The Era of COX-2 Inhibitors
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medication used to reduce pain, fever, and inflammation. Traditional NSAIDs like ibuprofen and naproxen work by blocking two enzymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) [1.3.6]. The COX-1 enzyme helps protect the stomach lining, while COX-2 is primarily involved in inflammation and pain [1.6.3]. Because traditional NSAIDs block both, they can cause gastrointestinal side effects like ulcers and bleeding [1.3.6].
In the late 1990s, a new class of NSAIDs known as COX-2 inhibitors was introduced. These drugs, including rofecoxib (Vioxx) and valdecoxib (Bextra), were designed to selectively block the COX-2 enzyme [1.6.3]. The goal was to provide the same pain relief as older NSAIDs but with a significantly lower risk of stomach problems [1.3.6]. Vioxx was approved by the FDA in 1999 and quickly became a blockbuster drug, with worldwide sales reaching $2.5 billion in 2003 [1.2.1, 1.2.6].
The Fall of Vioxx (Rofecoxib)
Despite its commercial success, concerns about Vioxx's cardiovascular safety began to emerge. A major clinical trial known as VIGOR (Vioxx GI Outcomes Research) showed that while patients on Vioxx had fewer stomach ulcers than those on naproxen, they also experienced a greater number of heart attacks [1.2.3]. This led to a new warning being added to Vioxx's label in April 2002 [1.2.3].
The final turning point came from the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial. This study was designed to see if Vioxx could prevent colon polyps, but it was stopped early because it revealed an increased risk for serious cardiovascular events like heart attacks and strokes after 18 months of continuous treatment [1.2.3, 1.9.3]. Based on these findings, Merck announced a voluntary worldwide withdrawal of Vioxx on September 30, 2004, citing safety concerns [1.2.1, 1.3.3]. The FDA's formal withdrawal of approval for the new drug applications for Vioxx occurred later [1.3.1].
Bextra (Valdecoxib) Follows Suit
With Vioxx off the market, other COX-2 inhibitors came under intense scrutiny. Valdecoxib (Bextra), marketed by Pfizer, faced similar concerns. On April 7, 2005, at the request of the FDA, Pfizer agreed to suspend sales and marketing of Bextra in the United States [1.4.3, 1.4.5]. The FDA's decision was based on several factors:
- An increased risk of serious cardiovascular adverse events [1.4.4, 1.4.6].
- Reports of serious and potentially life-threatening skin reactions, including Stevens-Johnson syndrome [1.4.3, 1.4.4].
- A lack of demonstrated unique advantages over other available NSAIDs [1.4.2, 1.4.6].
The Aftermath: Stricter Warnings for All NSAIDs
The withdrawal of these two major drugs led to significant changes in how NSAIDs are regulated. In 2005, the FDA mandated that all prescription NSAIDs carry a "boxed warning"—the agency's strongest type—highlighting the potential for increased cardiovascular risk and the risk of serious gastrointestinal bleeding [1.3.4]. This warning was later strengthened in 2015, clarifying that the risk of heart attack or stroke can occur even in the first weeks of using an NSAID and may increase with longer use and higher doses [1.5.1, 1.5.2]. This applies to both prescription and over-the-counter NSAIDs, with the exception of aspirin [1.5.6].
Comparison Table: Withdrawn vs. Available NSAIDs
| Drug Name (Brand) | Type | Status | Primary Reason for Withdrawal / Key Risk |
|---|---|---|---|
| Rofecoxib (Vioxx) | COX-2 Selective | Withdrawn | Increased risk of heart attack and stroke [1.2.1, 1.9.3] |
| Valdecoxib (Bextra) | COX-2 Selective | Withdrawn | Increased cardiovascular risk and serious skin reactions [1.4.4, 1.4.6] |
| Celecoxib (Celebrex) | COX-2 Selective | Available | Carries a boxed warning for cardiovascular and GI risks [1.4.2, 1.5.1] |
| Ibuprofen (Advil, Motrin) | Non-selective | Available | Risk of cardiovascular events and gastrointestinal bleeding [1.5.1, 1.5.6] |
| Naproxen (Aleve) | Non-selective | Available | Risk of cardiovascular events and gastrointestinal bleeding [1.5.1, 1.5.6] |
Conclusion
The story of what NSAID was taken off the market is dominated by Vioxx and Bextra. Their withdrawal serves as a critical lesson in pharmacology and drug regulation, emphasizing that a drug's full risk profile may only become apparent after it has been on the market for years. It highlighted the need for robust post-marketing surveillance and led to stronger warnings for the entire class of NSAIDs [1.2.2, 1.5.1]. Patients and healthcare providers are now more aware of the need to balance the pain-relieving benefits of NSAIDs against their potential cardiovascular and gastrointestinal risks, using the lowest effective dose for the shortest possible duration [1.5.1].
For more information on NSAID safety, consult the U.S. Food and Drug Administration.
