The Cleveland Clinic Foundation's
Recommendations for
Cyclooxygenase-2 Inhibitor Use
Volume VIII, Number 3 | May/June 2005
Meghan K. Lehmann, Pharm.D.
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On September 30, 2004, Merck and Company, Inc. voluntarily withdrew rofecoxib (Vioxx®) from the worldwide market. Their decision was based on results from the Adenomatous Polyp Prevention on Vioxx® (APPROVe) trial in which patients receiving rofecoxib were found to be at increased risk for cardiovascular (CV) events, such as myocardial infarction and stroke, compared to patients receiving placebo when taken for longer than 18 months.1
The APPROVe trial was not the first trial to report an increase in the occurrence of CV events in users of cyclooxygenase-2 (COX-2) inhibitors. The Vioxx® Gastrointestinal Outcomes Research (VIGOR) Study which compared gastrointestinal toxicities between rofecoxib and naproxen (Naprosyn®) found that myocardial infarctions occurred more often with rofecoxib 50 mg once daily than with naproxen 500 mg twice daily (0.4% vs. 0.1%; RR 0.2; 95% CI 0.1-0.7).2
The exact mechanism by which COX-2 inhibitors may cause CV events has not been fully elucidated; however, by selectively inhibiting the COX-2 enzyme they decrease the amount of prostacyclin (PGI 2), a vasodilator, while having no effect on thromboxane A2 , a potent vasoconstrictor and inducer of platelet aggregation. This disruption in the balance of these two substances can result in prothrombotic conditions.3 Because each of the COX-2 inhibitors works by the same mechanism, it has been postulated that all agents within this class have the potential to cause CV events.
Shortly following the removal of rofecoxib from the market, Pfizer Inc. released information stating that valdecoxib (Bextra®) was found to be associated with increased CV events when administered to treat post-operative pain following coronary artery bypass graft (CABG) surgery.4 Due to these CV concerns, the Cleveland Clinic Foundation (CCF) Pharmacy and Therapeutics (P&T) Committee recommended that valdecoxib use be prohibited in all CCF inpatients and outpatients. As such, valdecoxib was removed from all CCF inpatient and ambulatory pharmacies. Additionally, letters were sent to all CCF patients with active valdecoxib prescriptions to make them aware of the decision and to recommend that they contact their physician to discuss alternative therapies.5
It was also recommended that celecoxib (Celebrex®; Pfizer Inc.) remain on the inpatient Formulary and continue to be stocked at CCF ambulatory pharmacies. However, due to the potential for CV adversities, its use is restricted. Celecoxib should not be used as first-line therapy. Rather, naproxen is recommended as the preferred ther-apeutic alternative for both valdecoxib and celecoxib (See Table 1). An oral proton pump inhibitor should be administered concomitantly with naproxen in those patients at high risk for developing nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers. For those patients who have failed several NSAIDs, or are unable to tolerate them, celecoxib may be recommended as a therapeutic alternative. However, all patients must be evaluated for CV disease or risk factors for CV disease before celecoxib is initiated. Further, patients currently receiving celecoxib should also be assessed for CV disease and risk factors. If CV disease or risk factors are present, celecoxib should be avoided.5
Table 1: Naproxen Dosing for all Inpatient Celecoxib Orders
| Indication | Celecoxib Order Written For | Convert to Following Naproxen Dose |
|---|---|---|
| Osteoarthritis Symptoms | 200 mg PO as a single dose OR 100 mg PO twice daily |
Naproxen 250 mg, 375 mg, or 500 mg PO twice daily (May increase to 1500 mg/day)* |
| Rheumatoid Arthritis Symptoms | 100 mg - 200 mg PO twice daily | Naproxen 250 mg, 375 mg, or 500 mg PO twice daily (May increase to 1500 mg/day)* |
| Acute Pain | Day 1: 400 mg PO initially, followed by an additional 200 mg PO if needed. Subsequent Days: 200 mg PO twice daily as needed |
Naproxen 500 mg PO initially, followed by 250 mg every 6-8 hours as needed (Maximum Daily Dose: 1250 mg)* |
| Post-operative Pain | Day 1: 400 mg PO initially, followed by an additional 200 mg PO if needed. Subsequent Days: 200 mg PO twice daily as needed |
Naproxen 500 mg PO initially, followed by 250 mg every 6-8 hours as needed (Maximum Daily Dose: 1250 mg)* Additional pain medications may be warranted. |
* Patients at risk of developing NSAID-induced gastric ulcers (e.g., history of ulcers and symptoms, age >65 years, aspirin/anticoagulant use) should receive oral esomeprazole (Nexium ® ) 20 mg orally once daily (or an equivalent dose of the current preferred Formulary proton pump inhibitor) concomitantly with naproxen to prevent gastrointestinal bleeding.
It was also decided that for all COX-2 inhibitor orders and prescriptions received at CCF, a pharmacist will contact the prescribing physician to assist in assessing patient CV history and risk and to discuss alternative therapies if warranted.5
Following the implementation of these P&T Committee recommendations, a Food and Drug Administration (FDA) Advisory Committee convened to discuss the COX-2 inhibitors. Based on recommendations from this Committee and additional clinical data, the FDA decided to take further action with all prescription NSAIDs, including the COX-2 inhibitors, and non-prescription nonselective NSAIDs. The FDA urged Pfizer to withdraw valdecoxib from the market after concluding that its use was associated with increased CV events; increased risk of serious skin reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme; and because it offers no advantages over other NSAIDs. As a result, on April 7, 2005, Pfizer voluntarily withdrew valdecoxib from the United States market.6
Celecoxib will remain on the market, however, the FDA acknowledged that its use is not without risk; therefore, Pfizer has revised celecoxib product labeling to include a black-boxed warning stating the potential for increased CV events and serious, life-threatening gastrointestinal bleeding. In addition, the use of celecoxib to treat post-operative pain immediately following CABG surgery is listed as a contraindication. Prescribers are encouraged to discuss these risks and other treatment options with patients before deciding to initiate celecoxib. If celecoxib therapy is deemed to be appropriate, the lowest effective dose administered for the shortest duration possible is recommended. Each celecoxib prescription dispensed must be accompanied by a Patient Medication Guide detailing the potential health risks associated with its use. Additionally, Pfizer must conduct a long-term trial to compare the safety of celecoxib with other NSAIDs.6
Because long-term controlled trials are lacking for many of the nonselective prescription and non-prescription NSAIDs, each manufacturer must conduct and submit a review and analysis of CV events described in controlled clinical trial databases associated with their individual products. Similarly to celecoxib, labeling for prescription NSAIDs will also contain a black-boxed warning as well as the contraindication for pain in patients immediately following CABG. Prescriptions for these agents must also be accompanied by a Patient Medication Guide.
Product labeling for non-prescription NSAIDs will be revised to include information about potential CV and gastrointestinal risks, and will emphasize limiting doses and duration of use to prevent these adversities from occurring. No changes were required for aspirin labeling because of the large amount of clinical data supporting the benefits of its platelet inhibition in reducing serious adverse CV events.6
Because the FDA established specific requirements for celecoxib, there was speculation that Merck would attempt to bring rofecoxib back to the market; however, at least 4000 rofecoxib-related lawsuits have been filed against the company since its withdrawal.7 Even with the requirements, it is unlikely that valdecoxib will return to the market since it causes severe skin reactions in addition to CV adversities. Based on the recommendations of the FDA, CCF will continue to restrict celecoxib as a second-line agent with naproxen remaining the NSAID of choice.
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References
- Bresalier R, Sandler R, Quan H, Bolognese J, Oxenius B, Horgan K, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-102.
- Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastro-intestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-8.
- Hansen KE, Elliot ME. Osteosarthritis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A pathophysiologic approach. 6 th ed. New York : McGraw-Hill; 2005. p. 1694.
- Nussmeier N, Whelton A, Brown M, Langford R, Hoeft A, Parlow J, et al. Complications of the COX-2 Inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352:1081-91.
- The Cleveland Clinic Foundation Pharmacy and Therapeutics Committee. Position Paper on COX-2 Inhibitors. December 15, 2004.
- FDA Public Health Advisory. FDA announces important changes and additional warnings for COX-2s and NSAIDs. Located at http://www.fda.gov/cder/drug/advisory/COX2.htm. Accessed June 14, 2005.
- Jury finds Merck liable in landmark Vioxx case. Located at http://www.msnbc.msn.com/id/9006921/print/1/displaymode/1098. Accessed August 19, 2005.