6% with naproxen (500 mg bid) and 9.6% for ibuprofen (800 mg tid), compared to 1.5-4% and 1.5-5.9% for celecoxib at 100 mg bid and 200 mg bid, respectively.1 Higher than recommended doses of celecoxib (600 mg bid for 7 days) had no effect on platelet aggregation and bleeding time.1 A single dose of 800 mg of celecoxib did not inhibit platelet COX-1 dependent aggregation.2 Celecoxib does not appear to affect the anticoagulant effect of warfarin, although caution should be exercised if coadministration is considered.1
The occurrence rate of dyspepsia and abdominal pain with celecoxib appears to be numerically lower than that of naproxen, ibuprofen, and diclofenac but higher than placebo. The occurrence rates were 8.8% for dyspepsia and 4.1% for abdominal pain compared to 6.2%/2.8%, 12.2%/7.7%, 10.9%/9%, 12.8%/9% for placebo, naproxen, ibuprofen, and diclofenac, respectively.1
Potential Disadvantages
Dyspepsia and abdominal pain were the most common side effects of celecoxib, which led to discontinuation in clinical trials. The rates were 7.1% for celecoxib vs. 6.1% for placebo. Borderline elevation of one or more liver tests (ALT or AST) may occur in up to 15% of patients. Significant elevation (3 or more × ULN) has been reported in 1% of patients in clinical trials.1
Anemia has been reported in patients receiving celecoxib (incidence of 0.6% vs 0.4% with placebo) in clinical trials.1 Patients on long-term treatment should have their hemoglobin or hematocrit checked if there are any signs or symptoms of anemia or blood loss.1
Data presented to the FDA’s Arthritis Advisory Committee involving single-dose, post-surgical dental pain models suggest that celecoxib may be less effective than ibuprofen 400 mg and naproxen 550 mg.10
Celecoxib is metabolized by cytochrome P450 2C9 and fluconazole, an inhibitor of this isoenzyme, causes a two-fold increase in plasma level. The dose of celecoxib should be introduced at the lowest recommended dose.1 In vitro studies suggest that celecoxib is an inhibitor of P450 2D6 and there are potential interactions with substrates of this isoenzyme. Celecoxib increases the plasma level of lithium, and monitoring is recommended with coadministration.1
Celecoxib does not appear to be renal sparing as the renal effects are similar to other NSAIDs.
Comments
NSAIDs are among the most commonly prescribed drugs and many are also available over the counter (OTC). Gastrointestinal toxicities are among the most serious side effects of the drugs, including ulceration, hemorrhage, or perforation. The mechanism of action of NSAIDs have been explained largely on their ability to inhibit the enzyme cyclooxygenase (COX). Recently, two isoforms of COX were discovered. COX-1 is believed to have a gastroprotective effect, while COX-2 is responsible for the production of proinflammatory mediators.3,4 Older NSAIDs are generally better inhibitors of COX-1 than COX-2. Newer NSAIDs, such as nabumatone and etodolac, have more balanced inhibition.3 In contrast, celecoxib is primarily a COX-2 inhibitor.
The potential superiority of celecoxib over other NSAIDs in terms of serious upper GI side effects has not been clearly established. In the celecoxib trials, endoscopic ulcers were used as surrogate markers. The correlation between endoscopic findings or symptoms and serious GI side effects has not been established. Although this method has been widely used in clinical studies, endoscopically observed ulcers may not be reliable predictors of severe GI events.5,6,7 Endoscopic ulcers tend to be smaller and superficial and predominately gastric while serious events tend to be both gastric and duodenal.5,6
It is not clear how celecoxib compares to newer NSAIDs, such as nabumetone and etodolac, that have been reported to be less GI toxic8 or older drugs such as salsalate. Endoscopic superiority was demonstrated for two of three tested comparators. While superiority was demonstrated over ibuprofen and naproxen, results for diclofenac were not definitive.
Celecoxib is priced similar to branded NSAIDs. The average wholesale price is $2.42 for the 200 mg capsules and $1.43 for the 100 mg capsules. These are similar to nabumetone (1000 mg/d) and oxaprozin (1200 mg/d).
Clinical Implications
NSAIDs have been shown to increase the risk of peptic ulcer complication by 3- to 5-fold and that 15-35% of all peptic ulcer complications are due to NSAIDs.9
Risk factors for developing NSAID-associated ulcers include older age, history of previous peptic ulcer, prior use of antisecretory drugs, corticosteroid, anticoagulants, or previous NSAID intolerance.6,9 There has been an ongoing effort to develop GI sparing NSAIDs. Whether celecoxib will fill that role is yet to be determined. Safety and efficacy results from pivotal trials have not been published. It is not clear if improved endoscopic ulcer outcome will reduce serious GI events. Since patients at higher risk of developing NSAID-associated ulcers can be identified, one strategy would be to use celecoxib in these patients. Unfortunately, the safety of the drug in this population has not been established as these patients have generally been excluded from the clinical trials. Preliminary data suggest that celecoxib is similar to naproxen in treating osteoarthritis and rheumatoid arthritis, but it’s relative efficacy as an analgesic is unclear. The long-term effects of celecoxib mediated COX-2 inhibition or non-prostaglandin mediated effects are not known. Safety was generally established for 12 weeks and, in a few subjects, 24 weeks. Only time and more clinical experience will determine if celecoxib or future selective COX-2 inhibitors are equally as effective as the older NSAIDs and are safer agents in terms of serious GI events. Recently, meloxicam, which was launched and promoted as a COX-2 selective NSAID in the United Kingdom, had to update its labeling to contain a stronger warning about GI and skin reactions. While clinical trial results suggest improved GI tolerability of meloxicam compared to piroxicam and diclofenac, marketing experience showed otherwise.11,12 Forty-one percent of suspected adverse reaction reported (1339 in the first 21 months) were GI-related, including perforation, ulceration, and bleeding, and 14% were dermatological.12 While meloxicam is less COX-2 selective than celecoxib, the experience with meloxicam warrants attention.
References
1. Celebrex Product Information. G.D. Searle & Co. December 1998.
2. McAdam BF, et al. Proc Natl Acad Sci 1999;96(1): 272-277.
3. Jouzeau JY, et al. Drugs 1997;53(4):563-584.
4. Lipsky PE, et al. J Rheumatol 1997;24(suppl 49):9-14.
5. Walt RP. N Engl J Med 1992;327:1575-1580.
6. McCarthy D. Am J Med 1998;105(5A):3S-9S.
7. Kimmey MB. Am J Med 1998;105(5A):28S-31S.
8. Rothstein R. Am J Med 1998;105(5A):39S-43S.
9. Griffin MR. Am J Med 1998;104(3A):23S-29S.
10. FDA Report—"The Pink Sheet" 1998;60(49):6.
11. Furst DE. Semin Arthritis Rheum 1997;26(6 Suppl 1):21-27.
12. FDA Report—"The Pink Sheet" 1998;60(51):5.
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