Rofecoxib Tablets and Oral Suspension
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The cox-2 class of anti-inflammatory/pain relievers now has two entries with the May 21 approval of Merck’s rofecoxib (Vioxx). It joins celecoxib (Celebrex—Searle) in this class of "safer" NSAIDs. Selective cyclooxygenase-2 inhibitors reduce inflammation and produce analgesia without inhibiting COX-1 dependent prostaglandins that protect the gastric mucosa and affect platelet aggregation. Thus, these drugs have a much lower propensity to cause endoscopically detected ulcers and do not cause platelet dysfunction. COX-2 inhibitors, however, do have the same effect on renal blood flow as traditional NSAIDs.
Rofecoxib is approved for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of dysmenorrhea.
Rofecoxib is available as 12.5 mg or 25 mg tablets and as an oral suspension containing 12.5 mg or 25 mg per 5 mL. The recommended initial dose for osteoarthritis is 12.5 mg once daily. Some patients may achieve added benefit at a dose of 25 mg once daily, which is considered the maximal dose for this indication. The recommended dose for the management of acute pain or the treatment of primary dysmenorrhea is 50 mg once daily. It may be taken without regard to meals.
Rofecoxib should not be taken by patients who have experienced allergic-type reactions to aspirin or other NSAIDs.
Rofecoxib, 25 mg or 50 mg daily, has been reported to produce a lower percentage of endoscopic gastroduodenal ulcers than ibuprofen 2400 mg daily. Difference was statistically significant at 12- and 24-week assessments.1 Rofecoxib also appears to be well tolerated in terms of GI adverse events. In a clinical trial, the percent of patients experiencing diarrhea was 6.8% vs. 6.5% for placebo, 3.5% vs. 2.7% for dyspepsia, 3.8% vs. 2.8% for epigastric discomfort, and 4.2% vs. 3.6% for heartburn.1 The metabolism of rofecoxib does not involve the cytochrome P450 enzymes, thus minimizing potential drug interactions. A general enzyme inducer, rifampin, has been reported to produce a 50% decrease in the plasma concentration of rofecoxib.1 Rofecoxib has no effect on platelet function. Dosages up to 375 mg given daily for up to 12 days did not affect bleeding time relative to placebo.1
Rofecoxib is approved for osteoarthritis but not for rheumatoid arthritis. The renal effects of rofecoxib are similar to those of other NSAIDs.1 The use of rofecoxib for the relief of pain at the 50 mg dose is not recommended beyond five days.1 Coadministration of rofecoxib and warfarin have resulted in an increase of 8-11% in INR. Monitoring of INR is recommended with coadministration.1
Rofecoxib is a highly selective inhibitor of COX-2. In vitro studies using Chinese hamster ovary cell lines to express COX-1 and COX-2 showed that at doses up to 1000 mg (20 times the maximum recommended dose) no evidence of COX-1 inhibition was seen.2
Refocoxib was approved almost six months after the first COX-2 inhibitor, celecoxib, which was approved on Dec. 31, 1998. Merck took extra time to seek a pain indication for its drug, an indication that celecoxib does not have. In various acute pain models, the analgesic effect of rofecoxib 50 mg was similar to that of naproxen sodium 550 mg to ibuprofen 400 mg.1,2 In osteoarthritis, rofecoxib (12.5-25 mg) has been reported to be similar in effectiveness as ibuprofen 800 mg tid over six weeks or diclofenac 50 mg tid over six months.1,4,5 Study patients included patients with osteoarthritis of the hip or knee. Ninety percent had an increase in pain following withdrawal of NSAIDs and 10% had moderate symptoms while taking acetaminophen. Rofecoxib, ibuprofen, and diclofenac all showed about a 50% reduction in the WOMAC (Western Ontario and McMaster Universities osteoarthritis index) visual analog scale walking on a flat surface. This is a composite of pain, stiffness, and functional measures in osteoarthritis. Like celecoxib, rofecoxib (25 mg-50 mg) has been associated with fewer endoscopic ulcers (³ 3 mm) than ibuprofen (2400 mg daily) (4.1-8.8% vs 27.7-29.2%). This compares favorably to placebo (5.1-9.9%).1 However, endoscopic ulcers may not be reliable predictors of severe GI events.7,8
Merck will likely seek approval of the drug for treating rheumatoid arthritis; however the effective dose, 50 mg, may be associated with higher adverse events.9 Rofecoxib is priced competitively with celecoxib for osteoarthritis used (12.5-25 mg daily). For pain, rofecoxib is about $5 per day (2 × 25 mg).
Osteoarthritis is the most prevalent form of arthritis, and acute pain and dysmenorrhea are common problems. Pharmacologic management of osteoarthritis includes acetaminophen, topical capsacin, other analgesics, and NSAIDs.6 Gastrointestinal toxicities are problematic with the use of NSAIDs, especially for patients who have a history of gastritis, peptic ulcer disease, or GERD. COX-2 inhibitors are an attempt to find "safer" NSAIDs.
While the frequency of drug-induced endoscopic ulcers appears to be less with rofecoxib, it is not clear if long-term serious events are reduced. In addition, it is not known if there are any deleterious effects with prolonged COX-2 inhibition and how it would affect the homeostasis of other body systems such as the balance of prostacycline and thromboxane in blood vessels.10
1. Vioxx Product Information. Merck & Co. May 1999.
2. Ehrich EW, et al. Clin Pharmacol Ther 1999;65(3): 336-347.
3. Hawkey CJ. Lancet 1999;335:307-314.
4. Saag K, et al. Arthritis Rheum 1998;41(suppl 9):984.
5. Cannon G, et al. Arthritis Rheum 1998;41(suppl 9):985.
6. Hochberg MC, et al. Arthritis Rheum 1995;38: 1541-1546.
7. McCarthy D. Am J Med 1998;105(5A):3S-9S.
8. Kimmey MB. Am J Med 1998;105(5A):28S-31S.
9. FDC Report. The Green Sheet. 1999;48:22:1-2.
10. McAdam BF, et al. PNAS 1999;96:272-277.