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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