Pharmacology Update
Arthrotec for Osteo- and Rheumatoid Arthritis
By William T. Elliott, MD, and James Chan, PharmD, PhD
At least until the eagerly awaited selective COX-2 inhibitors hit the market next year, all NSAIDs will be saddled with the side effects attributed to the inhibition of COX-1 (cyclo-oxygenase isoform 1). Foremost among these side effects is gastrointestinal injury that appears to result from the inhibition of prostaglandin formation in the gastrointestinal tract-prostaglandins that are responsible for protecting and maintaining normal GI function.1
Misoprostol, a synthetic protaglandin, is currently the only FDA-approved product for the prevention of NSAID-induced gastric ulcers. Now Searle has combined 200 mcg of misoprostol with the NSAID diclofenac in the same tablet. The combination, named Arthrotec, was granted FDA clearance late last year. The combination joins the analgesic and anti-inflammatory properties of diclofenac with the mucoprotective properties of misoprostol.
Arthrotec is formulated with diclofenac in an enteric-coated core surrounded by an outer coat containing misoprostol. This permits misoprostol to be released in the stomach while diclofenac is released in the basic environment of the small intestine. It has been available in more than 40 countries, notably Germany, the United Kingdom, and Canada.
Indications
Arthrotec is indicated for the treatment of signs and symptoms of osteoarthritis and rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications.2 Risk factors for developing NSAID-induced gastrointestinal ulcers include age 60 years or older, history of peptic ulcer disease, history of cardiovascular disease, poor health, and concomitant therapy with oral corticosteroids, anticoagulants, antacids, or antisecretory drugs. Other risk factors include a previous adverse event with an NSAID, long duration of therapy, smoking, alcoholism, and positive Helicobactor pylori status.2-4
Dosing Information
Arthrotec is available in two strengths: diclofenac 50 mg/misoprostol 200 mcg and diclofenac 75 mg/misoprostol 200 mcg. The recommended doses for diclofenac are 100-150 mg daily for osteoarthritis and 150-200 mg daily for rheumatoid arthritis in divided doses. Diarrhea may be reduced if the drug is taken with meals, but food tends to decrease the bioavailability of both misoprostol and diclofenac.
Potential Advantages
The combination of an NSAID and misoprostol improves convenience and may improve medication adherence. Some preliminary data suggest that the combination product may enhance the analgesic/anti-inflammatory effects of diclofenac.5
Potential Disadvantages
Surprisingly, the most common side effects of misoprostol are gastrointestinal, including abdominal pain, nausea, diarrhea, and dyspepsia. Indeed, these are also the most common adverse effects of Arthrotec. In fact, while the benefits of the combination may be additive, so may be the side effects, since adverse events led to discontinuation of therapy in 9% of patients on Arthrotec compared to 5% on diclofenac alone.2
Comments
NSAID-related gastrointestinal injury is a common side effect of NSAID therapy. It has been estimated that 15-35% of all peptic ulcer complications are due to NSAIDs. An estimated 41,000 hospitalizations and 3300 deaths each year among the elderly are associated with NSAIDs.4 Gastric ulcers are generally more common than duodenal ulcers. Several strategies have evolved to address the side effects of NSAIDs. These include acid suppressive drugs such as H-2 antagonists and proton pump inhibitors, cytoprotective agents such as misoprostol and sucralfate, and more selective NSAIDs, which inhibit COX-2 but spare COX-1 isoenzyme. Arthrotec employs the strategy of combining an NSAID with a cytoprotective agent in the same tablet. Endoscopic results from clinical trials indicate that the incidence of GI ulcers was significantly lower in the Arthrotec-treated group compared to those treated with diclofenac or another NSAID alone.2
Clinical Implications
Misoprostol is the only FDA-approved drug for the prevention of NSAID-induced ulcers and has been reported to be effective in reducing serious GI complication in elderly patients on continuous NSAID therapy.6 It has been available since 1988, but its use has been limited by its side effects. One large clinical trial reported that 20% of patients withdrew from the trial due to diarrhea or related problems.6 While Arthrotec improves the convenience, it does not alter the side effects and limits the choice of the NSAID. Data suggesting potential synergy between diclofenac and misoprostol need to be established. H-2 antagonists have generally not been effective in preventing NSAID-induced gastric ulcers. They do provide symptomatic relief that actually may mask more serious injury. High doses of an H-2 antagonist (famotidine 40 mg twice daily) may be more effective.7 A recent study reported that omeprazole 20 mg was as effective as misoprostol 200 mcg twice daily in preventing the relapse of gastric ulcers but was more effective in preventing relapse of duodenal ulcers.8 Omeprazole was reported to be better tolerated than misprostol and provided better improvement of dyspeptic symptoms. The dose of misoprostol in this study is lower than the 200 mcg qid recommended in the labeling. However, 200 mcg twice daily or three times daily is effective and better tolerated than the four-times-a-day regimen.9 Omeprazole was also reported to be more effective than ranitidine in preventing ulcer.10 These omeprazole trials were secondary prevention trials (maintenance therapy after ulcer healing) compared to previous trials involving misoprostol, which were primary prevention trials (no ulcers during randomization).
The pursuit of less GI toxic COX-2 inhibitors continues to progress. Two current NSAIDs, etodolac and nabumetone, appear to have a more favorable COX-2:COX-1 activity compared to older NSAIDs. Two selective COX-2 inhibitors, Searle's celecoxib and Merck's MK-966, are progressing through the FDA (celecoxib was recently granted expedited review status). These drugs may provide a better alternative than the older NSAIDs in patients at risk for GI injury.
Arthrotec is priced at $1.32 per tablet for either strength. Misoprostol 200 mcg is $0.86 per tablet.
References
1. Vane JR, et al. Am J Med 1998;104(3A):2S-8S.
2. Arthrotec Product Information. Searle. January 1998.
3. Fries JF, et al. Am J Med 1991;91:213-222.
4. Griffin MR. Am J Med YEAR??;104(3A):23S-29S.
5. Shield MJ. J Rheumol 1998;51 (Suppl):31-41.
6. Silverstein FE, et al. Ann Intern Med 1995;123: 241-249.
7. Taha AS, et al. N Engl J Med 1996;334:1435-1439.
8. Hawkey CJ, et al. N Engl J Med 1998;338:727-734.
9. Raskin JB, et al. Ann Intern Med 1995;123:344-350
10. Yeomans ND, et al. N Engl J Med 1998;338:719-726.
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