Beruflich Dokumente
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) and rofecoxib
(Vioxx
). Celecoxib, the rst of these drugs to become available, is one of the best selling new
drugs to be marketed in the USA. It is likely that these agents will be covered by the PBS in the
year 2000. Both drugs are being aggressively marketed by the pharmaceutical industry, however
there is limited clinical experience, and monitoring adverse events in patients is a priority for
clinicians who prescribe these agents.
This document provides a review of the physiology and pharmacology of the COX system, and
published studies and clinical trials which have investigated the COX-2-selective NSAIDs.
2. Physiology and pharmacology of the COX
metabolites.
2.1 Biosynthesis of prostaglandins
The eicosanoids are autacoids (locally acting hormones) derived from arachidonic acid. They
comprise prostaglandins (PGs), thromboxanes (TXs) and leukotrienes (LTs). The PGs and TXs are
products of the cyclooxygenase (COX) pathway and are known as prostanoids. The leukotrienes
are byproducts of the 5-lipoxygenase pathway. Arachidonic acid is a component of cell
membranes, which is mainly released from membrane phospholipids by the enzyme phospholipase
A
2
. Many stimuli can liberate arachidonate, although this differs according to cell type. Examples
are thrombin in platelets, C5a in neutrophils and antigen-antibody reactions in mast cells. Cellular
damage, or inux of calcium into most cells will also activate phospholipases. Liberation of free
arachidonate is the rate determining step in the synthesis of PGs, TXs and LTs.
COX or prostaglandin H
2
synthase catalyses the rst two steps in the biosynthesis of the PGs from
the substrate arachidonic acid. These are the oxidation and cyclisation of the unesteried
arachidonic acid to the hydroperoxy endoperoxide PGG
2
, followed by its subsequent reduction to
PGH
2
.
1
PGH
2
in turn serves as a substrate for cell specic isomerases which produce a variety of
biologically active products (See Figure 1)
COX-2-selective NSAIDs:
New wonder drugs?
Figure 1. Synthesis of the clinically relevant prostaglandins and thromboxanes from
arachidonic acid.
The half-lives of most PGs in the serum are less than one minute. High concentrations of PG-
inactivating enzymes are present in the lung, and 95% of PGE
2
and PGF
2
. TXA
2
(Thromboxane A
2
) has a half-life of 30 seconds,
and breaks down nonenzymatically into the stable but inactive TXB
2
.
2
In healthy individuals, PG mediate a range of normal biological functions including gastric
protection, renal homeostasis, vascular homeostasis, uterine function, embryo implantation and
labour, regulation of the sleep wake cycle, body temperature and inammation (Table 1).
Although most tissues are able to synthesise the intermediate PGH
2
from free arachidonic acid, the
biologically active PGs synthesised varies in each tissue and depends on the complement of
enzymes that are present and their relative abundance. For example, lung and spleen are able to
synthesise a whole range of biologically active prostanoids, but the principal enzyme metabolising
PGH
2
in platelets is thromboxane synthetase, while endothelial cells contain primarily prostacyclin
synthase.
2, 3
Prostanoid receptors are all G-protein linked, and their stimulation activates distinct cell-signalling
pathways.3 Five main prostanoid receptors have been dened and cloned. These have been termed
DP-, FP-, EP- TP- and IP-receptors and are the ligands for the natural prostenoids PGD
2
, PGF
2
,
PGE
2
, TXA
2
and PGI
2
respectively. EP-receptors can be divided into four subtypes, EP1 to EP4.
4
Table 1. Physiologic Functions of Prostaglandins
(From Kaplan-Machlis et al, 1999
5
).
2.2 Comparisons between COX-1 and COX-2
2.2.1 COX regulation and biology
In 1990 it was reported that stimulation of human monocytes with lipopolysaccharide (LPS)
resulted in a substantial increase in the activity of COX, but did not change the activities of
phospholipase or 5-lipoxygenase.
6
It was also observed that dexamethasone could inhibit LPS-
induced increases in COX activity of macrophages, but did not affect basal production of
prostaglandins.
7
These results led the investigators to postulate the existence of an inducible
form of COX which could be upregulated by inammatory stimuli such as cytokines. This
inducible enzyme (COX-2) was cloned in 1991.
COX-1 is the constitutive form of the enzyme which is expressed in nearly all cell types
throughout the body at a constant level. Its expression can increase 2- to 4- fold under
stimulatory conditions and it is not appreciably affected by glucocorticoids. In contrast, COX-2
is an immediate early gene product. Its expression is rapidly upregulated by a variety of
inammatory stimuli including proinammatory cytokines (eg. interleukin (IL)-1, IL-2 and
tumour necrosis factor- (TNF-)) bacterial lipopolysaccharide, mitogens and reactive oxygen
intermediates. These stimuli can upregulate COX-2 in macrophages, monocytes, synoviocytes,
chondrocytes, broblasts and endothelial cells 10- to 80- fold.
8-10
COX-2 is not commonly
found in differentiated cells under normal physiological conditions, but it has been
constitutively found in the kidney,
11
vasculature,
12
brain,
13, 14
ovary, uterus (associated with
embryo implantation), cartilage and bone.
15
2.3 Basis of inhibitor selectivity
Differences between COX-1 and COX-2 are summarised in table 2. Although the genes of both
isoforms are different, COX-1 and COX-2 have similar structures and catalytic activities. The
amino acid sequences for the substrate binding and catalytic sites are almost identical, but
COX-2 has valine substituted for isoleucine at positions 434 and 523.
16, 17
Valine is smaller than
isoleucine by a methyl group. These substitutions result in a larger and more exible substrate
channel and a secondary internal pocket off the inhibitor binding site of COX-2 which is not
observed in COX-1. COX-2 selective inhibitors have structures which occupy this additional
pocket (See Figure 2).
Physiologic Function Prostaglandin(s) Involved
Relax vascular smooth muscle PGE
2
, PGF
2
, PGI
2
Promote platelet aggregation TXA
2
Inhibit platelet aggregation PGI
2
Relax bronchial smooth muscle PGE
2
, PGI
2
Contract bronchial smooth muscle PGF
2
Increase renal blood ow PGE
2
, PGI
2
Protect gastric mucosa PGE
2
, PGI
2
Contract uterine smooth muscle PGE
2
, PGF
2
Relax uterine smooth muscle PGI
2
Regulation of the sleep/wake cycle PGD
2
Figure 2. A single amino acid substitution is responsible for inhibitor selectivity.
Larger COX inhibitors cannot occupy the active site of COX-1 since the internal side
pocket is not present. (Figure reprinted with permission from Hawkey, C. J. 1999.
COX-2 inhibitors. The Lancet. 353: 307-14.
18
The Lancet Ltd.)
Table 2. Summary of the structure, distribution and regulation of
COX-1 and COX-2 (From Brooks, P. 1999
19
).
2.4 Non-selective COX inhibitors
NSAIDs are believed to exert their antiinammatory actions through the inhibition of PG
synthesis by blocking COX.
20, 21
The predominant effect of these drugs is in the periphery, but
the antipyretic effects are mediated by inhibition of PG synthesis in the central nervous system.
Aspirin covalently modies both COX-1 and COX-2 by acetylation of a distinct serine residue
within the active site of the enzyme. This results in an irreversible inhibition of COX activity.
This is an important distinction for aspirin compared to other NSAIDs, since the duration of
activity of aspirin relates to the turnover rate of COX in target tissues.
Traditional NSAIDs are weak organic acids (see Table 3) which serve as reversible inhibitors of
COX activity. Some non-selective NSAIDs such as ibuprofen and mefenamic acid are purely
competitive COX inhibitors. Others including naproxen and indomethacin have a more
complex mechanism of inhibition; they bind very tightly to COX and can be classied as time-
dependent inhibitors.
2.5 COX-2-selective NSAIDs
Two COX-2-selective NSAIDs are currently available to clinicians in Australia. Celecoxib
(Celebrex
, (Searle)) has been approved for use in Australia for the management of pain
associated with osteoarthritis (OA) and rheumatoid arthritis (RA) in adults. Rofecoxib (Vioxx
,
(Merck)) has been approved for the treatment of OA. A third agent, meloxicam (Boehringher
Ingelheim) has been released in Europe, and may be licensed in Australia at some future date.
The indications and recommended dosages for celecoxib and rofecoxib are show in Table 4.
COX-2-selective NSAIDs exhibit time-dependent inhibition of COX-2.
COX-1 COX-2
cDNA Chromosome 9; 22kB Chromosome 1; 8.3kB
mRNA 2.8kB 4.5kB
Protein 72kDa; 599 amino acids 72kDa; 604 amino acids
Amino acids: 90% between species for both isoforms;
similar Vmax and Km values for arachidonic acid
Differences Glucocorticoids inhibit expression of COX-2, not COX-1;
the active site of COX-2 is larger than that of COX-1
Regulation Predominantly constitutive. Predominantly inducible
Increased 2- to 4-fold (10- to 20-fold).
by inammatory stimuli Constitutive in certain tissues
Tissue Expression Most tissues, Induced by inammatory stimuli
but particularly platelets, and mitogens in macrophages/
stomach, kidney monocytes, synoviocyes. chondrocytes,
broblasts, endothelial cells. Induced
by hormones in the ovaries and foetal
membranes. Constitutive expression
in the CNS, kidney, testes, tracheal
epithelial cells.
Table 3. Chemical classication of NSAIDs available in Australia
* low dose analgesic, antipyretic and antiplatelet preparations of aspirin have been excluded from this list.
Table 4. Specic COX-2-selective NSAIDs available in Australia
Chemical Class Generic Name Proprietary Products Available
Salicylic acid derivatives Aspirin* Ecotrin
Diunisal Dolobid
Indole acetic acids Indomethacin Arthrexin
, Hicin
, Indocid
, Indomed
Sulindac Aclin
, Clinoril
, Saldac
, Fenac
, Voltaren
,
Voltaren Rapid
, Dinac
, Diclohexal
,
Arthrotec 50
(Diclofenac
50mg+misoprostil 200microg).
Ketorolac Toradol
, Actiprofen
, Brufen
,
Nurofen
Rafen
Ketoprofen Orudis
, Orudis SR
, Oruvail SR
Naproxen/ Anaprox
, Inza
, Naprogesic
,
Crysanal
,
Napoxen sodium Naprosyn
, Naprosyn SR
, Proxen SR
, Tiafen
, Ponstan
, Candyl-D
, Feldene
,
Feldene-D
, Moblis
, Moblis-D
Pirohexal-D
, Pirox
, Rosig
, Rosig-D
Tenoxicam Tilcotil
WOMAC - Western Ontario and McMaster Universities Osteoarthritis Index (Composite of pain, stiffness and functional measures)
VAS -Visual analog scale ACR-20 - American College of Rheumatology responder index (Composite of clinical, laboratory and functional measures)
Additional Study
92
- Four Phase 2 trials: 2 week OA efcacy trial; 4 week RA efcacy trial; 1 week endoscopic study of GI mucosal effects and a 1 week study of effects on platelet function.
Table 6. Published efcacy trials with celecoxib continued
RA randomised,
double-blind
parallel
active-
controlled
trial
Mean 54-55yo
any concomitant
rheumatic
condition, active
or suspected
peptic ulceration
or GI bleeding,
coagulation
defect or any
other disorder
precluding
NSAID use,
malignancy,
renal or hepatic
disorder,
inflammatory
bowel disease,
diclofenac
intolerance,
hypersensitivity
to NSAIDs, COX-
2-selective
NSAIDs or
sulphonamide,
any abnormal
clinical or
laboratory values
pretreatment
+others (see
study)
24 weeks
(assessed
wks 4, 8,
12, 16,20
& 24)
1. physician and patient
assessment of arthritis
2. number of tender or
painful joints
3. number of swollen
joints
4. patients responding
according to ACR-20
5 functional disability
score with the modified
health assessment
questionnaire
6. duration of morning
stiffness (VAS)
7. Cp C-reactive protein
8. withdrawals due to
treatment failure.
200mg bd 326 Diclofenac
SR
75mg bd
329 See table 2.1 for
GI side effects -
Celecoxib and
diclofenac were
similarly
effective in
managing RA
pain and
inflammation
Emery, P. et al. (1999).
Celecoxib versus
diclofenac in long-term
management of
rheumatoid arthritis:
randomised double-
blind comparison.
Lancet. 354: 2106-2111
Supported by Searle
OA, knee
and hip
Placebo and
active
controlled
clinical trials
up to 12
weeks
duration.
Approx. 4200
patients
Signs and symptoms of
arthritis, WOMAC, OA
flare
100mg bd
200mg od
200mg bd
Placebo Naproxen
500mg bd
Celecoxib
comparable to
naproxen.
Total daily dose
of 200mg
maximally
effective.
Celebrex product
information. (Some
details have not been
published, although
summaries may be
available in abstract
form)
RA Placebo and
active
controlled
clinical trials
up to 24
weeks
duration.
Approx. 2100
patients
100mg bd
200mg bd
Placebo Naproxen
500mg bd
Celecoxib doses
similar in
effectiveness
and
comparable to
naproxen
Celebrex product
information. (Some
details have not been
published, although
summaries may be
available in abstract
form)
5.1.2 Efcacy studies with rofecoxib
Rofecoxib has been approved by the TGA for the treatment of pain associated with OA. Rofecoxib 12.5mg or 25mg given as a daily dose is
signicantly superior to placebo for the treatment of the signs of osteoarthritis. To date (Jan 12, 2000) there have been no active controlled trials
published. However, studies published in abstract form report that a daily dose of 12.5mg or 25mg rofecoxib were comparable to ibuprofen 800mg
tds or diclofenac 50mg tds in treatment of OA of the hip and knee.
91, 93, 94
Table 7. Published efcacy trials with rofecoxib
Patients Design/Age Exclusions Dur-ation Main efficacy measures Drug &
Dose
n Better
than
n Comparable
to
n Significant
Adverse Effects
Notes Reference
OA,
knee
Randomised
placebo
controlled trial
Mean 63.5yo
Previous
gastric/duodenal
ulceration; history of
GI bleeding; renal
impairment,
diabetes, history of
cardiovascular,
hepatic, neurological
neoplastic or
coagulation disorder
6 weeks
(assessed
1,2,4 & 6
wks)
1) WOMAC
2) patient assessment of OA
pain on a VAS
3) physician and patient
global assessment of
response to Tx
4) physician global
assessment of disease status
(Likert scale)
5) patient global assessment
of disease status
6) % of patients who
discontinued due to lack of
efficacy
25mg od
125mg od
73
74
Placebo 72 1 gastric bleed
in association
with gastric
and duodenal
ulcers in
rofecoxib
125mg
treatment
group
Dose-related
peripheral
oedema 2.7%
and 6.8% in 25
and 125mg
treatment
groups
respectively
Both doses of
rofecoxib were
superior to
placebo from
1wk (1st
assessment) for
duration of study
125mg is 5 times
the maximum
recommended
dose for
treatment of OA
Ehrich, E. W. et al. (1999). Effect
of specific COX-2 inhibition in
osteoarthritis of the knee: A 6
week double blind, placebo
controlled pilot study of
rofecoxib. Journal of
Rheumatology. 26:2438-2447
RA Phase II
Randomised,
double-blind
placebo
controlled trial
Mean 54-55yo
other inflammatory
arthropathies,
uncontrolled
diabetes, active GI
bleeding or
ulceration,
positive stool guaiac
screen, malignancy,
recent serious
cardiovascular
disease, hepatic or
renal impairment,
NSAID or
paracetamol
sensitivity
8 weeks
(assessed
2,4 & 8
weeks)
1) swollen joint count
2) tender joint count
3) patient global assessment
of disease activity on a VAS
4) investigator global
assessment of disease activity
(Likert scale)
5) Stanford Health
assessment questionnaire
disability index
6) patient global assessment
of pain on a VAS
7) levels of C-reactive protein
5mg od
25mg od
50mg/od
158
171
161
Placebo 168
No clinically
significant
oedema or
hypertension.
No serious GI
effects
25 and 50mg
rofecoxib
significantly
better than
placebo. 5mg
not significantly
different to
placebo.
Rofecoxib Groups
well matched for
age and sex
Schnitzer, T. J. et al. (1999). The
safety profile, tolerability, and
effective dose range of
rofecoxib in the treatment of
rheumatoid arthritis. Clinical
Therapeutics. 21:1688-1702
OA,
knee or
hip
Six randomised
clinical trials of
rofecoxib
lasting from 6
to 86 weeks.
4035 patients
including
approx. 400 pts
>80yo
Signs and symptoms of OA
Joint space narrowing at one
year (compared to diclofenac
only)
1.25mg od
25mg od
Placebo Diclofenac
50mg tid
Ibuprofen
800mg tid
Rofecoxib
comparable to
diclofenac or
ibuprofen
Vioxx Product Information.
(Full details of studies not
published, although summaries
may be available in abstract
form)
5.2 Adverse effect studies with celecoxib and rofecoxib
The COX-2-selective NSAIDs are new drugs for which there is a limited amount of published comparative safety data. Most clinical trials are
powered to detect drug efcacy, not drug safety.. Drug side effects can be classied as being type A or type B reactions. Type A reactions are
common reactions which are dose-dependent and in line with the pharmacology of the drug. These effects will often emerge in the clinical trial
process, but this is not always the case. For example, it was some years after marketing that the ACE inhibitor cough emerged as one of the most
common side effects of this class of drug. In contrast, type B reactions are idiosyncratic, rare and more likely to be serious. Since they are infrequent,
these reactions are rarely detected by clinical trials but emerge as a consequence of vigilant reporting of adverse effects. Therefore, and accurate
picture of a drugs adverse effects prole may not appear until several years after a drug is introduced into therapeutics.
5.2.1 Gastrointestinal (GI) complications
The most common adverse effects of celecoxib and rofecoxib in clinical trials are dyspepsia, abdominal pain and diarrhoea. When compared to non-
selective NSAIDs, the COX-2-selective NSAIDs result in a lower incidence of dyspepsia, but the difference is modest and may not be clinically
relevant.
The major marketing tactic for the COX-2-selective NSAIDs is their relative safety compared with traditional NSAIDs. To date, no studies have
assessed the effect of celecoxib or rofecoxib on PG synthesis in the human gastric mucosa at therapeutic doses. However, in clinical trials there is a
statistically signicant decrease in the incidence of endoscopically proven ulcers in patients treated with both agents.
Several factors complicate the interpretation of published clinical trials. Firstly, most studies have dened an ulcer as a 3mm lesion with unequivocal
depth, although one study also used 5mm ulcers as a secondary end-point (see section 3.24). In the majority of patients these ulcers are
asymptomatic, and are a surrogate endpoint which may or may not reect the real risk of developing serious ulcer complications. This has been a
contentious issue in the literature, but there is evidence that endoscopic ulcers are predictive of adverse clinical events. Secondly, limited numbers of
patients have been treated with either agent so the incidence of potentially uncommon GI side effects may not become evident until the drugs are
more widely used in clinical practice. A third difculty is that although some studies permitted inclusion of patients with a history of GI ulcers or
bleeding, no published study has permitted inclusion of patients with active ulcers. Since COX-2 is detectable in the ulcerated mucosa, and animal
studies have suggested that COX-2 inhibitors may impair ulcer healing, care must be taken in using these agents in patients who have existing ulcers
or erosions. Because of these factors, large scale post-marketing surveillance and vigilant adverse event reporting will be required to determine to
what extent these agents signicantly decrease the incidence of clinically important ulcers, particularly in patients at high risk for ulcer
complications.
Peterson and Cryer in an editorial in JAMA make the following point In patients with RA with no risk factors for NSAID-induced ulcers, the risk
of developing an ulcer complication related to NSAID use is only 0.4%.38 Assuming that a COX-1-sparing NSAID will prevent complicated ulcers
in approximately 50% of patients taking NSAIDs (reducing the risk to 0.2%), 500 low-risk patients would need to be treated with a COX-1-sparing
NSAID to prevent each complicated ulcer that might have developed had all of these low-risk patients been taking traditional NSAIDs. These
gures are based on drug costs in the USA, and do not take into account the costs of endoscopies, concomitant treatment with gastroprotective
agents, or hospitalisations for serious GI toxicity.
Due to the perceived relative safety of celecoxib with regard to GI complications, it is likely that it will be prescribed for those patients at greatest
risk, such as patients with a history of GI erosion or ulceration. The GI complication rate in this group of patients is as yet unknown
5.2.2 Renal complications
The effects of celecoxib and rofecoxib on the renal system are not clear. Therefore caution should be exercised in prescribing these agents in patients
with congestive heart failure (CHF), uid retention, hypertension or impaired renal function. No studies have permitted the inclusion of patients
with moderate to severe renal failure, and most studies have excluded patients with mildly impaired renal function (i.e. creatinine clearance (CLCr) <
50mL/min).
A study of celecoxib in healthy males who were sodium restricted found that celecoxib decreased glomerular ltration rate (GFR) and renal blood
ow and signicantly reduced sodium excretion after 7 days. Another study assessed the effects of rofecoxib on the renal function of healthy elderly
subjects who were not renally impaired. This study found that rofecoxib did not signicantly affect GFR or sodium excretion, but the patients in
this study were not sodium restricted and fed a diet which had 10x the recommended daily allowance of sodium. COX-2 and the renin-angiotensin
system are induced in response to restriction of dietary sodium. It is therefore difcult to comment on the signicance of these studies and their
relevance to renally impaired elderly patients who may not be able to tolerate chances in uid volume. In healthy volunteers, both celecoxib and
rofecoxib can decrease renal biosynthesis of PGI2. It may therefore be predicted that problems with uid retention and overload could arise in the
elderly, and in patients with impaired renal function. This may be particularly important in patients on ACE inhibitor therapy with compensatory
mechanisms working to maintain renal blood ow. The addition of a COX-2 inhibitor may induce acute renal failure similar to that reported with
the combination of traditional NSAIDs and ACE inhibitors.
5.2.3 Bleeding time
In clinical trials, celecoxib and rofecoxib have no effect on platelets and bleeding times when administered alone. However, a study in healthy
volunteers has demonstrated that celecoxib and rofecoxib can decrease both renal and systemic synthesis of PGI
2
.
84
The signicance of this effect in
patients with thromboembolic disease remains to be determined. Furthermore, both celecoxib and rofecoxib may lead to increases in prothrombin
time when administered concomitantly with warfarin.
5, 89
5.2.4 NSAID-sensitive asthmatics
No trials have been conducted in patients who are hypersensitive to NSAIDs.
Table 9. Published trials assessing safety of celecoxib
Author Study Design Treatment n Measures Results and Comment
Simon, L.S. et al. (1999).
Anti-inflammatory and
upper gastrointestinal
effects of celecoxib in
rheumatoid arthritis - A
randomized controlled
trial. JAMA: Journal of the
American Medical
Association. 282:1921-1928
Supported by Searle
12 week randomised, double-blind
placebo & active controlled trial of
patients with RA
EXCLUDED: active renal GI hepatic or
coagulation disorders; oesophageal
or gastroduodenal ulceration in
prev. 30 days or if baseline
endoscopy showed ulcers or > 10
erosions
Placebo
Celecoxib 100mg bd
Celecoxib 200mg bd
Celecoxib 400mg bd
Naproxen 500mg bd
231
240
235
217
225
Upper GI endoscopy performed within
7 days prior to first dose of medication.
Mucosa of stomach and duodenum
evaluated separately for petechiae,
erosions and ulcers. Ulcers defined as
break in mucosa at least 3mm in
diameter with unequivocal depth.
Repeated at the final treatment or early
termination visit. Patients also tested
for H. pylori.
Gastroduodenal ulcers occurred in 4% of
placebo patients, 4-6% of celecoxib-
treated patients and 26% of naproxen-
treated patients. Few of the ulcers were
symptomatic. 1 naproxen-treated
patient developed two ulcers creating a
partial gastric outlet obstruction.
Very small study to detect rare GI events.
Rossat, J. et al. (1999).
Renal effects of selective
cyclooxygenase-2 inhibition
in normotensive salt-
depleted subjects. Clinical
Pharmacology and
Therapeutics. 66:76-84
Sponsored by Searle
7 day randomised, double blind trial
of 40 healthy young male volunteers
(Mean age 24.8yo).
All subjected to a low salt diet
(<50mmol Na
+
and 3500Calories/day)
beginning 5 days before the study
and continuing throughout. 40mg
Frusemide administered on day 1 to
achieve a faster Na
+
depletion
Placebo
Celecoxib 200mg bd
Celecoxib 400mg bd
Naproxen 500mg bd
10
10
10
10
Renal haemodynamic (renal plasma
flow and GFR) and tubular responses
(electrolyte excretion), blood pressure,
heart rate. 24hr electrolyte excretion
assessed daily; other effects assessed
pre- and post-dosing on days 1 and 7.
Celecoxib resulted in transient but
significant decrease in glomerular
filtration rate and a decrease in renal
plasma flow, comparable to the effect of
naproxen. Celecoxib also significantly
reduced urinary volume and sodium and
potassium excretion at day 7. The
authors concluded that celecoxib does
not spare the kidney in salt depleted
subjects and caution may need to be
exercised when celecoxib is
coadministered with diuretics or in
patients with hypertension and/or CHF.
Emery, P. et al. (1999).
Celecoxib versus diclofenac
in long-term management
of rheumatoid arthritis:
randomised double-blind
comparison. Lancet. 354:
2106-2111
Supported by Searle
24 week randomised, double-blind
parallel active-controlled trial.
Patients with a history of GI ulcer or
bleeding NOT excluded.
EXCLUDED: any concomitant
rheumatic condition, active or
suspected peptic ulceration or GI
bleeding, coagulation defect or any
other disorder precluding NSAID use,
malignancy, renal or hepatic
disorder, inflammatory bowel
disease, diclofenac intolerance,
hypersensitivity to NSAIDs, COX-2-
selective NSAIDs or sulphonamide,
any abnormal clinical or laboratory
values pretreatment +others
Celecoxib 200mg bd
Diclofenac SR
75mg bd
212
218
GI safety based on a single upper GI
endoscopy at week 24 or time of
withdrawal from study. Injury to
gastric and duodenal mucosa were
evaluated separately taking note of
petechiae, erosions and ulcer. An ulcer
was defined as a break in the mucosa of
at least 3mm with unequivocal depth.
GI tollerability based on clinical
laboratory tests, physical examinations,
adverse events and study withdrawals.
Data on perforation, bleeding or gastric
outlet obstruction were assessed using
prespecified criteria judged by a
blinded, external committee of
gastroenterologists
Gastrointestinal adverse events were
reported in 48% of patients taking
diclofenac and 36% of patients taking
celecoxib.
5 GI events required hospitalisation of
patients on diclofenac. These included
one ulcer.
The respective incidences of gastric and
duodenal ulcers were 34% and 11% for
patients on diclofenac, and 18% and 5%
for patients on celecoxib.
Haemoglobin levels were lower in
diclofenac-treated patients
McAdam, B.F.et al. (1999).
Systemic biosynthesis of
prostacyclin by
cyclooxygenase (COX)-2:
the human pharmacology
of a selective inhibitor of
COX-2. Proceedings of the
National Academy of
Sciences of the United
States of America. 96:272-7
24hr randomised, double-blind trial
of healthy volunteers aged 21-49.
EXCLUDED: history of coagulation
disorder, bleeding tendency, drug
allergy or GI disorder
Placebo
Single dose of:
Celecoxib 100mg
Celecoxib 400mg
Celecoxib 800mg
Ibuprofen 800mg
7
7
7
7
7
Platelet aggregation ex vivo,
Serum TXB
2
levels,
Whole blood monocyte COX-2 activity
and
Urinary metabolites of systemic and
renal prostacyclin biosynthesis (2,3-
dinor-6-keto PGF
1
and 6-keto PGF
1
respectively)
Celecoxib didnt affect platelet
aggregation, but had a significant
inhibitory effect on serum TXB
2
4hrs after
dosing.
Celecoxib and ibuprofen induced a
significant decrease in systemic and renal
prostacyclin biosynthesis, and similar
effects have been reported with
rofecoxib after chronic dosing in elderly
patients
Table 10. Published trials assessing safety of rofecoxib
Author Study Design Treatment n Measures Results and Comment
Langman, M. J.et al. (1999).
Adverse upper
gastrointestinal effects of
rofecoxib compared with
NSAIDs. JAMA: Journal of
the American Medical
Association. 282:1929-1933
Supported by Merck & Co.
Inc.
Pooled analysis of patients from 8
phase 2b/3 trials of rofecoxib for
OA
See article for details of trials.
Both active and placebo
controlled trials used.
Placebo
Rofecoxib (12.5, 25 and 50mg
od)
NSAID (ibuprofen 800mg tds,
diclofenac 50mg tds or
nambumetone 1500mg od)
514
3357
1564
Incidence of 1) upper GI perforations,
2) symptomatic gastroduodenal ulcers, and 3)
upper GI bleeding during treatment and within
14 days of drug discontinuation.
Based on survival analysis of time to first GI
incident , using prespecified criteria judged by
a blinded, external adjudication committee.
Cumulative incidence of dyspepsia up to 6 months was
23.5% with rofecoxib and 25.5% with NSAIDs, after
which the rates converged.
12 month cumulative incidences of study drug
discontinuation due to GI adverse effects was 5.2% for
rofecoxib and 7.8% for NSAIDs (P=0.02).
The cumulative incidence of ulcers, perforations and
bleeding over 12 months was 1.3% with rofecoxib vs
1.8% with NSAIDs.
Laine, L., et al (1999). A
randomzed trial comparing
the effect of rofecoxib, a
cyclooxygenase 2-specific
inhibitor, with that of
ibuprofen on the
gastroduodenal mucosa of
patients with
osteoarthritis.
Gastroeneterology.
117:776-783
6 month randomised double-
blind trial in OA patients 50yo.
Patients with gastroduodenal
erosions at baseline were eligible.
EXCLUSIONS: active GI ulceration,
pyloric obstruction or erosive
oesophagitis. SCr>2mg/dL or
CLCr 30mL/min (moderate renal
impairment), unstable medical
disease, prior cerebrovascular
events; treatment with
anticoagulants, ticlopidine,
aspirin or corticosteroids.
Placebo (ceased after wk 16)
Rofecoxib 25mg od
Rofecoxib 50mg od
Ibuprofen 800mg tds
177
195
186
184
Cumulative incidence of gastroduodenal ulcers
3mm in diameter. Secondary endpoint was
ulcers 5mm in diameter. Endoscopies
performed at baseline, then wks 6,12 & 24 and
at early discontinuation, moderate to severe
upper GI symptoms 2d duration or at
investigators discretion.
Adverse experiences analysed by life table
method and log-rank test
Incidence of 3 and 5mm ulcers significantly lower in
rofecoxib-treated groups compared to ibuprofen.
At week 24, cumulative 5mm ulcer incidences were 4.6,
11.6 and 30.2% for rofecoxib 25, 50 and ibuprofen
2400mg groups respectively.
Subgroup analysis at 12 weeks indicated that age65y,
history of past GI events and presence of GI erosions at
baseline were associated with an increased risk for
ulcer development which was similar in all treatment
groups
Lanza, F. L. et al. (1999).
Specific inhibition of
cyclooxygenase-2 with MK-
0966 is associated with less
gastroduodenal damage
than either aspirin or
ibuprofen. Alimentary
Pharmacology and
Therapeutics. 13:761-7
7 day randomised, double-blind
parallel study in healthy subjects
(age range 18-54y) with
endoscopically normal gastric and
duodenal mucosae
EXCLUSIONS: significant GI
disease, history of GI surgery,
recent thoracic or abdominal
surgery, significant medical
condition, history of using
antacids, H2 antagonists, proton
pump inhibitors or misoprostil or
NSAID use in previous 2 weeks.
Smoking, allergy to NSAIDs,
alcohol dependence or 4
caffeinated beverages/day.
Placebo
Rofecoxib 250mg od
Ibuprofen 800mg tds
Aspirin 650mg qid
51
51
51
17
Baseline endoscopy, physical examination and
laboratory evaluations (chemistry, haematology
and urinalysis). All repeated at day 8.
Erosive mucosal injury score used to assess GI
damage. Proportion of subjects developing
erosions or ulcers compared to those with a
normal mucosa or mucosal haemorrhages only.
Very short study. Proportion of patients with erosions
or ulcerations significantly lower in rofecoxib-treated
group compared to aspirin and ibuprofen, and not
significantly different to placebo.
Catella-Lawson, F.et al.
(1999). Effects of specific
inhibition of
cyclooxygenase-2 on
sodium balance,
haemodynamics, and
vasoactive eicosanoids.
Journal of Pharmacology
and Experimental
Therapeutics. 289:735-41
2 week randomised double-blind
placebo and active controlled
trial in healthy, elderly subjects
without renal impairment
All subjected to a fixed isocaloric
diet
(200mMol Na
+
and 60-80mMol K
+
)
EXCLUSIONS: hypertension or
diabetes requiring pharmacologic
intervention. SCr>2mg/dL and
CLCr<50mL/min. Smokers or
NSAID users.
Placebo
Rofecoxib 50mg od
Indomethacin
50mg tid
12
12
12
24hr Na
+
and K
+
excretion assessed daily. GFR
assessed days -1 and 14. Urinary excretion of N-
acetyl-b-glucosaminidase as an index of
proximal tubular dysfunction was assessed days
-2 and 13. BP was assessed q4h between 8am
and 8pm.
Urinary excretion of TXA
2
metabolites in
addition to renal and external PGI
2
metabolites
assessed days -2,1 and 13.
Short-term administration of rofecoxib and
indomethacin induced a transient decline in sodium
excretion during the first 72hrs of treatment.
Indomethacin but not rofecoxib decreased GFR at day
14.
TXA
2
biosynthesis by platelets was affected by
indomethacin only.
Urinary excretion of renal and systemic metabolites of
PGI
2
were significantly decreased compared to baseline
after treatment with rofecoxib and indomethacin.
6. Conclusions.
Celebrex
and Vioxx