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COX-2-selective NSAIDs:
New wonder drugs?
National Prescribing Service ACN 082 034 393
Level 1/ 31 Buckingham Street, Surry Hills 2010
Phone: 02 9699 4499 l Fax: 02 9699 5155 l email: [email protected]
COX-2-selective NSAIDs:
New wonder drugs?
1. Introduction
Aspirin and other non-steroidal antiinflammatory drugs (NSAIDs) are one of the most widely used
classes of drugs, with both prescription and over the counter sales of the agents contributing to
total usage. NSAIDs are believed to act through inhibition of prostaglandin (PG) synthesis
secondary to their inhibition of the enzyme cyclooxygenase (COX). This results in suppression of
inflammation, and effective analgesia. Most NSAIDs not only inhibit PGs at sites of inflammation,
but also PGs which serve important functions in other parts of the body, a factor which accounts
for some of the toxicity of these agents. The most frequent complications associated with NSAID
usage are those involving the gastrointestinal tract (GIT). GI bleeding, ulceration and perforation
are a significant cause of morbidity and mortality in patients who are treated with these agents.
A new approach to avoiding NSAID-induced complications became feasible with the discovery
that there are 2 isoforms of COX, COX-1 and COX-2. These enzymes are under distinct
regulatory control mechanisms. COX-1 is constitutively expressed in most tissues, and plays a
major role in normal functioning of the GIT, kidneys and platelets. In contrast, COX-2 is
expressed primarily in response to inflammation, but to some extent in other tissues including
kidneys and brain. Traditional NSAIDs are non-selective and inhibit both COX-1 and COX-2,
providing benefits in inflammation, but at the cost of potential adverse effects. Recently, two
COX-2-selective NSAIDs have been approved by the TGA, celecoxib (Celebrex®) and rofecoxib
(Vioxx®). Celecoxib, the first 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
A2. 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 influx 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 H2 synthase catalyses the first two steps in the biosynthesis of the PGs from
the substrate arachidonic acid. These are the oxidation and cyclisation of the unesterified
arachidonic acid to the hydroperoxy endoperoxide PGG2, followed by its subsequent reduction to
PGH2.1 PGH2 in turn serves as a substrate for cell specific isomerases which produce a variety of
biologically active products (See Figure 1)
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 PGinactivating enzymes are present in the lung, and 95% of PGE2 and PGF2 are inactivated on first
passage. PGI2 (Prostacyclin) is not taken up into the lung, but is hydrolysed nonenzymatically (t1/2
=3 minutes) to the inactive 6-keto-PGF1. TXA2 (Thromboxane A2) has a half-life of 30 seconds,
and breaks down nonenzymatically into the stable but inactive TXB2.2
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 inflammation (Table 1).
Although most tissues are able to synthesise the intermediate PGH2 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
PGH2 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 defined and cloned. These have been termed
DP-, FP-, EP- TP- and IP-receptors and are the ligands for the natural prostenoids PGD2, PGF2,
PGE2, TXA2 and PGI2 respectively. EP-receptors can be divided into four subtypes, EP1 to EP4.4
Table 1. Physiologic Functions of Prostaglandins
(From Kaplan-Machlis et al, 19995).
Physiologic Function
Relax vascular smooth muscle
Promote platelet aggregation
Inhibit platelet aggregation
Relax bronchial smooth muscle
Contract bronchial smooth muscle
Increase renal blood flow
Protect gastric mucosa
Contract uterine smooth muscle
Relax uterine smooth muscle
Regulation of the sleep/wake cycle
Prostaglandin(s) Involved
PGE2, PGF2, PGI2
TXA2
PGI2
PGE2, PGI2
PGF2
PGE2, PGI2
PGE2, PGI2
PGE2, PGF2
PGI2
PGD2
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 LPSinduced 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 inflammatory 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. It’s 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. It’s expression is rapidly upregulated by a variety of
inflammatory stimuli including proinflammatory 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, fibroblasts 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 flexible 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).
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. 199919).
cDNA
mRNA
Protein
Differences
Regulation
Tissue Expression
COX-1
COX-2
Chromosome 9; 22kB
Chromosome 1; 8.3kB
2.8kB
4.5kB
72kDa; 599 amino acids
72kDa; 604 amino acids
Amino acids: 90% between species for both isoforms;
similar Vmax and Km values for arachidonic acid
Glucocorticoids inhibit expression of COX-2, not COX-1;
the active site of COX-2 is larger than that of COX-1
Predominantly constitutive.
Predominantly inducible
Increased 2- to 4-fold
(10- to 20-fold).
by inflammatory stimuli
Constitutive in certain tissues
Most tissues,
Induced by inflammatory stimuli
but particularly platelets,
and mitogens in macrophages/
stomach, kidney
monocytes, synoviocyes. chondrocytes,
fibroblasts, endothelial cells. Induced
by hormones in the ovaries and foetal
membranes. Constitutive expression
in the CNS, kidney, testes, tracheal
epithelial cells.
2.4 Non-selective COX inhibitors
NSAIDs are believed to exert their antiinflammatory 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 modifies 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 classified as timedependent 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.
Table 3. Chemical classification of NSAIDs available in Australia
Chemical Class
Salicylic acid derivatives
Generic Name
Aspirin*
Proprietary Products Available
Ecotrin®
Indole acetic acids
Diflunisal
Indomethacin
Dolobid
Arthrexin®, Hicin®, Indocid®, Indomed®
Sulindac
Heteroaryl acetic acids
Aclin®, Clinoril®, Saldac®
Diclofenac
Diclohexal®, Fenac®, Voltaren®,
Voltaren Rapid®, Dinac®, Diclohexal®,
Arthrotec 50® (Diclofenac
50mg+misoprostil 200microg).
Ketorolac
Ibuprofen
Toradol®
ACT-3®, Actiprofen®, Brufen®,
Nurofen® Rafen®
Ketoprofen
Orudis®, Orudis SR®, Oruvail SR®
Naproxen/
Anaprox®, Inza®, Naprogesic®,
Crysanal®,
Napoxen sodium
Naprosyn®, Naprosyn SR®, Proxen SR®
Anthranilic acids (Fenamates)
Tiaprofenic acid
Mefenamic acid
Surgam®, Tiafen®
Mefic®, Ponstan®
Enolic acids Oxicams
Piroxicam
Candyl®, Candyl-D®, Feldene®,
Feldene-D®, Moblis®, Moblis-D®
Pirohexal-D®, Pirox®, Rosig®, Rosig-D®
Tenoxicam
Tilcotil®
Phenylbutazone
Butazolidin®
Propionic acid derivatives
Pyrazolidinediones
* low dose analgesic, antipyretic and antiplatelet preparations of aspirin have been excluded from this list.
Table 4. Specific COX-2-selective NSAIDs available in Australia
Generic Name
Proprietary Products Available
Celecoxib
Celebrex®
Rofecoxib
Vioxx®
TGA approved indications and
recommended dosages
Rheumatoid arthritis, 100-200mg twice
daily Osteoarthritis, 200mg once daily or
100mg twice daily. Maximum: 200mg
twice daily
Osteoarthritis, Initially 12.5mg once daily,
may be increased if necessary to 25mg
once daily
2.6 Assessment of COX-2 specificity
A number of disparate methods have been used to assess the potency of inhibitors against
COX-1 and COX-2. These assays have utilised COX derived from different species and tissues,
and as such the results for individual compounds can vary widely.19 At the International
Consensus Meeting on the Mode of Action of COX-2 Inhibition, it was proposed that the
human whole blood assay (WBA)22 should be adopted as the standard method for assessing
differential inhibition of COX isoforms.19 The human whole blood assay has a number of
advantages, including the ability to make assessments of inhibitor activity when a drug is taken
by a patient before blood collection, or when the inhibitor is added to the blood after sample
collection. In the former case, biologically active metabolites can also be assessed.
For assessment of COX-1 activity in this assay, blood is allowed to clot for one hour at 37°C in
the presence or absence of inhibitor, and then the serum is assayed for TXB2. Since TXB2 is
predominantly derived from platelets in this system, and platelets cannot synthesise COX-2 (See
Blood Clotting below), serum TXB2 levels reflect platelet COX-1 activity. For assessment of
activity against COX-2, blood is collected in heparinised tubes and incubated for 24hrs at 37°C
in the presence or absence of inhibitor, together with LPS. LPS results in PGE2 production by
circulating monocytes as a consequence of inducing COX-2, so after 24hrs, serum is assayed for
PGE2.22
Enzyme inhibitors are usually described according to their efficiency in inhibiting enzyme
activity. The most common variable is the IC50 (concentration of inhibitor which results in a
50% reduction in COX activity). A low IC50 indicates a drug is more potent than one with a
high IC50. For COX, the results of inhibitor assays are commonly expressed as a ratio of IC50
for COX-2/COX-1. A smaller value therefore implies a greater selectivity of an agent for COX2.
Recently, a number of modifications have been made to the COX-2 component of the WBA.
This modified assay is the William Harvey Human Modified Whole Blood Assay (WHMA).23
The changes were made in an attempt to compensate for the longer incubation times in the
COX-2 component of the WBA (24hrs) compared to the COX-1 component (1hr), since it is
now obvious that the potency of inhibitors for prostanoid formation is dependent upon the
supply of arachidonate both in vivo and in vitro.24, 25 In addition, the investigators who
developed this assay expressed their results as the ratio of IC80, since steady state plasma
concentrations of many NSAIDs, aspirin and meloxicam produce approximately 80%
inhibition of both COX-1 and COX-2 in this assay system 23 (see Figure 3).
Figure 3. Selectivity of COX-2 inhibitors and NSAIDs given as log inhibitory
concentration (IC80) ratio. The ‘0 line’ indicates equipotency (i.e. an IC80 ratio of 1).
(Figure reprinted with permission, from Brooks, P.M. COX-2 inhibitors. Australian
Prescriber 2000. 23:30-2. See http://www.australianprescriber.com )
Although these data may be used to suggest advantages of one drug over another. their
significance is not clear. For example, the results are based on concentrations of drug in plasma,
which may not reflect the steady state concentration in the synovial fluid. Furthermore, if these
log IC80 ratios of traditional and widely utilised non-selective NSAIDs are compared with the
risk of serious GI toxicity of these agents as determined by a large meta-analysis,26 there is a
correlation, but it is not strong. This suggests that the clinical significance of these data for
predicting adverse GI events is of uncertain importance, and the safety profile of one drug over
another will only be determined by wide use in a clinical setting.
2.7 Rheumatoid arthritis and osteoarthritis
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder characterised by a
deforming polyarthritis and a spectrum of extra-articular manifestations. Therapy with diseasemodifying antirheumatic drugs (DMARDs) is instituted to alter the progress of the disease and
therefore prevent joint deformity and disability. NSAIDs are primarily used in RA for the relief
of pain and inflammation, but do not modify the natural history of RA. Any NSAID may be
used, usually chronically and at the higher end of the dose range. Paracetamol can also be
useful in RA, sometimes allowing use of a reduced dosage of NSAID.27
Osteoarthritis (OA) is a disease affecting the weight-bearing joints and peripheral and axial
articulations. One of the hallmarks of the disease is the progressive degeneration of cartilage
resulting in pain and restricted motion. It is classified as a non-inflammatory arthropathy, but
there may be inflammatory components. Treatment in OA is aimed at pain relief. The first line
treatment is paracetamol in adequate dosage (maximum 4g/day) on an occasional or regular
basis according to symptoms. If this does not control symptoms adequately, a low-dose NSAID
can be added, and dosage increased only if response is unsatisfactory. NSAIDs can also be used
intermittently during flares of OA pain.27
2.7.1 COX-2 in RA and OA
2.7.1.1 Studies in experimental animals
The role of COX-2 has been studied in animal models of inflammatory arthropathies. COX-2
but not COX-1 is induced in the synovial tissues of rats with adjuvant arthritis (a model of
rheumatoid arthritis).28 In this model, a COX-2-selective inhibitor (SC-58125) reduced paw
oedema and decreased PGE2 concentrations in the paw to baseline levels with an efficacy
indistinguishable from indomethacin.
2.7.1.2 Studies in humans
COX-2 is also induced in humans with RA and OA. Using immunohistochemistry with a
specific antibody directed against COX-2, Crofford et al demonstrated that COX-2 is present in
vivo in synovial tissues from patients with RA.29 Siegle et al studied the expression of COX-1
and COX-2 in patients with inflammatory arthropathies (RA, ankylosing spondylitis, or
psoriatic arthritis) and in patients with OA. Using both immunohistochemistry with image
analysis and reverse transcription polymerase chain reaction (RT-PCR), expression of COX-2
protein and mRNA respectively were significantly higher in inflammatory arthropathies
compared to OA.30 The upregulated COX-2 expression in inflammatory arthropathies in this
latter study is consistent with a recent study which reported significantly higher concentrations
of PGE2 in the synovia of patients with RA compared to those with OA.31
Despite low levels of COX-2 expression in the synovium of patients with OA, cartilage may be
a significant source of COX-2 and PGs in these patients. A recent study employing explant
cultures of cartilage from OA-affected patients reported upregulation of COX-2 mRNA and
protein which coincided with superinduction of PGE2.32
3. Physiological and pathophysiological roles of
prostanoids/adverse effects of NSAIDs
The main adverse effects of the non-selective NSAIDs involve the GI tract, the kidney and blood
clotting. Since PGs mediate a variety of physiological functions, inhibiting their production
likely accounts for some of the adverse events associated with NSAID therapy. It is largely the
inhibition of COX-1 which is believed to contribute the adverse effect profile of the NSAIDs as
a class. However, some effects of individual NSAIDs may be unrelated to COX inhibition. For
example, aplastic anaemia has been reported following phenylbutazone treatment, and
tiaprofenic acid can cause cystitis. It has been hypothesised that specific COX-2-selective
NSAIDs will have a superior adverse effect profile compared to the non-selective inhibitors
(particularly GI side effects), but it is possible that the COX-2-selective NSAIDs will cause
unwanted effects independent of their selective actions on COX-2.
Drug adverse effects can be classified 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.
Type B reactions are idiosyncratic, rare and more likely to be serious. Most clinical trials are
powered to detect drug efficacy, not safety. Therefore, although type A reactions will often
emerge in the clinical trial process, 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 adverse
effects of this class of drug. Since type B reactions are infrequent, they are rarely detected by
clinical trials. These reactions emerge as a consequence of vigilant reporting of adverse
reactions.
This section reviews some of the physiological roles of COX and PGs, in addition to describing
some of the adverse effects commonly associated with COX inhibition by non-selective
NSAIDs. The adverse effects of the COX-2-selective NSAIDs which have emerged in clinical
trials are discussed below in section 5.2.
3.1 Inflammatory and immune responses
PGs are released by a large variety of mechanical, thermal, chemical and microbiological
insults, and they contribute significantly to the signs and symptoms of inflammation.33 In areas
of acute inflammation, PGE2 and PGI2 are generated by local tissues and blood vessels, while
mast cells release PGD2. Monocyte-lineage cells (macrophages) can release PGE2 and TXA2.
PGs, in particular PGE2 are major mediators of the inflammatory response. PGEs and PGE2 in
particular, modulate the oedema and pain which constitute the classical signs of inflammation.
PGEs do not directly increase vascular permeability, but can increase plasma exudation induced
by other mediators such as C5a.34 PGEs can also increase blood flow to inflamed areas thereby
enhancing leukocyte infiltration and contributing to the development of oedema.2
PGE2 also lowers nociceptive thresholds, sensitising peripheral sensory nerve endings and
thereby potentiating the effects of nociceptive agents such as bradykinin and histamine. In
addition, COX products are thought to act in the spinal cord to facilitate the transimission of
pain responses.35 PGE2 is also a pyretic agent and contributes to fever associated with
infections.36
Inhibition of the synthesis of PGs is believed to account for the clinical efficacy of the NSAIDs.
It is important to remember that the inflammatory process is a defence mechanism to protect
the body from noxious stimuli. It is only when the inflammatory response is not appropriately
limited and continues unnecessarily that COX-2 activity becomes detrimental.
3.2 The GI tract
3.2.1 PG’s and their role in gastric protection
Cytoprotective PGs in the stomach are thought to be synthesised primarily by COX-1 which is
widely distributed throughout the GIT. Basal expression of COX-2 mRNA and protein can also
be detected in the GI mucosa.37 In the stomach, PGE2 and PGI2 inhibit gastric acid secretion
stimulated by feeding, histamine or gastrin. Volume, acidity and pepsin content of secretion are
all reduced. Both PGE2 and PGI2 are vasodilators in the GI mucosa, and PGI2 may be directly
involved in the regulation of blood flow. Mucous secretion in the stomach and small intestine is
increased by PGEs. These effects help to maintain the integrity of the GI mucosa.2 In addition,
PGEs and their analogues inhibit gastric damage caused by a variety of ulcerogenic agents and
promote healing of duodenal and gastric ulcers.38
3.2.2 Incidence and awareness of adverse GI effects after NSAID therapy
The most common adverse events associated with NSAID therapy involve the GI tract.39 There
is a major risk of GI disturbances, perforation, ulcers and bleeding associated with NSAID
usage which represents a significant socioeconomic burden. The risk of an adverse GI event
increases linearly with age 40, and remains constant over time.41, 42 Other risk factors for GI
damage are higher doses of NSAIDs (including the use of two or more NSAIDs), a history of
gastroduodenal ulcer or gastrointestinal bleeding, concomitant use of corticosteroids, serious
coexisting conditions, and concomitant use of anticoagulants.40
Within a six month period of treatment, between 5 and 15% of patients can be expected to
discontinue therapy because of dyspepsia 43, and it has been estimated that approximately 0.42% of patients who take an NSAID for a year are at risk of developing a serious ulcer
complication.38, 39 The mortality rate amongst patients who are hospitalised for NSAID-induced
upper GI bleeding is approximately 10%. In the USA, the number of deaths per year attributed
to NSAID gastropathy is estimated to be 7600 and the number of hospitalisations is
76000/year.39 In the UK, it has been estimated that 12 000 ulcer complications and 1200
deaths/year are attributable to NSAID usage.44 There are no recent figures which document the
incidence of serious NSAID-induced GI complications in Australia, although it has been
estimated that in 1988 there were approximately 1200 hospital admissions for ulcer
complications attributable to NSAID usage, in people aged 65 years and over.45
Surveys in Australia in the late 1980s showed that approximately 20% of the elderly
population were taking NSAIDs, and that 43% of community use of NSAIDs was in patients
over 60 years of age.45, 46 Since this time there has been a significant reduction in prescription
sales of NSAIDs in Australia (Figure 4a) as a consequence of educational and regulatory
interventions.45 In 1996 Henry and coworkers published a meta-analysis of clinical trials which
highlighted differences in GI risk associated with specific NSAIDs.26 This study reported the
lowest pooled risk was associated with diclofenac and ibuprofen at doses of less than
1600mg/day. The highest pooled relative risk was with piroxicam and ketoprofen (See Figure
5). It is important to note that the relative risk for ibuprofen increases at doses greater than
1600mg/day, and for all NSAIDs, the antiinflammatory effects and the incidence of adverse
effects are both dose related.47
Figure 4. a) Graph showing the declining number of NSAID prescriptions dispensed
from June 89 to June 99. b) Graph showing NSAID usage stratified by GI Risk for the
corresponding period.
Figure 4b.
Figure 5. Graph showing comparison by meta-analysis of the pooled relative risk
(±95% confidence intervals) of serious upper GI complications from exposure to
individual NSAIDs compared with exposure to ibuprofen. Risk was not established for
diflunisal due to an insufficient number of studies) and tenoxicam or tiaprofenic acid
due to unavailability of comparative data.
The National Prescribing Service (NPS) conducted an educational campaign early in 1999 to
alert to differences in relative risk associated with NSAIDs. Although statistics for the latter half
of 1999 are not yet available, data obtained from the PBS show that in the first half of 1999,
prescribing of longer acting (higher risk) agents fell. There has been a corresponding increase in
the number of prescriptions of shorter acting (lower risk) agents (Figure 4b).
Although prescribers are generally aware of the potential for adverse effects with NSAID
therapy, public perceptions and understanding about side effects and drug usage may not
always reflect that of health care professionals. For example, a recent survey of 4799 people
conducted in the USA reported that 45% of the group took NSAIDs for five or more
consecutive days/month, and 40% of these took both OTC and prescribed NSAIDs. Many of
the group were unaware or unconcerned about the possibility of adverse GI effects, and
incorrectly believed that warning signs would precede a serious GI episode.42 There are
currently no data available on OTC consumption of naproxen sodium, ibuprofen, mefenamic
acid, topical diclofenac or aspirin in Australia.
3.2.3 Pathogenesis of mucosal injury
Gastroduodenal mucosal injury develops when the normal defensive properties of the mucosa
are overwhelmed by gastric acid. NSAIDs contribute to mucosal injury by two independent
mechanisms: 1) a topical effect related to the physico-chemical properties of NSAIDs themselves
48
and 2) a systemic effect through decreased mucosal PG synthesis.49 The vast majority of
NSAIDs are weak organic acids. In the stomach, they remain in unionised form and can freely
diffuse across the membrane of mucosal cells. Once inside the neutral cytoplasm, the drug
ionises resulting in trapping of hydrogen ions within the cell.50
Systemic inhibition of PG synthesis impairs mucosal repair and microvascular blood flow, and
also results in inhibition of hepatocyte growth factor production which may delay healing of
mucosal ulcers.51 Indeed, the systemic effects of these agents appear to have the predominant
role in ulcer development, even though superficial mucosal injury may be reduced. In support of
this, the use of enteric coated aspirin preparations and parenteral or rectal administration of
NSAIDs have failed to prevent the development of ulcers.46, 52, 53
3.2.4 Clinical spectrum of injury
The spectrum of NSAID-related gastroduodenal injury includes a combination of subepithelial
haemorrhages, erosions, and ulcerations that is often referred to as NSAID gastropathy. The
distinction between erosions and ulcerations depends on pathological definitions: erosions are
defined as lesions confined to the mucosa, and ulcers are defined as lesions that penetrate the
muscolaris mucosae into the submucosa. An ulcer can cause haemorrhages when it erodes into
the arteries below the mucosa. In practice, an endoscopic definition is used, which is based on a
subjective assessment of the size, shape, and depth of the lesion. The likelihood of a lesion
being an ulcer increases with lesion size. Erosions are likely to be small and superficial, whereas
ulcers tend to be at least 5 mm in diameter with apparent depth.54 Although some studies have
defined ulcers as a mucosal break of ≥ 3mm in diameter, Graham in an editorial in
Gastroenterology makes the point that ‘a 5mm lesion provides a more acceptable standard for a
potentially serious lesion, and results of any study that provide data about 3mm ‘ulcers’ should
be viewed with caution.’55
3.2.5 COX-2 in the GI tract
Helicobacter pylori infection can also lead to ulcers which are often accompanied by a wide
field of non-erosive inflammatory gastritis. H. pylori infection is more common in elderly
patients, as is NSAID use.56 The relationships between NSAID use, H. pylori infection and
gastric damage are not well understood. NSAID usage does not increase susceptibility to H.
pylori infection but whether a mucosa which has been damaged by H. pylori infection is more
susceptible to the toxic effects of NSAIDs is unclear. Eradication of H. pylori before starting
NSAID therapy reduces the occurrence of gastroduodenal ulcers in patients who have not
previously taken NSAIDs.57 However, another study investigating the effects of H. pylori
eradication in patients with current or previous NSAID-induced ulcers or dyspepsia who
continued to use NSAIDs found that H. pylori eradication did not alter the outcome in terms of
ulcer recurrence or dyspepsia.58
COX-2 is induced by gastric injury, and gastritis caused by H. pylori is associated with COX-2
expression not only in mononuclear cells, but also parietal cells and gastric epithelium.59, 60
Eradication of H. pylori leads to reduced expression of COX-2 in the gastric epithelium, but
levels remain elevated and are strongly correlated with the severity of chronic inflammatory cell
infiltrate.60 The relationship of COX-2 induction in the gut secondary to H. pylori infection
needs further exploration. It was initially hypothesised that COX-2 may play a role in the
immune response against H. pylori since COX-2 is expressed around the rim of the ulcer, and
in animal studies, COX-2 inhibition retarded ulcer healing.61 Recent studies have highlighted
the importance of both COX isoforms in the formation of new capillary blood vessels
(angiogenesis).62 Angiogenesis is essential for wound and ulcer healing, and also for the growth
and metastasis of solid tumours. This action of COX-2-selective NSAIDs accounts for their
activity in the prevention of colon and other cancers.63-67 However it also suggests these agents
should be used with caution in patients with active GI ulcers.
3.3 The kidney
Adverse renal effects occur in approximately 5% of patients who are taking NSAIDs, and
advanced age is a primary risk factor in these individuals. PG’s synthesised by the kidneys affect
haemodynamics and sodium and water metabolism. PGI2, PGE2 and PGD2 dilate the glomerular
arterioles and enhance renal perfusion.68 PGE2 and PGF2 have diuretic and natriuretic effects
since they inhibit sodium reabsorption at the thick ascending limb of the loop of Henle.69
Despite these many actions, PGs modulate but do not maintain normal renal blood flow in
healthy individuals.
However, PG production becomes important in maintaining blood flow and glomerular
filtration in the compromised kidney.70, 71 This is particularly important in patients with
congestive heart failure, liver cirrhosis, compromised renal function or when diuretics are
administered concomitantly (hypovolaemic subjects).72-74 In individuals with these clinical
conditions, renal function is highly dependent upon local production of PGE2 within the kidney
to offset the vasoconstrictor effects of high concentrations of angiotensin, vasopressin and
catecholamines that result from the activation of pressor reflexes. Inhibition of PG synthesis by
NSAIDs in these patients can lead to sodium and water retention and weight gain, and can also
precipitate acute renal failure when reduced PG synthesis leads to unopposed vasoconstriction.2,
73
Renin release is also partially controlled by PGI268 and inhibition of PG synthesis by NSAIDs
can occasionally affect the renin-angiotensin-aldosterone system leading to a reduction in
aldosterone secretion. In patients with renal impairment, especially those treated with agents
that increase serum potassium levels (for example, potassium sparing diuretics, potassium
supplements, ACE inhibitors and angiotensin II receptor antagonists), this can lead to
hyperkalaemia.73, 75
3.3.1 COX-2 expression in the kidney
The role of COX-2 in generating PGs in the kidney is complex and still being defined. In the
adult human kidney, constitutive expression of COX-2 protein and mRNA is detectable in
endothelial and smooth muscle cells of arteries and veins and intraglomerularly in podocytes.11
Studies in the rat have demonstrated that high levels of COX-2 can be induced in the kidney in
response to appropriate stimuli. Salt restriction alters the intra-renal distribution of COX-2 and
dramatically upregulates its expression in the macula densa and surrounding cortical thick
ascending limb.76 There may also be important feedback loops between the renin-angiotensin
system and renal expression of COX-2. For example, administration of a selective COX-2
inhibitor blocked increases in renal renin production in response to a low-salt diet or after
administration of ACE inhibitors,77, 78 and administration of ACE inhibitors led to increased
COX-2 expression in the macula densa of rats on control or low sodium diets.78
In a study assessing the influence of COX inhibition on renal function in young, healthy and
salt-depleted males, celecoxib was found to cause Na+ and K+ retention. These are early clinical
features of renal dysfunction induced by NSAIDs in hypovolaemic patients. Conversely
rofecoxib had minimal effects on renal function in healthy, elderly patients with normal renal
function (defined as creatinine clearance > 50mL/min or serum creatinine < 2mg/dL) and a high
intake of dietary sodium (200mEq/day). These data support the findings in animals which
suggest that COX-2 expression may be important in the physiological response to a low sodium
diet.
An important role of COX-2 in kidney function and development is suggested by studies
utilising COX knockout mice. COX-2 homozygous knockout (-/-) mice show severe renal
pathology which progressively deteriorates with age 79, 80, but the kidneys of COX-1
homozygous (-/-) knockouts show only minor abnormalities even at 5 months of age.81
3.4 Blood clotting
The endothelial cells which line the circulatory tree serve as a barrier between flowing blood
and the vessel wall, and actively elaborate antithrombotic factors such as PGI2 and nitric oxide
which maintain fluidity of blood. PGI2 derived from endothelial cells effects relaxation of
vascular smooth muscle cells, and also blocks platelet activation when released into the
bloodstream. At sites of vascular injury the antithrombotic properties of the endothelium is lost,
and the platelets are exposed to thrombotic substances that lead to platelet activation. Activated
platelets release ADP and TXA2. ADP leads to the activation of other platelets. TXA2 which is
the major product of arachidonate metabolism in platelets is a powerful inducer of platelet
aggregation and a potent vasoconstrictor.
Platelets do not have nuclei and therefore cannot produce inducible COX, so COX-1 is the only
isoform detectable in the these cells. Inhibition of COX-1 is the aim of ‘half an aspirin a day’
prophylaxis against thromboembolic disease, and is achieved by decreased production of TXA2.
Within 2 hours of a single dose of aspirin, COX-1 is irreversibly inhibited for the life of the
platelet in the circulation (8-10 days). PGI2 production by endothelial cells is also temporarily
decreased, but COX-1 in these cells can regenerate within hours, so PGI2 synthesis is
reestablished.2, 82
Although PGI2 is a potent vasodilator and inhibitor of platelet activation, its role in the intact
organism has remained speculative in the absence of an antagonist of the PGI2 receptor.
However, mice deficient in the IP- receptor (the receptor through which PGI2 mediates its
effects) suggest an important role for PGI2 in mediating inflammation and preventing
thrombosis.83 Furthermore, a recent study by McAdam and coworkers suggests that COX-2
may play a major role in the biosynthesis of both systemic and renal PGI2 under physiological
conditions.84 In this study, celecoxib (doses up to 800mg), rofecoxib and ibuprofen (800mg) all
suppressed excretion of the metabolite of PGI2. However, only ibuprofen significantly inhibited
TXB2 formation ex vivo. This study was conducted in young, healthy volunteers and it remains
to be determined whether these effects are sustained during chronic dosing in patients at risk
for cardiovascular disease.
3.5 Gestation and parturition
Both COX-1 and COX-2 are involved in reproduction. COX-2 is important in rupture of the
follicle during ovulation, and implantation of the embyro in the uterine endometrium.15 PGs are
expressed in the uterine epithelium, and can lead to contraction of uterine smooth muscle. They
are important for inducing uterine contractions during labour, and NSAIDs can therefore
increase the duration of gestation and delay premature labour.85 However, they are rarely used
for this purpose, since in the foetus, PGs maintain the patency of the ductus arteriosis. NSAIDs
can therefore lead to premature duct closure and disruption of fetal circulation.86
The significance of COX in reproduction is supported by studies in knockout mice. COX-2
knockout mice are infertile, and COX-1 knockout mice have few live births when female
homozygotes are mated to male homozygotes.79, 81
4. Drug interactions
Celecoxib is metabolised to inactive metabolites via CYP2C9. Drugs known to inhibit this
isoenzyme should be coadministered with caution due to the potential risk of increasing the
plasma concentration of celecoxib.
Although not involved in its metabolism, celecoxib is an inhibitor of CYP2D6, and hence has
the potential to cause an interaction resulting in the elevation of plasma concentrations of any
drugs metabolised via this isoenzyme.
Table5. Drug interactions involving celecoxib
5, 87, 88
Drug involved in interaction
Mechanism and result of interaction
Inhibitors of CYP2C9:
amiodarone, cimetidine,
fluoxetine, zafirlukast,
fluconazole, fluvastatin,
fluvoxamine, metronidazole
ACE inhibitors, angiotensin II
receptor antagonists
Elevated plasma concentration of celecoxib. Two fold
increase in celecoxib plasma concentration with
coadministration of fluconazole.
Frusemide and thiazides
Lithium
Antacids
Warfarin
Substrates of CYP2D6: betablockers (metoprolol,
propanolol), certain
antidepressants (amitriptyline,
desipramine, clomipramine,
fluoxetine, paroxetine,
venlafaxine), perhexiline and
antipsychotics (haloperidol,
risperidone, thioridazine)
Codeine and oxycodone
Coadministration of celecoxib may diminish the
antihypertensive effect of ACE inhibitors, potential to
induce acute renal impairment in patients who are
renally compensated.
Inhibition of renal prostaglandins by celecoxib may
reduce the natriuretic effect.
Increased lithium plasma levels by 17%, monitor
closely.
Coadministration of aluminium and magnesium
containing antacids reduce plasma concentration of
celecoxib due to impaired oral bioavailability.
Increased prothrombin time and bleeding events
reported, predominantly in elderly patients on
warfarin and celecoxib, monitor carefully 8 9
Increased plasma concentration of substrates due to
inhibition of metabolism by celecoxib.
Potential for the conversion of codeine to morphine
and oxycodone to oxymorphone via CYP2D6 to be
inhibited by celecoxib, some patients may experience
a decrease in pain relief from codeine and oxycodone
preparations.
Cytochrome P450 enzymes play a minor role in metabolism of rofecoxib, which is mainly
metabolised in the liver by reduction and then excreted in the urine. There are a number of
drug interactions when rofecoxib is coadministered with other agents. Concomitant
administration of antacids led to a 20% decrease in serum concentrations of rofecoxib.
Concomitant administration of rifampicin decreases rofecoxib plasma concentrations by 50%.
Plasma concentrations of methotrexate are increased by a mean of 23% when administered
with rofecoxib, and plasma concentrations of lithium are also increased by rofecoxib.
Rofecoxib taken with warfarin resulted in a 10% increase in prothrombin time. The mechanism
of these interactions is unknown, but therapy with these agents should be carefully monitored
in patients who are taking rofecoxib. Rofecoxib also may decrease the anti-hypertensive effect
of ACE inhibitors.5, 90, 91
5. Published trials of efficacy and adverse effects with celecoxib and rofecoxib.
This section reviews published efficacy studies and adverse event studies for celecoxib and rofecoxib, and makes recommendations on dosage in RA
and OA. Both celecoxib and rofecoxib were approved for use by TGA when full details of studies comparing the active drug to placebo or other
NSAIDs were available only in abstract form, making critical appraisal and assessment by independent reviewers extremely difficult. The experience
in other countries has been similar (see http://www.ti.ubc.ca/pages/letter31/htm). Several studies have now appeared in the literature, and in this
section, efficacy studies with celecoxib and rofecoxib are reviewed. When the details of phase III studies are available, data from phase 2 studies is
not presented. Some additional data is also presented from the approved product information for both drugs.
5.1. Efficacy studies
5.1.1 Efficacy studies with celecoxib
Celecoxib has been approved for use in Australia for the management of pain associated with osteoarthritis (OA) and rheumatoid arthritis (RA) in
adults. In OA, celecoxib at doses of 100mg bd and 200mg bd provides significant reduction in pain associated with OA compared with placebo.
When compared with naproxen 500mg bd, celecoxib 100mg bd is as efficacious as higher doses. Hence, the recommended dose of celecoxib in OA
is 100mg bd with or without food.
In RA, celecoxib 100mg bd and 200mg bd provides a significant reduction in pain and inflammation compared to placebo. These doses are equally
efficacious and comparable to naproxen 500mg bd or diclofenac SR 75mg bd, although the product information reports that some patients derived
additional benefit with 200mg bd.
Table 6. Published efficacy trials with celecoxib
Patients
Design/Age
Exclusions
Dur-ation
Main efficacy measures
OA, knee
Multicentre,
randomised,
double-blind
placebo &
active
controlled
trial
Patients with
NSAID or
sulphonamide
sensitivity
excluded
malignancy
active renal GI
hepatic or
coagulation
disorders;
oesophageal or
gastroduodenal
ulceration in
previous 30 days
12 weeks
1. patient and physician’s
global assessment of OA;
2. WOMAC†;
3. patient’s assessment of
OA pain on a VAS¶
4. OA severity index
Mean 62-3 yo
(assessed
wks 2,6
& 12)
Drug &
Dose
50mg bd
100mg bd
200mg bd
n
203
197
202
Better
than
n
204
placebo
placebo
Comp-arable
to
Naproxen
500mg bd
n
198
Significant
Adverse Effects*
Most common
events were GIT
symptoms , and
these were
similar amongst
all groups
One patient in
naproxen group
had a bleeding
ulcer, one
patient in
celecoxib 50mg
group had an
ulcer
OA, knee
RA
Notes
Reference
50mg celecoxib
minimally
effective
compared to
higher
celecoxib doses
or naproxen
Bensen, W. G., et al.
(1999). Treatment of
osteoarthritis with
celecoxib, a
cyclooxygenase-2
inhibitor: A randomized
controlled trial. Mayo
Clinic Proceedings.
74:1095-1105
Higher doses
were of
comparable
efficacy to each
other and to
naproxen
Identical to
previous study
Multicentre,
randomised,
double-blind
placebo &
active
controlled
trial
Mean 54-5 yo
continued next page
active renal GI
hepatic or
coagulation
disorders;
malignancy,
oesophageal or
gastroduodenal
ulceration in
prev. 30 days or
if baseline
endoscopy
showed ulcers or
> 10 erosions
12 weeks
(assessed
wks 2,6 &
12)
1. patient and physician’s
global assessment of
arthritis
2. patients assessment of
arthritis pain on a VAS
3. count of painful/tender
joints
4. count of swollen joints
5. duration of morning
stiffness
6. functional disability
index questionnaire
7. Cp C-reactive protein
100mg bd
200mg bd
400mg bd
240
235
218
placebo
*
placebo
placebo
*
patient
but not
physician
global
assessment
231
Naproxen
500mg bd
225
See table 2.1 for
GI adverse events
No adverse renal
effects.
0-2% incidence
of fluid retention
& hypertension
in all groups
all celecoxib
doses were
similarly
efficacious
Supported in part by
Searle
Zhao, S. Z., et al. (1999).
Evaluation of the
functional status aspects
of health-related quality
of life of patients with
osteoarthritis treated
with celecoxib.
Pharmacotherapy.
19:1269-1278
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. 282:19211928
Supported by Searle
Table 6. Published efficacy trials with celecoxib
RA
randomised,
double-blind
parallel
activecontrolled
trial
Mean 54-55yo
OA, knee
and hip
RA
Placebo and
active
controlled
clinical trials
up to 12
weeks
duration.
Approx. 4200
patients
Placebo and
active
controlled
clinical trials
up to 24
weeks
duration.
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, COX2-selective
NSAIDs or
sulphonamide,
any abnormal
clinical or
laboratory values
pretreatment
+others (see
study)
24 weeks
(assessed
wks 4, 8,
12, 16,20
& 24)
326
Diclofenac
SR
75mg bd
329
continued
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 doubleblind comparison.
Lancet. 354: 2106-2111
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
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)
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)
Supported by Searle
Approx. 2100
patients
*
Studies in efficacy section - were included again in the Side effects section if the title of the article made a specific reference to side effect profile
†
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 efficacy trial; 4 week RA efficacy trial; 1 week endoscopic study of GI mucosal effects and a 1 week study of effects on platelet function.
5.1.2 Efficacy 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
significantly 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 efficacy trials with rofecoxib
Patients
Design/Age
Exclusions
Dur-ation
Main efficacy measures
OA,
knee
Randomised
placebo
controlled trial
Previous
gastric/duodenal
ulceration; history of
GI bleeding; renal
impairment,
diabetes, history of
cardiovascular,
hepatic, neurological
neoplastic or
coagulation disorder
6 weeks
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
Mean 63.5yo
RA
Phase II
Randomised,
double-blind
placebo
controlled trial
Mean 54-55yo
OA,
knee or
hip
Six randomised
clinical trials of
rofecoxib
lasting from 6
to 86 weeks.
4035 patients
including
approx. 400 pts
>80yo
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
(assessed
1,2,4 & 6
wks)
8 weeks
(assessed
2,4 & 8
weeks)
Drug &
Dose
25mg od
125mg od
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
Signs and symptoms of OA
1.25mg od
25mg od
Joint space narrowing at one
year (compared to diclofenac
only)
n
73
74
158
171
161
Better
than
Placebo
Placebo
n
Comparable
to
72
n
Significant
Adverse Effects
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
No clinically
significant
oedema or
hypertension.
No serious GI
effects
168
Notes
Reference
Both doses of
rofecoxib were
superior to
placebo from
1wk (1st
assessment) for
duration of study
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
125mg is 5 times
the maximum
recommended
dose for
treatment of OA
25 and 50mg
rofecoxib
significantly
better than
placebo. 5mg
not significantly
different to
placebo.
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
Rofecoxib Groups
well matched for
age and sex
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 efficacy, not drug safety.. Drug side effects can be classified 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 drug’s adverse effects profile 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 nonselective 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 significant 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 defined 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 reflect 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 difficulty 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 significantly 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
figures 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), fluid 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 filtration rate (GFR) and renal blood
flow and significantly 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 significantly 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 difficult to comment on the significance of these studies and their
relevance to renally impaired elderly patients who may not be able to tolerate chances in fluid volume. In healthy volunteers, both celecoxib and
rofecoxib can decrease renal biosynthesis of PGI2. It may therefore be predicted that problems with fluid 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 flow. 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 PGI2.84 The significance 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
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
12 week randomised, double-blind
placebo & active controlled trial of
patients with RA
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 celecoxibtreated patients and 26% of naproxentreated patients. Few of the ulcers were
symptomatic. 1 naproxen-treated
patient developed two ulcers creating a
partial gastric outlet obstruction.
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
Results and Comment
Very small study to detect rare GI events.
Supported by Searle
Rossat, J. et al. (1999).
Renal effects of selective
cyclooxygenase-2 inhibition
in normotensive saltdepleted subjects. Clinical
Pharmacology and
Therapeutics. 66:76-84
Sponsored by Searle
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
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
7 day randomised, double blind trial
of 40 healthy young male volunteers
(Mean age 24.8yo).
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.
Celecoxib 200mg bd
212
Diclofenac SR
75mg bd
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.
Gastrointestinal adverse events were
reported in 48% of patients taking
diclofenac and 36% of patients taking
celecoxib.
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
The respective incidences of gastric and
duodenal ulcers were 34% and 11% for
patients on diclofenac, and 18% and 5%
for patients on celecoxib.
Platelet aggregation ex vivo,
Serum TXB2 levels,
Whole blood monocyte COX-2 activity
and
Urinary metabolites of systemic and
renal prostacyclin biosynthesis (2,3dinor-6-keto PGF1 and 6-keto PGF1
respectively)
Celecoxib didn’t affect platelet
aggregation, but had a significant
inhibitory effect on serum TXB2 4hrs after
dosing.
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
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-2selective NSAIDs or sulphonamide,
any abnormal clinical or laboratory
values pretreatment +others
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
5 GI events required hospitalisation of
patients on diclofenac. These included
one ulcer.
Haemoglobin levels were lower in
diclofenac-treated patients
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
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
Pooled analysis of patients from 8
phase 2b/3 trials of rofecoxib for
OA
Placebo
Rofecoxib (12.5, 25 and 50mg
od)
NSAID (ibuprofen 800mg tds,
diclofenac 50mg tds or
nambumetone 1500mg od)
514
3357
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.
Placebo (ceased after wk 16)
Rofecoxib 25mg od
Rofecoxib 50mg od
Ibuprofen 800mg tds
177
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.
Incidence of 3 and 5mm ulcers significantly lower in
rofecoxib-treated groups compared to ibuprofen.
Supported by Merck & Co.
Inc.
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
Lanza, F. L. et al. (1999).
Specific inhibition of
cyclooxygenase-2 with MK0966 is associated with less
gastroduodenal damage
than either aspirin or
ibuprofen. Alimentary
Pharmacology and
Therapeutics. 13:761-7
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
See article for details of trials.
Both active and placebo
controlled trials used.
6 month randomised doubleblind 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.
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.
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.
1564
195
186
184
Adverse experiences analysed by life table
method and log-rank test
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.
Results and Comment
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 age≥65y,
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
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.
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.
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 Nacetyl-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 TXA2 metabolites in
addition to renal and external PGI2 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.
TXA2 biosynthesis by platelets was affected by
indomethacin only.
Urinary excretion of renal and systemic metabolites of
PGI2 were significantly decreased compared to baseline
after treatment with rofecoxib and indomethacin.
6. Conclusions.
Celebrex® and Vioxx® are not more effective as antiinflammatory agents than existing NSAIDs,
although they have a slightly different adverse event profile. Randomised, double-blind,
controlled trials have demonstrated a decreased incidence of gastric and duodenal ulceration
compared to non selective NSAIDs. Patients with existing ulcers have largely been excluded
from these published trials, but some trials have allowed enrolment of patients with a history of
peptic or duodenal ulcers, and amongst these patients there did not appear to be an increased
incidence of GI injury. As such, COX-2-selective NSAIDs appear to be drugs of choice for
patients with gastric sensitivity to non-selective NSAIDs, and provide new options for patients
who could not tolerate non-selective NSAIDs. COX-2-selective NSAIDs seem also to be an
appropriate option for elderly patients (over the age of 65 years) with RA or OA who at high
risk for adverse GI events with non-selective NSAIDs. Further trials are required to investigate
the impact of H. pylori infection in patients who are treated with COX-2-selective NSAIDs, as
is investigation into the role and efficacy of gastroprotective agents in combination with COX2-selective NSAIDs.
COX-2-selective NSAIDs can lead to other problems in certain groups of patients, but it seems
as though the same cautions apply as for traditional NSAIDs. For example, care should be
exercised in prescribing COX-2-selective NSAIDs for patients with renal insufficiency, cardiac
disease and thromboembolic disease. The drugs are contraindicated in pregnancy and in
patients with aspirin-sensitive asthma.
Because of the improved GI safety profile of these agents, there seems to be an assumption that
these agents will be ‘safer’ drugs. In support of this, ADRAC has more than 300 reports
describing adverse reactions to celecoxib in the first 3 months after marketing, and most of
these events have been documented in clinical trials and described in the product information.
The improved GI safety profile of celecoxib has formed the basis of the advertising campaign in
this country, and this seems to have impacted on public and prescriber perceptions of the
adverse event profile. (For a discussion of the issues involved in the promotion of drugs see
http://www.camtech.net.au/malam and for a specific discussion of the advertising of celecoxib
see http://www.camtech.net.au/malam/Inter.htm.) It is almost certain that adverse effects other
than those reported in clinical trials will emerge as more people take these drugs. Prescribers
who use these agents need to aware of the potential for adverse effects which may be new and
rare events, and report these events to ADRAC.
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