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9780521704632c09 CUFX213A/Peck 9780521618168 December 28, 2007 11:33
Section IICoredrugs in anaesthetic practicegastrointestinal side-effect rate equal to standard NSAIDs after 12 months therapy
as well as a number of other side-effects – hypertension, heart failure, hepatotoxicity
and oedema.
The Committee on Safety of Medicines have advised that COX-2 use is contraindi-
cated in patients with ischaemic heart disease, cerebrovascular disease, mild heart
failure and peripheral vascular disease. Careful consideration should be given before
their use in patients with risk factors for cardiovascular events (hypertension, hyper-
lipidaemia, diabetes, smoking).Rofecoxib
Rofecoxib (withdrawn September 2004) is presented as 12.5 mg tablets and as a
suspension containing 12.5 mg per 5 mls. The daily dose is 12.5–25 mg. It has a
COX-1:COX-2 inhibitory ratio of 1:276.
The VIGOR study demonstrated that rofecoxib significantly reduces the number of
clinically important gastric complications when compared to a non-specific NSAID.
However, more comprehensive analysis of further data beyond 12 months, not pub-
lished with the original article, revealed a much less favourable picture. The incidence
of MI was 1.7% in those taking rofecoxib compared with 0.7% in the control group
which prompted its withdrawl from the market.Kinetics
Rofecoxib is well absorbed from the gut (oral bioavailability >90%) with plasma con-
centration peaking at 3 hours. It is 85% protein bound and the plasma half-life is
around 17 hours allowing once-daily administration. Its volume of distribution is
1.2 l.kg. It is metabolized in the liver by cytosolic reduction (not CYP450) to inactive
products that are excreted in the urine. As rofecoxib is not metabolized by CYP450
it has fewer potential interactions than celecoxib. Rofecoxib appears to be safe in
subjects with previous adverse cutaneous reactions (erythema, urticaria
angioedema) to non-specific NSAIDs.Celecoxib
Celecoxib is presented as 100 mg tablets and used to a maximum dose of 200 mg bd
for osteoarthritis and rheumatoid arthritis. It has a COX-1:COX-2 inhibitory ratio of
1:30.
The CLASS trial demonstrated the incidence of ulcer complications in patients
treated with celecoxib was similar to those treated with non-specific NSAIDs,
although this may have been confused by concurrent aspirin therapy. Also the inci-
dence of stroke and MI was not increased by celecoxib. Other studies designed to
assess the ability of celecoxib to prevent colon cancer have confused the picture
regarding stroke and MI because on this point they did not agree.