NSAIDs - COX-2 Inhibitors - Risks and Benefits

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Chapter: Pharmacovigilance: NSAIDs - COX-2 Inhibitors – Risks and Benefits

The worldwide market withdrawal of rofecoxib in September 2004 was a major lesson in pharmacovigilance.

NSAIDs - COX-2 Inhibitors – Risks and Benefits


The worldwide market withdrawal of rofecoxib in September 2004 was a major lesson in pharmacovigilance (Edwards, 2005). Sales of rofecoxib in US increased substantially after licensure in 1999 and, due to its extensive use, even a moderate increase in the risk of serious adverse reactions among rofecoxib users would have major public health implications. This chapter is a review of the cardiovascular safety signal detection and safety assessment process for the cyclo-oxygenase-2 (COX-2) inhibitors in chrono-logical order after their market approval. As safety assessment of any drug should not be isolated from potential benefits of the drug, we conclude the chapter with a succinct risk–benefit assessment for non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors

Several non-scientific events after the market with-drawal of rofecoxib were widely reported in the press and generated much public attention and debate. They include financial impact on pharmaceutical companies, congressional hearings in the US, prod-uct liability litigations, the role of direct-to-consumer advertisement, promotional activities of pharmaceuti-cal companies, and calls for overhaul of post-approval drug safety review system in the US (Ray and Stein, 2006; Strom, 2006). These are important questions for the society in general but are beyond the scope of this chapter and are not covered.

NSAIDs for symptomatic relief of pain and inflammation comprise one of the most widely used group of drugs in the industrialized world. Gastrointesti-nal toxicity of NSAIDs is associated with substantial morbidity and mortality (Wolfe, Lichtenstein and Singh, 1999). Advances in pharmacologic knowl-edge about prostaglandins that mediate inflammatory reactions and the discovery of two isoforms of cyclooxygenase (COX-1 and COX-2) have led to development of promising new drugs. Traditional NSAIDs are non-selective with regards to inhibition of COX-1 and COX-2 and are now referred to as non-selective NSAIDs. While inhibition of the inducible COX-2 results in anti-inflammatory effects, inhibi-tion of the constitutive COX-1 increases the risk of gastrointestinal toxicity (Warner et al., 1999). Drugs that selectively inhibit COX-2 but have minimal effect on COX-1 would theoretically result in targeted anti-inflammatory actions and reduced gastrointesti-nal toxicity. The COX-2 inhibitors, as a subclass of NSAIDs, were developed to achieve this favorable risk–benefit profile (FitzGerald, 2003). In the US, the first COX-2 inhibitor, celecoxib, was approved at the end of 1998 and the second, rofecoxib, was approved in May 1999.

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