E-DRUG: Rofecoxib ADRs
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Dear All,
I wish to draw attention to the piece on Cyclooxygenase 2 - inhibitors in
the WHO Pharmaceuticals Newsletter No. 5, 2004, copied below for ready
reference.
By using rofecoxib as an example, we have tried to highlight the importance
of the WHO Programme for International Drug Monitoring in capturing, well
ahead of time, drug-safety problems that may otherwise go unreported or
remain under-stated.
With best wishes,
Shanthi Pal
Quality Assurance and Safety of Medicines
Essential Drugs and Medicines Policy
WHO
pals@who.int
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CYCLO-OXYGENASE - 2 INHIBITORS
On 30 September Merck & Co., Inc. announced a voluntary withdrawal of
rofecoxib (Vioxx) from the United States and worldwide market due to safety
concerns of an increased risk of cardiovascular events (including heart
attack and stroke) in patients on rofecoxib. Rofecoxib is a prescription
cyclooxygenase-2 (COX-2) selective, non-steroidal anti-inflammatory drug
(NSAID) that was approved by the US FDA in May 1999 for the relief of the
signs and symptoms of osteoarthritis, for the management of acute pain in
adults, and for the treatment of menstrual symptoms, and was later approved
for the relief of the signs and symptoms of rheumatoid arthritis in adults
and children.
Merck withdrew rofecoxib (Vioxx) from the market following the
recommendations of the data safety monitoring board overseeing a long-term
study in patients at risk of developing recurrent colon polyps1. This study
was halted because of an increased risk of serious cardiovascular events,
including heart attacks and strokes, among study patients taking rofecoxib
compared with patients receiving placebo.
The rofecoxib market-withdrawal announcement has come more than five years
after the launch of the product in 1999, when more than 80 million patients
have already used this medicine, with the annual company sales topping US $
2.5 billion.
The first trial which showed the association of COX-2 inhibitors with
cardiovascular events came as a surprise result from the Vioxx
Gastrointestinal Outcomes Research (VIGOR) study in 2000 in which 0.4% of
the rofecoxib group and 0.1% of the naproxen group developed myocardial
infarction2. This result was extended by a between-study comparison
conducted by Mukherjee et al.3. The comparison, which included celecoxib and
rofecoxib, implicated both medicines as being associated with a
significantly higher rate of myocardial infarction than placebo. The
authors postulated that COX-2 inhibitors may have a prothrombotic effect
through inhibition of prostacyclin and concluded that 'it is mandatory to
conduct a trial specifically assessing cardiovascular risk and benefit of
these agents'.
Such a specific trial, however, was never conducted. While the world debates
whether the rofecoxib story deserves a full congressional review, it is
important, now more than ever, to pay critical attention to the importance
of adverse drug reaction (ADR) reporting in a post-marketing set-up and to
the 'signal' generating capabilities of the WHO global ADR database.
It is to the credit of the WHO Programme for International Drug Monitoring
that the risk of cardiovascular adverse reactions with rofecoxib-use was
discussed (in early November 2000, well before the VIGOR study was reported)
in the session on 'Drugs of Current Interest', at the 23rd Annual Meeting of
Representatives of the National Centres participating in the programme. It
was pointed out that within 10 months of its introduction in 2000 in the
Netherlands, there were eight reports of cardiovascular problems with four
fatalities associated with rofecoxib use; all four cases occurred within
four days of commencing therapy and one case occurred two hours after taking
the first tablet. It also came to light that there had been one report of a
fatality in Malaysia, three reports of cardiac failure in Australia and a
total of five reports with various cardiovascular events in Portugal.
COX-2 inhibitors and cardiovascular events were also discussed during the
25th and 27th Annual Meetings of the Programme. Data from the New Zealand
Intensive Medicines Monitoring Programme (IMMP) database demonstrated a
higher proportion of prothrombotic events and a shorter time to onset of
death associated with the use of COX-2 inhibitors than with comparator drugs
(that is, all other drugs in the IMMP cohorts for the proportion of
prothrombotic events and versus omeprazole in the survival analysis). The
only identifiable difference to explain the shorter survival was the higher
rate of myocardial infarction and stroke. A cohort of 32 630 patients on
celecoxib (mean age 63 years) and 26 666 on rofecoxib (mean age 58 years)
was reviewed; ischaemic heart disease was the fourth most common type of
event reported for celecoxib and rofecoxib. Of note, there was no difference
in rate between the two but celecoxib had twice the rate of cardiac
dysrhtyhmias. Deaths were most commonly represented in the cardiovascular
system organ classification for celecoxib and the second most common for
rofecoxib.
The WHO Collaborating Centre for International Drug Monitoring uses the
BCPNN (Bayesian Confidence Propagation Neural Network) data mining method,
to assess disproportionality of a specific ADR-drug combination against the
ADR distribution for all drugs in the global ADR database. Of interest is
the paper by Zhao et al4 who used the BCPNN method to compare the
renal-related adverse drug reactions between rofecoxib and celecoxib, from
ADR reports in the WHO database at the end of the second quarter of 2000.
They concluded that rofecoxib had greater renal toxicity than celecoxib and
other traditional NSAIDs; and that, this negative renal impact may have the
potential to increase the risk for serious cardiac and/or cerebrovascular
events. This paper was published in 2001, nearly three years ahead of the
current company withdrawal.
A similar analysis of the WHO global database for celecoxib has also shown
an association of myocardial infarction with celecoxib use ('Signal'
2001-09, Restricted document from the WHO Collaborating Centre for
International Drug Monitoring). At the time Pharmacia Corporation had
responded that it was likely a false-positive association. Sulphonamide
reaction terms were reported significantly more frequently with celecoxib
compared to rofecoxib in the WHO database (overall sulphonamide relative
reporting rate 1.8, 95%CI 1.6-1.9)5. Amongst these type of reactions, fatal
reactions were reported 80% more often (relative reporting rate 1.8, 95%CI
0.9-4.0). These observations, as well as the recent experience with
rofecoxib should caution us against dismissing the findings with celecoxib,
particularly amidst concerns that the cardiovascular effects of rofecoxib
may be a class effect, applicable to all COX-2 selective inhibitors6,7.
References:
1. Merck & Co Press Release, 30 September 2004. Available on the
Internet at www.merck.com
2. Bombardier C, Laine L, Reicin A, et al. Comparison of upper
gastrointestinal toxicity of rofecoxib and naproxen in patients with
rheumatoid arthritis. New Engl J Med 2000;343:1520-1528.
3. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events
associated with selective COX-2 inhibitors. JAMA 2001;286:954-959.
4. Zhao SZ, Reynolds MW, Lejkowith J, Whelton A, Arellano FM. A
comparison of renal-related adverse drug reactions between rofecoxib and
celecoxib, based on the World Health Organization/Uppsala Monitoring Centre
safety database. Clin Ther 2001; 23(9):1478-1491.
5. Wiholm BE. Identification of sulfonamide like adverse reactions to
celecoxib in the World Health Organization database. Curr Med Res Opin 2001;
17(3): 210-216
6. Editorial. Lessons from the withdrawal of rofecoxib. BMJ 2004; 329:
867-868
7. Press Release. EMEA to review COX-2 inhibitors.
http://www.emea.eu.int, 22 October 2004, EMEA/117908/2004.