248
P A R T 3
Drugs acting on the immune system
TABLE 16.2
DRUGS IN FOCUS Non-steroidal anti-inflammatory drugs (NSAIDs) and related agents (continued)
Drug name
Dosage/route
Usual indications
etoricoxib (Arcoxia)
30 mg/day PO up to maximum 60mg/day PO Treatment of osteoarthritis, gouty arthritis,
acute pain
paracoxib (Dynastat)
40 mg IM or IV as single dose
Postoperative pain
Related agent
paracetamol (Panadol,
Panamax, Dymadon,
Febridol and others)
Adults and children over 12 years:
one
to two tablets every 4–6 hours with water
Maximum of eight tablets in 24 hours
Maximum daily dose: 4000 mg
Children 7 to 12 years:
Half to one tablet
every 4–6 hours with water
Maximum of four tablets in 24 hours
For Adults:
Do not use for more than a few
days at a time, except on medical advice
For children ages 7–17:
Do not use for more
than 48 hours, except on medical advice
Relief of pain and fever in a variety of
situations
Cyclooxygenase-2 inhibitors
In late 2004, Merck voluntarily withdrew their
cyclooxygenase-2 (COX-2) inhibitor, rofecoxib (Vioxx),
from the market following release of a midstudy finding
that the use of the drug over an 18-month period led to
a significant increase in cardiovascular (CV) mortality in
those taking the drug compared with a placebo group.
The study, called the APPROVe study (Adenomatous Polyp
Prevention on Vioxx), was targeted at testing whether the
blocking of such growth factors as angiogenesis could
decrease cancer risk in a specific population.The study
participants took 25 mg of Vioxx each day for 18 months
(the halfway point in the study) when the finding of
increased CV events was announced and the study was
stopped.The CV outcomes were not noted earlier than
18 months. Interestingly, other studies, including a 4-year
study of the effects on Alzheimer’s disease, did not show
a significant difference in CV events between the placebo
and drug groups.Yet, in the VIGOR (Vioxx Gastrointestinal
Outcomes Research) study, in which rofecoxib was
compared with naproxen (another NSAID) for 12 months,
increased CV events were noted in the rofecoxib group
after only 2 months.
The US Food and Drug Administration (FDA) formed a
committee to study the COX-2 inhibitors and then all of the
NSAIDs on the market to see if there were any problems
in oversight of drug safety and to make recommendations
about the future use of these drugs.
Valdecoxib (Bextra) was withdrawn from the market at
FDA request after the committee reviewed data. A small
study did show an increase in CV events, including death,
when Bextra was used immediately in postoperative
people recovering from coronary artery bypass graft
(CABG) surgery.The drug was not proven to be especially
more effective than other NSAIDs for relieving pain, and
already had a black-box warning about the increased
possibility of severe skin reactions, including Stevens–
Johnson syndrome. With those facts in mind and the
possibility of a COX-2 link to increased CV events, the FDA
believed that the benefits of marketing the drug did not
outweigh the potential risks for using the drug.
Celecoxib (Celebrex) remains on the market.The APC
study (Adenoma Prevention with Celecoxib) did show a
two- to threefold increase in CV events among people
using the drug compared with a placebo over 33 months.
There did seem to be a dose correlation, with more events
in the group using a higher dose. A nearly identical study,
the PreSAP trial (Prevention of Spontaneous Adenomatous
Polyps), showed no increase in CV events in the group
using celecoxib. A small study, the ADAPT (Alzheimer’s
Disease Anti-inflammatory PreventionTrial), did not appear
to show an increase in CV events in the people in that
study.
The media helped to fuel a real concern about the
safety of any anti-inflammatory medication.The questions
remain: Were the CV events related to dosage, length
of drug use, or the underlying conditions of the people
being studied?Were the CV events a direct effect of the
COX-2 inhibitor?Would these same events have occurred
if the drug were used at the dosages approved and for
the approved length of time? More long-term, controlled
studies are needed to answer these questions. In the
meantime, the FDA has recommended that valdecoxib
and rofecoxib stay off the market until appropriate
guidelines and controls are in place for their return; that
all NSAIDs’ packaging information include warnings that
there is potential risk for increased CV events as well as
the risk of GI bleeding, and that healthcare providers use
caution in recommending these drugs to anyone with
an established CV risk; that all prescription NSAIDs be
contraindicated in people immediately after CABG surgery;
and that the prescribing information for celecoxib include
a black-box warning referencing the available data about
increased CV risk.Two new COX-2 inhibitors being studied,
lumiracoxib and etoricoxib, will be carefully reviewed for
data on the incidence of increased CV events before they
will be considered for approval.
The evidence
BOX 16.4
