Context In recent years, US patients have increasingly been the first to receive
new medications, some of which are subsequently discovered to have suspected
adverse drug reactions (SADRs). As a result, the challenge of early detection
has largely shifted to the US postmarketing systems.
Objective To review the association between the use of cerivastatin sodium and
the risk of rhabdomyolysis in an effort to illustrate the operation and limitations
of the current US postmarketing safety-surveillance system.
Data Sources and Selection For the published literature, we used previous reviews and MEDLINE searches
from all years through 2003. For the unpublished literature, we used internal
company documents that have become part of the public record during a trial
in Nueces County, Texas.
Data Synthesis In the published literature, cerivastatin was associated with much larger
risks of rhabdomyolysis than other statins. Although only a small percentage
of cerivastatin users also took gemfibrozil, approximately half of the case
reports of rhabdomyolysis occurred in users of this combination therapy, and
a cerivastatin-gemfibrozil interaction was supported by the results of a 3-day
pharmacokinetic study. In internal company documents, multiple case reports
suggested a drug-drug interaction within approximately 100 days of the launch
in 1998; however, the company did not add a contraindication about the concomitant
use of cerivastatin and gemfibrozil to the package insert for more than 18
months. Unpublished data available in July 1999 also suggested an increased
risk of rhabdomyolysis associated with high doses of cerivastatin monotherapy.
In late 1999 and early 2000, company scientists conducted high-quality analyses
of the US Food and Drug Administration adverse event reporting system data.
These analyses suggested that compared with atorvastatin calcium, cerivastatin
monotherapy substantially increased the risk of rhabdomyolysis. To our knowledge,
these findings were not disseminated or published. The company continued to
conduct safety studies, some of them inadequately designed to assess the risk
of rhabdomyolysis, until cerivastatin was removed from the market in August
Conclusions Despite limitations of the available data, the asymmetry between the
information available to the company and the information available to patients
and physicians seems striking. A subjective element is present in the effort
to infer whether or not the occurrence of untoward outcomes in users of a
particular drug was actually the consequence of the use of that drug, and,
under the current system, a pharmaceutical company’s appraisal of SADRs
may be influenced by economic considerations. Such an appraisal would best
be made by an independent group. The US Congress should mandate and provide
adequate support for independent reviews and analysis of postmarketing data.
Conclusions Published online November 22, 2004 (doi:10.1001/jama.292.21.2622).