Aceclofenac A Reappraisal of Its Use in The.12

ADIS DRUG EVALUATION
Drugs 2001; 61 (9): 1351-1378

0012-6667/01/0009-1351/$27.50/0
Adis International Limited. All rights reserved.
Aceclofenac
A Reappraisal of its Use in the Management
of Pain and Rheumatic Disease
Mukta Dooley, Caroline M. Spencer and Christopher J. Dunn
Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by:
G.S. Alarcn, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham,
Birmingham, Alabama, USA; A. Crema, Department of Internal Medicine and Therapeutics, University of
Pavia, Pavia, Italy; A. Gause, Rheumaklinik Bad Bramstedt, Bad Bramstedt, Germany; N. Lane, Division of
Rheumatology, San Francisco General Hospital, San Francisco, California, USA; J.-P. Pelletier, Unit des
Maladies Rheumatismales, Hpital Notre-Dame, Montreal, Quebec, Canada; F. Perez-Ruiz, Seccin de
Rheumatologia, Hospital de Cruces, Pais Vasco, Spain; R. Yamazaki, Yakult Central Institute for Microbiology
Research, Tokyo, Japan.
Data Selection
Sources: Medical literature published in any language since 1966 on aceclofenac, identified using AdisBase (a proprietary database of Adis
International), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical
information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: AdisBase search terms were aceclofenac and pain. Medline and EMBASE search terms were aceclofenac and
biofenac. Searches were last updated 25 Jun 2001.
Selection: Studies in patients with pain who received aceclofenac. Inclusion of studies was based mainly on the methods section of the
trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and
pharmacokinetic data are also included.
Index terms: Aceclofenac, NSAID, pain, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pharmacodynamics, pharmacokinetics,
therapeutic use, tolerability, dosage and administration, review.
Contents
Summary
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Overview of Osteoarthritis, Rheumatoid Arthritis and Ankylosing Spondylitis
2. Overview of Pharmacodynamic Properties . . . . . . . . . . . . . . . . . .
2.1 Effects on Mediators of Inflammation and Cartilage Matrix . . . . . .
2.1.1 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.2 Ex Vivo Studies in Patients Receiving Aceclofenac . . . . . . . .
2.2 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Overview of Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . .
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . .
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . .
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3 Ankylosing Spondylitis . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4 Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5 Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . .
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1352
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Dooley et al.
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1 General Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2 Gastrointestinal Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Place of Aceclofenac in the Management of Pain and Rheumatic Disease
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Summary
Abstract
Aceclofenac is an orally administered phenylacetic acid derivative with effects

on a variety of inflammatory mediators. Through its analgesic and anti-inflammatory properties, aceclofenac provides symptomatic relief in a variety of painful
conditions. In patients with osteoarthritis of the knee, the drug decreases pain,
reduces disease severity and improves the functional capacity of the knee to a
similar extent to diclofenac, piroxicam and naproxen. Aceclofenac reduces joint
inflammation, pain intensity and the duration of morning stiffness in patients with
rheumatoid arthritis, and is similar in efficacy to ketoprofen, diclofenac, indomethacin and tenoxicam in these patients.
The duration of morning stiffness and pain intensity are reduced, and spinal
mobility improved, by aceclofenac in patients with ankylosing spondylitis, with
improvements being similar to those observed with indomethacin, naproxen or
tenoxicam. Aceclofenac is also effective in other painful conditions (e.g. dental
and gynaecological). In contrast to some other NSAIDs, aceclofenac has shown
stimulatory effects on cartilage matrix synthesis.
Aceclofenac is well tolerated, with most adverse events being minor and reversible, and affecting mainly the GI system. Although the incidence of GI adverse events with aceclofenac was similar to those of comparator NSAIDs in
individual clinical trials, withdrawal rates due to these events were significantly
lower with aceclofenac than with ketoprofen and tenoxicam. Superior overall
and/or GI tolerability of the drug relative to other NSAIDs has been indicated by
a nonrandomised comparison with sustained release diclofenac in 10 142 patients, a meta-analysis of 13 comparisons with diclofenac, naproxen, piroxicam,
indomethacin, tenoxicam or ketoprofen in 3574 patients, and preliminary details
of a comparison with 10 other NSAIDs in 142 776 patients. Further analysis of
the above meta-analytical data has indicated that costs incurred as a result of
adverse event management are lower with aceclofenac than with a range of comparator NSAIDs.
Conclusions: Trials of 2 to 6 months duration have shown aceclofenac to be
an effective agent in the management of pain and rheumatic disease. Data from
in vitro studies indicate properties of particular interest with respect to cartilage
matrix effects and selectivity for cyclo-oxygenase2. Aceclofenac is well tolerated, with encouraging reports of improved general and GI tolerability relative
to other NSAIDs from a meta-analysis of double-blind trials and from large nonblind studies.
Overview of
Pharmacodynamic
Properties
Aceclofenac has been shown to exert effects on a variety of mediators of inflammation. The drug inhibits synthesis of the inflammatory cytokines interleukin
(IL)-1 and tumour necrosis factor, and inhibits prostaglandin E2 (PGE2) production. Effects on cell adhesion molecules from neutrophils have also been noted.
Aceclofenac did not affect IL-6 synthesis in 1 ex vivo study, but significantly
Drugs 2001; 61 (9)
Aceclofenac: A Reappraisal
1353
decreased basal and IL-1stimulated production of this mediator in human

chondrocytes in vitro. In another ex vivo study, aceclofenac did not affect the
production of leukotriene B4, but a decrease in the stimulated production of
reactive oxygen species was observed after 15 (but not 180) days of treatment
with aceclofenac 100mg twice daily. The inhibitory effects of aceclofenac on
synovial levels of PGE2 have been confirmed in patients with acute knee pain
and synovial fluid effusions. In vitro data indicate inhibition of cyclo-oxygenase
(COX)-1 and -2 by aceclofenac in whole blood assays, with selectivity for COX-2
being evident.
In contrast to some other NSAIDs, aceclofenac has shown stimulatory effects
on cartilage matrix synthesis that may be linked to the ability of the drug to inhibit
IL-1 activity. In vitro data indicate stimulation by the drug of synthesis of
glycosaminoglycan in osteoarthritic cartilage. There is also evidence that
aceclofenac stimulates the synthesis of IL-1 receptor antagonist in human articular chondrocytes subjected to inflammatory stimuli, and that 4-hydroxyaceclofenac has chondroprotective properties attributable to suppression of
IL-1mediated promatrix metalloproteinase production and proteoglycan release.
In studies in rodents, aceclofenac alleviated induced pain and hyperthermia;
the ulcerogenic potential of the drug was less than that of indomethacin or
naproxen, and less than or similar to that of diclofenac. Although statistical analyses were not consistently available, faecal bleeding and endoscopy studies in
humans have indicated overall less GI bleeding and GI mucosal damage with
aceclofenac 100mg twice daily than with naproxen 500mg twice daily or
diclofenac 50mg 3 times daily. The incidence of endoscopically evident GI mucosal damage was significantly (p < 0.05) lower after aceclofenac 75mg twice
daily than after diclofenac 25mg 3 times daily in a 2-week randomised, doubleblind study in 30 healthy volunteers.
Overview of
Pharmacokinetic
Properties
Aceclofenac is rapidly and completely absorbed after oral administration, with

peak plasma concentrations (Cmax) being reached 1.25 to 3 hours after ingestion.
The volume of distribution (Vd) is approximately 25L, and the drug is highly
protein-bound (>99%) in plasma.
Maximum plasma concentrations (Cmax) of aceclofenac and times to Cmax
(tmax) are similar after single (100mg) and multiple (100mg twice daily for 7 days)
oral doses: in 1 study in 12 young and 12 elderly volunteers, mean Cmax values
ranged from 8.94 to 9.86 mg/L and were achieved in 1.08 to 1.37 hours. Areas
under plasma drug concentration versus time curves (AUCs) were increased over
those seen after single doses in young individuals and decreased in the elderly
after multiple doses. No significant differences were observed between young
and elderly volunteers in Cmax, absorption half-life or Vd values. The presence
of food reduced the rate (increased tmax value) but not the extent (Cmax or AUC)
of absorption in trials in young volunteers. The plasma concentration of
aceclofenac was approximately twice that in synovial fluid after multiple doses
of the drug in patients with knee pain and synovial fluid effusion.
Aceclofenac is metabolised to a major metabolite, 4-hydroxyaceclofenac, and
a number of minor metabolites including 5-hydroxyaceclofenac, diclofenac, 4hydroxydiclofenac and 5-hydroxydiclofenac. The drug is eliminated mainly via
the renal route, with a plasma elimination half-life (t12) of approximately 4 hours.
In 1 trial, the t12 of aceclofenac was similar after single and multiple doses in
Drugs 2001; 61 (9)
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Dooley et al.
elderly volunteers (2.69 and 3.08 hours, respectively), but was increased after
multiple doses (from 3.52 to 4.65 hours; p = 0.017) in young participants. Both
t12 values were significantly shorter in elderly than in young volunteers.
Therapeutic Efficacy
Aceclofenac (administered orally unless stated otherwise in all clinical studies

discussed in this review) decreases pain, reduces the severity of osteoarthritis and
improves the functional capacity of the affected joint in patients with osteoarthritis of the knee. The drug was similar in efficacy to diclofenac, piroxicam and
naproxen in randomised, double-blind trials in 49 to 378 patients. Aceclofenac
(100mg twice daily for 1 to 6 months) significantly reduced pain levels (expressed
on a visual analogue scale), Lequesne Osteoarthritis Severity Index/Severity Index of Gonarthritis and knee function scores, improved the ability to extend and
flex the affected knee, and significantly increased numbers of patients with an
improvement in signs and symptoms according to investigators and patients
assessments. In 1 trial, paracetamol (acetaminophen) consumption in the first 2
weeks was significantly lower, and patient-perceived pain intensity significantly
less, with aceclofenac than with diclofenac. Furthermore, in this trial, the improvement in knee flexion in patients initially unable to straighten the knee was
greater after aceclofenac than diclofenac during, but not at the end of, the 3-month
study period.
In a nonblind trial, aceclofenac decreased pain, Severity of Gonarthritis Index
scores and paracetamol consumption to a similar extent to nabumetone 1 to 2g
daily after 12 weeks in 274 patients with osteoarthritis.
The anti-inflammatory and analgesic efficacy of aceclofenac is similar to that
of ketoprofen, indomethacin, tenoxicam and diclofenac in patients with rheumatoid arthritis. In randomised, double-blind trials in 169 to 261 patients,
aceclofenac (100mg twice daily for 3 or 6 months) significantly reduced relative
to baseline joint inflammation, pain intensity and the duration of morning stiffness, and improved hand grip strength. Improvements from baseline in functional
capacity were reported in 27% of patients receiving aceclofenac or indomethacin
in 1 trial in which this end-point was assessed, and both aceclofenac and
ketoprofen improved functional capacity statistically significantly (p < 0.01) in
1 other study.
Aceclofenac reduces pain and morning stiffness and improves mobility of the
spine to a similar extent to indomethacin, tenoxicam and naproxen in patients
with active ankylosing spondylitis. These effects were observed after aceclofenac
100mg twice daily for 3 months in randomised, double-blind trials involving 104
to 308 patients. In addition, emergency paracetamol use was similar with all
agents. In a comparison with naproxen, both agents significantly reduced numbers of patients with moderate or severe pain on movement or at rest (by 55 to
79%; p < 0.05 vs baseline), and increased numbers of patients with no or mild
pain and no or slight limitation of movement. The number of patients with moderate or severe limitation of movement decreased from baseline by 92% after
treatment with aceclofenac.
In general, the time of onset of action of aceclofenac appears similar to that
of comparator agents. In the above trials, significant improvements in symptoms
versus baseline were generally apparent by the time of the first assessment at 2
weeks. Withdrawal rates because of lack of efficacy were also similar between
aceclofenac and comparator drugs [although the rate was lower with aceclofenac
Drugs 2001; 61 (9)
1355
than with ketoprofen in a study in 169 patients with rheumatoid arthritis (4.6 vs
13.4%; p < 0.05)].
The analgesic efficacy of aceclofenac has been shown in comparisons with
placebo in patients with moderate to severe dental pain and in comparisons with
paracetamol in women undergoing episiotomy. Aceclofenac (150mg intramuscularly for 2 days, then 100mg orally, both twice daily) was superior to diclofenac
(75mg twice daily intramuscularly for 2 days, then 50mg 3 times daily orally) in
alleviating functional impairment in a 7-day study in 100 patients with acute
lumbago; lower back pain decreased progressively from baseline (p < 0.01) with
both treatments, and the physicians overall assessment of efficacy was good or
better in more than 85% of aceclofenac and 76% of diclofenac recipients (p <
0.05). Data from noncomparative studies suggest benefit in patients with dysmenorrhoea and in patients with musculoskeletal trauma, although the lack of
control groups in these trials limits the scope of any conclusions.
Pharmacoeconomic data derived from 12 of 13 studies (3239 patients) included in a meta-analysis of randomised, double-blind studies have indicated
aceclofenac 200 mg/day to be associated with overall daily costs of treatment
similar to those of a range of other NSAIDs (direct costs only for a 3-month period
from the perspective of a healthcare provider), despite its acquisition cost. This
observation was attributed to reductions in costs associated with the management
of adverse events and substitution of alternative treatments in patients receiving
aceclofenac relative to recipients of diclofenac, indomethacin, naproxen, tenoxicam or ketoprofen.
Tolerability
Most adverse events reported after aceclofenac are mild and reversible and primarily involve the GI system. Most common events include dyspepsia and abdominal pain (5% incidence). Dizziness, vertigo, pruritus, rash and dermatitis
have been reported with aceclofenac, but the incidence of these events is low
(<5%).
Aceclofenac has shown a tolerability profile similar to that with placebo in
controlled trials in patients with rheumatoid or osteoarthritis. In individual trials
with active comparators, the overall incidence of non-GI adverse events with
aceclofenac did not differ significantly from those with ketoprofen, piroxicam,
diclofenac or tenoxicam, but was lower than that with naproxen. Withdrawal rates
with aceclofenac were generally similar to those with comparator agents. Incidences of adverse events (overall) were significantly lower after aceclofenac than
indomethacin in 1 trial, but not in a second. In the first study, major events leading
to treatment withdrawal were significantly more frequent in the indomethacin
group, and events affecting the CNS were significantly more common after indomethacin than aceclofenac in the second trial. A meta-analysis of 13
randomised, double-blind trials in a total of 3574 patients with rheumatic disease
has shown patients receiving aceclofenac to be 1.38 times more likely than those
receiving other NSAIDs to be free of adverse events after 3 to 6 months treatment
(p < 0.001). The rate of withdrawal from treatment because of adverse events was
significantly lower with aceclofenac than with other NSAIDs overall in this analysis.
In a large (n = 10 142) nonblind, comparative trial, the overall incidence of
adverse events was significantly lower with aceclofenac than with a sustained
release formulation of diclofenac (p < 0.001) after 12 months treatment; this led
to a lower rate of treatment discontinuation with aceclofenac (p < 0.001). Al-
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Dooley et al.
though CNS events were significantly more frequent with aceclofenac than with
diclofenac (p = 0.007), the incidence was low in both groups (3 and 1.9%, respectively). Other body systems were affected to a similar extent by the 2 drugs.
Incidences of serious adverse events (1.5 and 1.9% for aceclofenac and diclofenac, respectively) did not differ significantly between the 2 treatment groups.
As with other NSAIDs, aceclofenac can elevate circulating levels of hepatic
enzymes. Increases after aceclofenac treatment appear to be broadly similar to
those observed after diclofenac, indomethacin, naproxen, piroxicam or tenoxicam. However, the effect of aceclofenac on hepatic enzymes is difficult to
interpret because many participants in studies in which this effect was examined
were receiving concurrent medication, and some had elevated levels at baseline.
Although GI adverse events were reported with similar frequencies after treatment with aceclofenac or comparator agents, withdrawal rates due to these effects
were significantly lower after aceclofenac than after ketoprofen or tenoxicam in
individual clinical trials. Faecal blood loss was noted in similar numbers of patients receiving aceclofenac or comparator drugs. Nausea, diarrhoea, flatulence,
gastritis, constipation, vomiting and ulcerative stomatitis may also occur with
aceclofenac (<5% incidence).
The incidence of GI adverse events was significantly lower with aceclofenac
than with sustained release diclofenac (p < 0.001) in the nonblind study in 10 142
patients. The meta-analysis of 13 randomised, double-blind studies in 3574 patients indicated that a significantly higher proportion of patients who received
aceclofenac than of those who received other NSAIDs (diclofenac, naproxen,
piroxicam, indomethacin, tenoxicam or ketoprofen) remained free of GI symptoms after 3 or 6 months treatment. Other data from 142 776 Spanish patients
have suggested that aceclofenac is associated with a lower incidence of upper GI
bleeding events than 10 other NSAIDs (demonstration of statistical significance
not included in data analysis).
Increases in blood urea nitrogen and blood creatinine levels have also been
reported with aceclofenac treatment (incidence <5%).
Dosage and
Administration
The recommended dosage of aceclofenac is 100mg twice daily. Although a dosage reduction is generally not needed in elderly patients or in those with mild
renal impairment, monitoring is recommended in such cases. A dosage reduction
to 100mg daily is suggested in patients with hepatic impairment. Aceclofenac
should be given with caution to elderly patients with renal, hepatic or cardiovascular impairment, and to those receiving other medication.
Aceclofenac should not be administered to patients with peptic ulcers or GI
bleeding, moderate or severe renal impairment, sensitivity to aceclofenac or other
NSAIDs, or a history of aspirin (acetylsalicyclic acid)- or NSAID-related allergic
or anaphylactic reactions. The drug is not recommended in pregnant or breastfeeding women.
Renal and hepatic function and blood counts should be monitored during long
term treatment. Persistently elevated hepatic enzyme levels necessitates withdrawal of aceclofenac. Drug interactions associated with the drug are similar to
those seen with other NSAIDs.
Drugs 2001; 61 (9)
1. Overview of Osteoarthritis,
Rheumatoid Arthritis and
Ankylosing Spondylitis
Osteoarthritis is an insidious and progressive
osteoarticular condition that affects mainly the
weight-bearing joints and is seen most commonly
late in life.[1] Although men and women are equally
affected, onset of osteoarthritis is earlier in men.[2]
The prevalence of this condition in the 75- to 90year-old population is about 85%.[3] Osteoarthritis
is characterised by the degeneration of cartilage,
subchondral sclerosis and cyst formation, and osteophyte formation.[1,4] These result in joint pain
and tenderness, limited movement, crepitus, effusion and inflammation, but have no systemic manifestations.[4]
Risk factors associated with the development of
osteoarthritis include increasing age, obesity, female gender, postmenopausal state, occupation
and sporting activities.[4]
It has been proposed that the cytokines interleukin (IL)-1 and tumour necrosis factor (TNF),
which are produced in response to inflammation of
the synovial membrane, play a role in causing the
joint damage associated with osteoarthritis.[5,6] IL1, in particular, may inhibit matrix synthesis and
repair in cartilage.[7,8]
Rheumatoid arthritis is a chronic condition, affecting around 1% of the general population, that
involves synovial proliferation and cartilage destruction.[9] It is characterised by symmetrical inflammation of the peripheral joints in the hands,
feet, wrists, elbows or ankles. The condition is 2 to
3 times more common in women than in men and
usually manifests between the ages of 25 and 50
years. Common signs and symptoms include tenderness of inflamed joints, stiffness lasting more
than 30 minutes after awakening or after prolonged
inactivity, synovial thickening, afternoon fatigue
and malaise, subcutaneous nodules and fever.[2]
For rheumatoid arthritis to be diagnosed, any 4
of the following American College of Rheumatology (ACR) criteria must be present, and the first 4
should have been present for at least 6 weeks:[10]
morning stiffness for at least 1 hour
1357
arthritis of at least 3 joint areas

arthritis of hand joints (wrist, metacarpophalangeal or proximal interphalangeal joints)
symmetrical arthritis
subcutaneous nodules
serum rheumatoid factor (determined by a
method for which the result has been positive in
less than 5% of normal individuals)
radiographic changes (hand x-ray changes typical of rheumatoid arthritis that must include
erosions or unequivocal decalcification).
Ankylosing spondylitis is a disorder of the hyaline cartilage and subchondral bone, which is
characterised by inflammation of the spine and
large peripheral joints. Onset of this condition is
usually between the ages of 20 and 40 years, and
the disease is 3 times more common in men than
in women. A strong familial link has been identified: immediate relatives of patients with ankylosing spondylitis are 10 to 20 times more likely than
the general population to develop this disease. Persistent back pain and morning stiffness are common, and the condition recurs in a cyclical pattern.[2,11] Systemic involvement results in decreased chest expansion, fever, fatigue, anaemia,
anorexia, weight loss, iritis, neurological and cardiovascular effects.[2]
NSAIDs are commonly used in these conditions
to relieve pain and inflammation and to improve
mobility, and are also used in the management of
a variety of other painful conditions (e.g. dysmenorrhoea and dental or musculoskeletal pain). The
orally administered phenylacetic acid derivative
aceclofenac has demonstrated efficacy in various
conditions associated with acute and chronic pain,
and has been previously reviewed in Drugs.[12]
This article updates the previous review, and focuses on the use of aceclofenac in the management
of rheumatic disease and other painful conditions.
2. Overview of
Pharmacodynamic Properties
A summary of the major pharmacodynamic
properties of aceclofenac is presented in table I.
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Dooley et al.
Table I. Overview of pharmacodynamic properties of aceclofenac as identified in in vitro investigations and in studies in animals, healthy
volunteers and patients with rheumatic disease
Model or study type
Effects on mediators of inflammation and cartilage matrix
Anti-inflammatory activity: similar to diclofenac, less than
indomethacin and greater than naproxen or phenylbutazone
Inhibition of production of the inflammatory mediators IL-1a and

tumour necrosis factora
Inhibition of basal and IL-1stimulated IL-6a production
Inhibition of cyclo-oxygenase activity
Inhibition of basal and stimulated prostaglandin E2 production by
blood mononuclear and polymorphonuclear cells, and by synovial
cells, articular chondrocytes and osteoarthritic cartilage
Reduction of stimulated generation of reactive oxygen speciesa
after 15, but not 180, days of treatment
Interference with expression of cell adhesion moleculesa
(implicated in cell migration and inflammation)
Stimulation of glycosaminoglycan synthesis in osteoarthritic
cartilageb by inhibition of actions of IL-1
Suppression of IL-1mediated promatrix metalloproteinase
production and proteoglycan release
Rodent and canine models of acute and chronic inflammation[12]

Ex vivo: blood from patients with osteoarthritis of the knee[5] and
synovial fluid from patients with knee pain and synovial effusions[13]
In vitro: human osteoarthritic synovial cells[6] and human articular
chondrocytes.[14] Ex vivo: patients with osteoarthritis of the knee and
high basal levels of these mediators[5]
In vitro: human articular chondrocytes[14]
In vitro: human synovial cells[15,16] and human articular
chondrocytes[14]
In vitro: human synovial cells,[15] articular chondrocytes[14] and
osteoarthritic cartilage[6]
Ex vivo: patients with osteoarthritis of the knee[5]
In vitro: human neutrophils[17]
In vitro: human osteoarthritic cartilage[7,8]
In vitro: rabbit articular chondrocytes[18] and human rheumatoid
synovial cells[19]
Other effects
Reduction of induced acute pain and fever
Rodent models[20]
Lower ulcerogenic activity according to an index of ulceration than Rodent models[12,21]
diclofenac or indomethacin after single and multiple doses
Induced gastric lesions similar to those with diclofenac as
Rodent models[12,21]
determined by histopathological studies
Less gastroduodenal damage as determined by endoscopy than
Healthy volunteers[22,23] and patients with osteoarthritis[24]
with diclofenac or naproxen after 2 or 4 weeks treatment. Trend
towards less faecal blood loss than after diclofenac for 10 days
a Involved in inflammatory and immune changes in patients with arthritis.
b Synthesis of glycosaminoglycan (a major cartilage protein) reflects cartilage metabolism; increases are associated with maintenance or
stimulation of matrix synthesis and decreases with inhibition of matrix synthesis.
IL = interleukin.
2.1 Effects on Mediators of Inflammation

and Cartilage Matrix
The anti-inflammatory effects of aceclofenac

were originally shown in rodent and canine models
of acute and chronic inflammation (reviewed by
Brogden and Wiseman[12]). Further studies in in
vitro systems and in humans have shown the drug
to exert these effects via a variety of mechanisms.
2.1.1 In Vitro Studies
In in vitro studies, aceclofenac decreased the expression or synthesis of mediators of inflamma Adis International Limited. All rights reserved.
tion, including some cell adhesion molecules from

neutrophils, IL-1, TNF and prostaglandin E2
(PGE2) [table I].[6,14,15,17] In 1 study, the effect of
aceclofenac (2, 4 or 8 mg/L) on TNF production
(inhibited by a mean of 46% after all 3 doses) and
IL-1 synthesis (inhibited by 35 to 49%) in osteoarthritic synovial membranes was similar to that of
diclofenac (125 or 250 g/L) and was not related
to drug concentration.[6] In a more recent investigation in human articular chondrocytes, aceclofenac inhibited basal IL-6 production at a concentration of 30 mol/L and IL-1stimulated IL-6
Drugs 2001; 61 (9)
production at concentrations of 1 to 30 mol/L.[14]

At concentrations of 6 and 30 mol/L, 4-hydroxyaceclofenac and diclofenac (both metabolites of
aceclofenac; see section 3.2) caused significantly
greater inhibition of both basal and IL-1stimulated IL-6 production than aceclofenac in this
study. Neither aceclofenac nor diclofenac had any
effect on IL-8 production in these chondrocyte cultures, whereas a small reduction in this parameter
was seen with the highest concentration (30
mol/L) of 4-hydroxyaceclofenac. Aceclofenac
had no effect on IL-1 or lipopolysaccharide
(LPS)-stimulated nitric oxide production, but 30
mol/L of 4-hydroxyaceclofenac inhibited both,
whereas diclofenac inhibited LPS-stimulated production of nitric oxide only.[14]
Both aceclofenac and diclofenac inhibited the
production of PGE2 by more than 90% in osteoarthritic synovial membranes and cartilage;[6] in another study,[15] drug concentrations needed to produce 50% inhibition (IC50) of PGE2 synthesis were
0.051 mol/L with aceclofenac and 0.0015 mol/
L with diclofenac in human rheumatoid synovial
cells. The IC50 of indomethacin, which was used
as a control, was 0.0047 mol/L.[15] Aceclofenac
reduced basal and IL-1stimulated PGE2 production in human articular chondrocytes in a concentration-dependent manner, with full blockade in 4
of 6 cell cultures at a concentration of 30 mol/
L.[14] Diclofenac and 4-hydroxyaceclofenac inhibited PGE2 production fully at concentrations of
1, 6 and 30 mol/L in this investigation.
It has been suggested that aceclofenac blocks
PGE2 production via cyclo-oxygenase (COX)-1
and COX-2 inhibition after intracellular metabolism to 4-hydroxyaceclofenac and diclofenac in
human rheumatoid synovial and other inflammatory cells.[15,16] However, data from human whole
blood assays show inhibition of COX-2 (with minimal effects on COX-1) by both the parent compound and 4-hydroxyaceclofenac:[14] IC50 values
for COX-1 and COX-2, respectively, were >100
and 0.8 for aceclofenac and >100 and 36 for 4hydroxyaceclofenac. Diclofenac strongly inhibited both COX-1 and COX-2 (IC 50s of 0.6 and
1359
0.04 mol/L, respectively). All agents had a weak

or no effect on COX activity in a purified enzyme
system.[14] Taken together, these and the other data
discussed suggest multiple mechanisms of action
for aceclofenac, with the possible contribution of
active metabolites to the drugs overall effect.
Further evidence of COX-2 selectivity of aceclofenac has been shown by an IC50 ratio (COX-2 :
COX-1) of 0.26, which fell between IC50 ratios of
0.7 and 0.12 for the COX-2 inhibitors celecoxib
and rofecoxib, respectively, in another study.[25]
Most recent data have shown aceclofenac to have
the highest COX-1 : COX-2 IC50 ratio of a range
of agents, including rofecoxib, celecoxib, nimesulide, diclofenac and tenoxicam.[26] According to the
preliminary reports available, human whole blood
assays were used in both studies, with COX activity being determined by radioimmunoassay of
thromboxane B2 and/or PGE2 in plasma after incubation of whole blood samples with the drugs being tested.
In contrast to some other NSAIDS (e.g. diclofenac and naproxen[7]), aceclofenac has shown
stimulatory effects on cartilage matrix synthesis
that may be linked to the ability of the drug to inhibit the suppression by IL-1 of various growth
factors. In vitro data show stimulation by aceclofenac of glycosaminoglycan (GAG) synthesis
in human osteoarthritic cartilage. GAG is the main
extracellular cartilage matrix macromolecule, the
synthesis of which can be inhibited by IL-1, and
the stimulation of GAG synthesis reflects maintenance and repair of the matrix.
There is also evidence that aceclofenac stimulates the synthesis of IL-1 receptor antagonist (IL-1
Ra) in human articular chondrocytes subjected to
inflammatory stimuli (IL-1 Ra plays an important
role in cartilage degradation by blocking stimulation by IL-1 of PGE2 synthesis).[27] In addition,
recent studies in rabbit articular chondrocytes[18]
and human rheumatoid synovial cells[19] indicate
that 4-hydroxyaceclofenac has chondroprotective
properties attributable to suppression of IL-1
mediated promatrix metalloproteinase production
and proteoglycan release.
Drugs 2001; 61 (9)
1360
2.1.2 Ex Vivo Studies in Patients

Receiving Aceclofenac
The inhibitory effects of aceclofenac on IL-1,

TNF and PGE2 production have also been demonstrated in peripheral blood mononuclear and polymorphonuclear cells from 15 patients with osteoarthritis of the knee who participated in a randomised, double-blind comparison with diclofenac
(50mg 3 times daily in 15 patients).[5] After 6
months of treatment with oral aceclofenac 100mg
twice daily, production of IL-1 (p = 0.0351 vs
baseline) and TNF (statistical significance not
stated) was reduced in those patients with basal
levels of these mediators of above 380 g/L at
baseline. Both basal and stimulated PGE2 production were also decreased from baseline (p < 0.05).
The synthesis of IL-6 and production of leukotriene B4 were not affected by aceclofenac in the
above study.[5]
A reduction in the stimulated generation of reactive oxygen species (O2), which may play a role
in joint damage, was observed after 15 days (p =
0.01 vs control group) in these patients, but not
after 180 days. At day 180, O2 release was similar
to that seen in a group of 41 healthy untreated individuals.[5]
The effects of aceclofenac on PGE2, IL-1, TNF
and leukotriene B4 production were similar to
those of diclofenac in this study.[5] However, a significant decrease in mean IL-6 production was observed after oral diclofenac treatment. Across both
treatment groups, patients who failed to show an
improvement in symptoms (>30% improvement in
osteoarthritis severity index score) also showed
significant decreases in IL-6 production.[5]
The inhibitory effect of aceclofenac on synovial
levels of PGE2 has also been confirmed in a
randomised, double-blind trial in 12 patients with
acute knee pain and synovial fluid effusions.[13] A
statistically significant 41% reduction from baseline in synovial PGE2 levels was observed after
oral treatment with aceclofenac 75mg 3 times daily
for 6 days. In contrast, the reduction observed after
oral diclofenac 50mg 3 times daily (21%) did not
reach statistical significance.[13]
Dooley et al.
2.2 Other Effects
Oral aceclofenac alleviated pain induced by

phenylquinone or paw compression and pain related
to silver nitrate-induced arthritis, and attenuated induced hyperthermia, in previously reviewed[12]
studies in rodents. The analgesic potency of the
drug, expressed as the dose required for a 50% reduction relative to control animals in response to
various stimuli (means of 0.8 to 3.3 mg/kg), was
similar to that of diclofenac. The mean antipyretic
potency (dose required for a 50% reduction in rectal
temperature = 0.4 mg/kg) was half that of diclofenac
(0.2 mg/kg).[20]
Studies in rodents have shown the ulcerogenic
potential (based on ulcer index results, faecal radioactive quantification or histopathological examination) of oral aceclofenac to be less than that
of indomethacin or naproxen, and less than or similar to that of diclofenac.[12,20,21] In addition, a previously reviewed 10-day study in 12 healthy volunteers suggested less GI bleeding (shown by
measurement of faecal blood loss) with aceclofenac 100mg twice daily than with diclofenac
50mg 3 times daily.[23]
Endoscopic examination showed fewer patients
receiving aceclofenac (100mg twice daily) than
naproxen (500mg twice daily) to have evidence of
gastric damage in a 4-week single-blind study in
42 patients with osteoarthritis (15 vs 50%; statistical analysis not reported).[24] Furthermore, in a
randomised, double-blind, placebo-controlled study
involving 30 healthy volunteers,[28] endoscopic assessments at 2 weeks showed the incidence of gastric and duodenal mucosal damage with oral aceclofenac (75mg twice daily) to be significantly
lower than that with oral diclofenac (25mg 3 times
daily) [20 vs 50% and 0 vs 20%, respectively, p <
0.05 for both comparisons] and not significantly
different to that observed with placebo.[28]
Whereas diclofenac significantly (p < 0.05) reduced gastric mucosal levels of the cytoprotectant
hexosamine (from 58 to 27 mg/g) and gastroduodenal blood flow (measured by laser Doppler analysis) [from 2.5 to 1.5mV], aceclofenac significantly
increased hexosamine levels (from 33 to 53 mg/g;
Drugs 2001; 61 (9)
p < 0.001) and did not alter blood flow. Aceclofenac, but not diclofenac, was associated with a
significant decrease in intragastric pH (from 1.6 to
1.5; p < 0.05) that was associated with an increase
in serum secretin levels (from 121 to 142 ng/L; p
< 0.05) [estimated from graph]. When the effects
of treatment were compared in participants with
and without mucosal damage, serum gastrin levels
were significantly decreased (p < 0.01) and serum
secretin levels significantly increased (p < 0.05) in
the former group.[28]
Data on the GI tolerability of aceclofenac as
seen in clinical trials are presented in section 5.2.
3. Overview of
Pharmacokinetic Properties
The pharmacokinetic properties of oral aceclofenac have been well characterised in young and
elderly healthy volunteers.[12,29-32] Data are also
available from patients with knee pain and synovial
fluid effusion[13] and from women with postepisiotomy pain.[33]
3.1 Absorption and Distribution
In general, aceclofenac is rapidly and completely absorbed after oral administration, with
peak plasma concentrations (Cmax) being reached
1.25 to 3 hours after ingestion.[34] The volume of
distribution (Vd) is approximately 25L, and the
drug is highly protein-bound (>99%) in plasma.[34]
The mean Cmax of aceclofenac and times to Cmax
(tmax) ranged from 8.94 to 9.86 mg/L and 1.08 to
1.37 hours, respectively, after single (100mg) and
multiple (100mg twice daily for 7 days) doses of
aceclofenac in 12 young (aged 18 to 31 years) and
12 elderly (aged 60 to 80 years) healthy volunteers.[30] After multiple doses, the mean area under
the plasma drug concentration versus time curve
(AUC) from time 0 to 48 hours increased by 8.1%
relative to the single-dose value (from 20.57 to
22.24 mg/L h; p = 0.028) in young volunteers,
and decreased by 8% in elderly volunteers (from
19.48 to 17.92 mg/L h; p = 0.049).[30]
1361
Cmax and AUC values increased linearly after

single doses of 50, 100 and 150mg of aceclofenac
in 64 women with postepisiotomy pain.[33]
Cmax, absorption half-life and Vd did not differ
significantly between young and elderly study participants[30] (dosage reductions are therefore not generally necessary in elderly patients; see section 6).
The presence of food did not alter the extent of
absorption (Cmax or AUC) of aceclofenac after a
single 100mg dose in healthy young volunteers,
but the absorption rate was reduced as shown by
the increase in median tmax from 2 to 3.5 hours (p
< 0.01).[31]
In 12 patients with acute knee pain and synovial
fluid effusion, the mean plasma concentration of
aceclofenac was twice that in synovial fluid after
administration of 75mg 3 times daily for 6 days
(1350 vs 775 g/L as estimated from graph; statistical analysis not reported).[13]
3.2 Metabolism and Elimination
Aceclofenac is metabolised to a major metabolite, 4-hydroxyaceclofenac, and to a number of

other metabolites including 5-hydroxyaceclofenac, diclofenac, 4-hydroxydiclofenac and 5hydroxydiclofenac.[29] These other metabolites account for the fate of approximately 20% of each
dose of aceclofenac.[15,29,32]
Renal excretion is the main route of elimination
of aceclofenac, with 70 to 80% of an administered
dose found in the urine,[29,32] mainly as the glucuronides of aceclofenac and its metabolites.[32] Of
each dose of aceclofenac, 20% is excreted in the
faeces.[32] The plasma elimination half-life (t12) of
the drug is approximately 4 hours.[34]
In the pharmacokinetic trial in 24 young and
elderly volunteers[30] (section 3.1), the t12 of
aceclofenac was similar after single (100mg) and
multiple (100mg twice daily for 7 days) doses
(2.69 and 3.08 hours, respectively) in elderly study
participants. In young participants, however, t12
values increased significantly after multiple doses
(3.52 vs 4.65 hours; p = 0.017). t12 was significantly shorter after both single and multiple doses
in elderly than in young volunteers (p < 0.001).
Drugs 2001; 61 (9)
1362
4. Therapeutic Efficacy
This updated review focuses on the use of aceclofenac in rheumatic disease (osteoarthritis, rheumatoid arthritis and ankylosing spondylitis) and in
analgesia. Aceclofenac has been shown to be superior to placebo in pain management and in patients
with rheumatoid arthritis or osteoarthritis in studies reviewed previously.[12] Comparisons with placebo are not available in patients with ankylosing
spondylitis.
In all studies discussed, aceclofenac was given
orally unless stated otherwise.
4.1 Osteoarthritis
Aceclofenac decreases pain levels, reduces the

severity of symptoms and improves the functional
capacity of the affected joint in patients with osteoarthritis of the knee (gonarthritis), and is similar in
efficacy to diclofenac, piroxicam and naproxen (table II). Similar efficacy of aceclofenac and
diclofenac was also shown in 2 earlier trials in 49
and 229 patients after 1 or 3 months treatment (see
Brogden and Wiseman[12] for further information).
Three of the 5 comparative trials presented in
this section used the following parameters to assess
efficacy:[1,3,35]
pain intensity as measured on a visual analogue
scale (VAS) with a scale of 0 to 100mm, where
0mm indicates no pain and 100mm indicates
worst pain
capacity for knee flexion and extension as measured by goniometer
knee function scores (sum of scores for pain,
crepitation, muscular atrophy and swelling),
used to assess overall function of the affected
joint (a lower score indicates fewer symptoms).
These studies also used the Lequesne Osteoarthritis Severity Index (OSI)/Severity Index of
Gonarthritis (SIG), an assessment tool based on a
series of questions on pain intensity and functional
capacity, to assess the severity of the condition.
In the other 2 trials,[36,37] assessments of pain
intensity, joint swelling and tenderness, functional
capacity and the ability to flex the knee were made
Dooley et al.
by investigators and patients by use of 5-point

scales in which lower scores indicated fewer symptoms. The primary efficacy measure in these trials
was the investigators assessment of joint pain.[36,37]
Most of these randomised, double-blind trials were
preceded by a 1- to 2-week washout period.[3,35-37]
The use of paracetamol (acetaminophen) was permitted at this time[35-37] and in the first 2 weeks of
the study period.[36,37] In 1 trial,[37] physical therapy was continued. Information on concurrent
medication for other conditions was not provided.
In the first 3 trials outlined above, which involved 178 to 278 patients with osteoarthritis of the
knee,[1,3,35] aceclofenac 100mg twice daily for 2 to
6 months significantly decreased pain intensity, osteoarthritis severity (as shown by OSI/SIG scores)
and knee function scores and improved the ability
to flex or extend the affected knee (table II).
A similar improvement in symptoms was observed in the other 2 trials[36,37] (involving 367 and
378 patients with osteoarthritis of the knee who
were assessed according to investigators assessments of efficacy). Aceclofenac 100mg twice daily
for 3 months significantly improved pain at rest
and on movement, joint tenderness and swelling,
functional capacity (table II and fig. 1) and the duration of joint stiffness (from 20 to 10 minutes; p
= 0.001)[37] when compared with values at baseline. In addition, objective assessments of knee
flexion showed significant improvement after
aceclofenac treatment (table II).[36,37] Patients
subjective assessments of the effect of aceclofenac
on symptoms reflected those of investigators.[36,37]
The number of patients observed by investigators as showing a deterioration across all symptoms
during treatment ranged from 0.5 to 6% in the last
2 studies;[36,37] 24.3[37] and 23.4%[36] of aceclofenac recipients showed no change from baseline
over the range of symptoms. Aceclofenac appeared
to be less effective at reducing erythema than other
symptoms, with proportions of patients showing
no change being greater than proportions of those
showing improvement (56.1 vs 43.4%[37] and 75 vs
23.4%[36]).
Drugs 2001; 61 (9)
Reference
(study duration)
Treatment
regimen
(no. of
evaluable
pts)
Knee flexion/extension
(degrees)d
Knee function scoree
baseline
change
baseline
change
70.2
33.8***
12.1
4.6***
116.4/4.5
+12.4***/2.5*** 7.7
3.7***
P 20mg od
(91-92)
71.8
34.8***
12.1
5***
117.9/4.5
+8.1***/1.7**
6.6
2.8***
A 100mg bid
(89)
58.9
35.7**
12.9
5.6**
96.5/3.6
+10**/2.6**
P 20mg od
(89-90)
58.6
38.5**
12.7
5.5**
97.2/3.1
+9.1**/2.3**
29.1***
11.4
5.1***
121/1.4
+6**/0.5
6.4
3.4**
29.2***
11.5
5***
120/1.5
+5**/0.3
6.0
3**
Comparisons with diclofenac (D)

Daz et al.[3]
A 100mg bid
63.5
(6mo)
(120-130)
D 50mg tid
(109-148)
Ward et al.[36]
(3mo)
Pts with
OSI/SIG scorec
reduced pain
intensity score baseline
change
at rest/on
movement (%)b
baseline
Comparisons with piroxicam (P)

Prez Busquier
A 100mg bid
et al.[35] (2mo)
(94)
Torri et al.[1]
(3mo)
Pain intensity scorea
64.1
change
Pts with
improvement
in joint
tenderness/
swelling (%)b
A 100mg bid
(188-192)
74.5***/70.2*
NR
+7*f/NR
72.4*/58.3*
D 50mg tid
(180-186)
70.4***/62.8*
NR
+5*f/NR
66.7*/53.8*
76.2/83.4g
81.7/NR
+14*/NR
82/73
81.8/86.1g
82.4/NR
+14*/NR
85.6/75.1
Comparison with naproxen (N)

Kornasoff et
A 100mg bid
al.[37] (3mo)
(187-189)
N 500mg bid
(180-181)
a
b
c
1363
Drugs 2001; 61 (9)
Measured on a visual analogue scale (VAS) from 0mm (no pain) to 100mm (worst pain).
Investigators assessments of the percentage of pts with improvement on a 5-point scale (lower scores indicate fewer symptoms).
Measures severity of osteoarthritis and gives total scores for a series of questions on pain intensity and functional capacity of the involved joint (lower scores indicate
improvements).
d Assesses functional capacity and is measured by a goniometer.
e Assesses knee function by adding scores (from 0 to 3, where 0 denotes absence of symptoms) for pain on movement, pain on pressure, spontaneous pain, crepitation,
muscular atrophy and swelling.
f Median value.
g Statistical analysis not provided.
bid = twice daily; NR = not reported; od = once daily; OSI = Lequesne Osteoarthritis Severity Index; SIG = Severity Index of Gonarthritis; tid = 3 times daily; * p < 0.05, ** p < 0.01,
*** p < 0.001 vs baseline; p < 0.01 vs aceclofenac.
Table II. Efficacy of aceclofenac (A) in comparison with other NSAIDs in patients (pts) with osteoarthritis of the knee. Mean results (unless stated otherwise) from randomised,
double-blind trials. All treatments were given orally
Reductions in pain levels and improvements in

functional capacity produced by aceclofenac, together with overall assessments of the drugs efficacy by investigators and patients, did not differ
significantly from those observed in patients receiving piroxicam (20mg once daily), diclofenac
(50mg 3 times daily) or naproxen (500mg twice
daily) [table II]. However, in 1 study,[36] patientassessed pain intensity was reduced to a significantly greater extent with aceclofenac than with
diclofenac (improvement in 71.4 vs 59.1% of patients; p = 0.005). Paracetamol use (500mg tablets),
which was permitted during the first 2 weeks of the
trial, was significantly reduced in aceclofenac relative to diclofenac recipients (median consumption
of 14 vs 22 tablets; p = 0.043). Furthermore, in this
trial, aceclofenac improved knee flexion to a significantly greater extent than diclofenac during,
but not at the end of, the 3-month study in patients
who were unable to straighten their knees at baseline.[36] Significant improvements from baseline in
knee flexion were also noted with aceclofenac and
naproxen in another trial examining this end-point
(table II).[37]
The onset of action of aceclofenac was similar
to that of comparator drugs in trials examining
this end-point:[1,3,35] in general, pain intensity and
OSI/SIG scores, knee function and the ability to
flex or extend the knee had improved significantly
by the time of the first assessment at day 15. In 1
of the studies,[1] the mean OSI/SIG scores had
improved significantly after 1 month (first assessment).
Proportions of patients discontinuing treatment
because of lack of efficacy were 0,[1] 4.2[37] and
4.5%[36] in patients receiving aceclofenac; these results were compared with rates of 1,[1] 2.3[37] and
4.6%[36] in patients receiving piroxicam, naproxen
or diclofenac, respectively, in studies providing
these data. Resolution of symptoms also led to
withdrawal from treatment of similar percentages
of patients receiving aceclofenac or piroxicam (3.4
and 1.1%, respectively) in 1 trial,[1] and aceclofenac or naproxen (11.1 and 12.5%, respectively)
in another study.[37]
Dooley et al.
Percentage of patients
1364
100
90
80
70
60
50
40
30
20
10
0
Kornasoff et al.[37]
Aceclofenac
(n = 188)
Naproxen
(n = 180)
Ward et al.[36]
Aceclofenac
(n = 192)
Diclofenac
(n = 186)
Fig. 1. Improvement in functional capacity in patients with osteoarthritis of the knee. The percentage of patients with an improvement in functional capacity after 3 months treatment with
aceclofenac 100mg twice daily, diclofenac 50mg 3 times daily
or naproxen 500mg twice daily; results from 2 randomised, doubleblind trials involving 368[37] or 378[36] patients with osteoarthritis
of the knee. A significant improvement versus baseline was
observed with aceclofenac and diclofenac (statistical significance not stated) in 1 study;[36] details of statistical analysis were
not reported in the other.[37]
A randomised, nonblind, multicentre trial compared the efficacy of 12 weeks treatment with
aceclofenac 100mg twice daily with that of
nabumetone 1 to 2g daily (dosage based on clinical
efficacy).[38] The primary efficacy end-point was
pain intensity according to VAS. Secondary variables included OSI/SIG (assessing pain, maximum
walking distance and ability to perform activities
of daily living), researcher- and patient-based assessments of arthrosis activity and overall assessments of change in arthrosis, and paracetamol usage.
Lower assessment scores indicated greater improvements. Efficacy was assessed in the intention-totreat (ITT) population (n = 274) after 3 months
treatment and in the per-protocol population (patients completing the trial; n = 189) at 1, 2 and 3
months. Other analgesic preparations were not allowed during the study period, but patients could
take up to 200 mg/day of aspirin (acetylsalicyclic
acid) as an antiplatelet agent.[38]
In the ITT population, aceclofenac 100mg twice
daily significantly reduced the mean pain intensity
Drugs 2001; 61 (9)
(from 61.3 to 44mm; p < 0.001 vs baseline) and

OSI/SIG scores (from 10.61 to 7.83; p < 0.001 vs
baseline) after 3 months.[38] Nabumetone 1 to 2g
daily showed similar significant reductions from
baseline, and no significant differences were observed between the 2 drugs in either assessment.
Both drugs also significantly improved researcherand patient-based assessments of arthrosis activity
at 3 months versus baseline. According to the investigators assessment, all patients showed moderate or severe arthrosis activity at baseline; at
month 3, 32 and 36% of all patients showed slight
or absent arthrosis activity, respectively. Similar
results were reported after 3 months in the per-protocol population. In this group, a significant improvement in symptoms was observed from 1
month after the start of treatment. Paracetamol usage was not reported for the ITT population, but no
significant differences in this respect were observed between aceclofenac and nabumetone recipients in the per-protocol analysis.
4.2 Rheumatoid Arthritis
The anti-inflammatory and analgesic efficacy

of aceclofenac has been shown to be generally similar to that of ketoprofen, indomethacin, tenoxicam
and diclofenac in patients with rheumatoid arthritis. In 1 previously reviewed small double-blind
trial (n = 53),[39] aceclofenac 100mg twice daily for
6 months reduced Ritchie index (an articular index
for the evaluation of tenderness of joints[40]) scores
to a significantly greater extent than ketoprofen
50mg 3 times daily.[12] Since that time, larger
randomised, double-blind trials have compared
aceclofenac with ketoprofen, indomethacin, tenoxicam and diclofenac in 169 to 261 evaluable patients (table III).
Patients included in the trials shown in table III
had active disease as defined by the American
Rheumatism Association (ARA) [now known as
the American College of Rheumatology (ACR)[2]]
criteria.[9,41-43] In addition, they had pain corresponding to a measurement of at least 40mm on the
VAS,[42,43] or Steinbrocker progression stage (a
measure of functional capacity [44]) of I, II or III
1365
and an ARA functional class of I, II or III.[41] Existing therapy with stable dosages of oral corticosteroids or disease-modifying antirheumatic drugs
(DMARDs) was continued,[41-43] and in 1 trial,
paracetamol was permitted during the first 2 weeks
of the study period.[41] However, information on
concurrent medication for other conditions was not
provided in any trial. Physical rehabilitation was
also continued during the study period in 2 trials.[41,42] In 2 trials,[9,42] disease severity at baseline
was significantly greater in aceclofenac recipients
than in patients receiving ketoprofen or diclofenac
in terms of morning stiffness[42] or Ritchie index.[9]
In general, aceclofenac 100mg twice daily for 3
to 6 months significantly reduced joint inflammation (Ritchie index), pain intensity (VAS) and
numbers of patients with (or duration of) morning
stiffness relative to baseline (table III). Furthermore, mean grip strength in both hands was significantly improved from baseline in all trials (table
III). In studies in which functional capacity was
assessed,[41,42] improvements with aceclofenac
were similar to those seen with comparators. Improvement from baseline in Steinbrocker or ARA
functional classification was reported in 27% of
patients receiving aceclofenac or indomethacin
(50mg twice daily) in 1 study;[41] both aceclofenac
and ketoprofen (50mg 3 times daily) improved
functional capacity to a statistically significant (p
< 0.01) extent in the other.[42] Patients in the latter
trial also showed significant reductions in median
numbers of painful and swollen joints (painful
joints reduced from 24 to 8 and from 21 to 10 with
aceclofenac and indomethacin, respectively;
swollen joints correspondingly reduced from 16.5
to 8 and 16 to 7; p < 0.05 vs baseline for all reductions).[41]
The reductions in pain and inflammation with
aceclofenac did not differ significantly from those
observed with indomethacin (50mg twice daily),[41]
ketoprofen (50mg 3 times daily),[42] tenoxicam
(20mg once daily)[43] or diclofenac (50mg 3 times
daily)[9] [table III]. However, in the smallest trial
(n = 169),[42] the improvement in grip strength with
ketoprofen was numerically, but not significantly,
Drugs 2001; 61 (9)
1366
Table III
Dooley et al.
smaller than with aceclofenac (table III). Overall

or global assessments of efficacy (based on investigators and patients perceptions of overall improvement) were similar for aceclofenac and indomethacin[41] or diclofenac[9] in the 2 studies in
which these end-points were reported, with improvement[41] or efficacy ratings of good to very
good[9] being reported in 62.1 to 76.3% of patients.
In general, onset of action was similar with
aceclofenac and comparator drugs:[9,41-43] improvements in symptoms were observed at the first
assessment, 14 to 15 days after the start of treatment.[9,41,43] In the comparison with ketoprofen,[42]
however, a significant reduction from baseline in
the Ritchie index was noted after 15 days treatment with aceclofenac, but not until 1 months
therapy with ketoprofen had been taken.[42]
Fewer patients receiving aceclofenac (4.6 to
8%) than recipients of other agents discontinued
therapy because of lack of efficacy in 2 studies.
Percentages of patients were significantly lower
than with ketoprofen (13.4 vs 4.6%; p < 0.05),[42]
numerically lower than with indomethacin (5.5 vs
12%; statistical analysis not reported)[41] and numerically similar to percentages reported for
diclofenac (9.1 vs 7.4% with aceclofenac)[9] and
tenoxicam (8.1 vs 8.3%)[43] [statistical analyses not
reported].
4.3 Ankylosing Spondylitis
Aceclofenac 100mg twice daily reduced pain

and morning stiffness and improved mobility of the
spine to a similar extent to naproxen 500mg twice
daily,[11] tenoxicam 20mg once daily[45] or indomethacin 25mg twice daily and 50mg at night[46]
in three 3-month randomised, double-blind studies
in 104,[11] 235 [45] or 308 [46] evaluable patients
with active ankylosing spondylitis (New York criteria[45,46]).
In the comparisons with indomethacin[46] and
tenoxicam,[45] paracetamol tablets were provided
as emergency medication; in 1 of these trials,[46]
antacid use was also permitted and physical therapy was maintained at the same level throughout
Drugs 2001; 61 (9)
Reference
(study duration)
Treatment
Ritchie index
Grip strength of right hand/left
Duration of morning
No. of pts with no
regimen (no. of
hand (mm Hg)
stiffness (min)
morning stiffness
evaluable pts)
baseline
change
baseline
change
baseline
change
baseline
change
Kornasoff et
A 100mg bid
NR
120b
60*b
+8*/+8*b
al.[41] (3mo)
(109)
I 50mg bid (110)
NR
120b
42*b
+10*/+10*b
5
A 100mg bid
24.4
6.5***
67.6/65.9
Martn-Mola et
+12.4***/+14.1***
+9**
(87)
al.[42] (3mo)
K 50mg tid (82) 23.1
4.4***
74.9/73.3
8
+3.4*/+3
+2*
Pasero et
A 100mg bid
22.4
10.1**
74.6c
81.3
32.6**
+16.6**c
al.[9] (6mo)
(131)
D 50mg tid
20
8.2**
80.9c
84.9
38.9**
+14.1**c
(130)
Perez-Ruiz et
A 100mg bid
22
8**
81/81
2
+13**/+11**
+22***
al.[43] (3mo)
(124)
T 20mg od
23
11**
80/82
1
+19**/+12**
+23***
(113)
a Measured on a visual analogue scale (VAS; 0mm = no pain, 100mm = worst pain).
b Median values.
c Mean values for both hands.
bid = twice daily; NR = not reported; od = once daily; tid = 3 times daily; * p 0.05, ** p < 0.01, *** p < 0.001 vs baseline; p 0.05 vs comparator.
1366
Table III. Efficacy of aceclofenac (A) in comparison with indomethacin (I), ketoprofen (K), diclofenac (D) or tenoxicam (T) in patients (pts) with rheumatoid arthritis. Mean results
(unless stated otherwise) from double-blind, randomised, multicentre trials. All treatments were given orally
baseline
NR
change
22.6b
NR
68.4
18.9b
20.3***
67.7
62
19.3***
24.1**
57.6
20.8**
63
21**
62
23**
Dooley et al.
Drugs 2001; 61 (9)
Table IV
1367
the study. However, information on the use of concurrent medication for other conditions was not
provided in any of the 3 trials.
Baseline characteristics were similar between
treatment groups with 1 exception: in the comparison with naproxen,[11] spinal mobility at baseline
was significantly better in the aceclofenac group
when assessed by hand-to-floor distance (table
IV).[11]
Compared with baseline, aceclofenac significantly reduced pain intensity (VAS scores) and duration of morning stiffness, and improved spinal
mobility as shown by the modified Schbers test,
the C7 to iliac crest (in all but 1 study[45]) or handto-floor distance measurement, lateral spinal
flexion and chest expansion, and the occiput-towall distance (table IV).
Improvements in aceclofenac recipients were
not significantly different from those observed in
patients receiving indomethacin 100mg daily,[46]
tenoxicam 20mg daily[45] or naproxen 500mg
twice daily.[11] In 1 trial,[45] tenoxicam, but not aceclofenac, significantly increased the C7 to iliac
crest distance relative to baseline values. Aceclofenac treatment was associated with statistically
significant improvements relative to baseline in all
other end-points measured in this study, however.
The overall clinical efficacies of both aceclofenac and indomethacin were moderate to good
according to a 5-point rating scale used by patients
and physicians in 1 study.[46] Similarly, a final assessment based on duration of morning stiffness
and pain intensity (VAS scores) resulted in efficacy ratings of good (improvement of 40 to 70%)
for aceclofenac and tenoxicam in one of the other
trials.[45] In addition, paracetamol consumption did
not differ significantly between patients receiving
aceclofenac and those receiving indomethacin[46]
or tenoxicam.[45] Overall efficacy was also stated
to be similar between treatments in the comparison
of aceclofenac with naproxen,[11] although further
details were not given.
Both aceclofenac and naproxen significantly reduced numbers of patients with moderate or severe
pain on movement or at rest (measured on a 4-point
Drugs 2001; 61 (9)
Reference
(study duration)
Treatment regimen
(no. of evaluable pts)
Batlle-Gualda et
al.[46] (3mo)
A 100mg bid (155)
Pasero et
al.[11] (3mo)
Villa Alczar et
al.[45] (3mo)
Duration of morning
stiffness (min)
Modified Schbers test C7 to iliac crestc or

measurement (cm)b
hand-to-floor
distanced (cm)
baseline change
baseline change
3.7c
3.4
+0.7***
+0.4*c
baseline change
60.2
22.4***
baseline
60.1
change
30.4***
I 25mg bid and

50mg on (153)
A 100mg bid (47)
N 500mg bid (57)
A 100mg bid (120)
61.2
25***
65.1
30***
3.7
+0.6***
3.5c
+0.5**c
54.4e
54.4e
57.9
27.2**e
23.3**e
25.7**
31.4**
+0.7**
+0.9**
+0.9*
21.9d
27d
4c
4.7**d
7.2**d
55.3
12.9
12.7
4.7
T 20mg od (115)
58.1
27.5**
61.1
38.9**
4.8
+1.1**
3.7c
+0.7**c
+0.5c
Lateral spinal
flexion/chest
expansion (cm)
baseline change
9.9/3.8 +0.6*/0.6***
Occiput-to-wall
distance (cm)
baseline change
4.5
0.5***
10.2/3.8 +1***/0.8*** 3.8
0.4*
11.5/
+0.8*/0.5** 3.4
3.4
11.5/3.5 +1.5**/0.8** 3.4
0.6**
Table IV. Efficacy of aceclofenac (A) in comparison with tenoxicam (T), indomethacin (I) or naproxen (N) in patients (pts) with ankylosing spondylitis. Mean results from double-blind,
randomised, multicentre trials. All treatments were given orally
0.4*
a Measured on a visual analogue scale (VAS) from 0 (no pain) to 100mm (worst pain).
b Increase in length of the 10cm of spine above L5 after extension (flexion) of the lumbar spine.
c Overall spinal movement as shown by C7 to iliac crest line measurement.
d Hand-to-floor distance (distance between extended fingertips and floor when trying to touch the floor with knees kept straight).
e Estimated from graph.
bid = twice daily; od = once daily; on = at night; * p < 0.05, ** p <0.01, *** p < 0.001 vs baseline; p < 0.05 vs naproxen.
1367
Drugs 2001; 61 (9)
1368
scale; 0 = no pain to 3 = severe pain) by 55 to 79%

(p < 0.05 vs baseline).[11] Conversely, the number
of patients with no or mild pain on movement or at
rest increased after treatment with either agent by
a factor of approximately 2 to 3 (p < 0.05 vs baseline for pain at rest; no statistical analysis was
available for reduction in pain on movement).[11]
Aceclofenac also increased the capacity of patients
to perform normal daily activities: the number of
patients with moderate or severe limitation of
movement decreased from baseline by 92% (statistical significance not stated), and the number with
no or slight limitation at baseline increased by 31%
(statistical significance not stated). These improvements were similar to those observed with
naproxen.[11]
In 2 trials,[45,46] significant responses to aceclofenac were reported at the first assessment on day
15 (similarly to indomethacin and tenoxicam). In
the other study,[11] significant improvements in severity of pain on movement and at rest on a 4-point
scale were observed within 1 to 2 months with
aceclofenac, but were seen earlier with naproxen
(15 days to 1 month). However, spontaneous pain
according to a 100mm VAS improved from the
first assessment (15 days) onwards in both groups.
Rates of treatment discontinuation because of
lack of efficacy were similar with aceclofenac and
indomethacin or tenoxicam, and ranged from 4.6
to 6%.[45,46]
4.4 Analgesia
As discussed in the preceding sections (4.1, 4.2

and 4.3), aceclofenac 100mg twice daily significantly reduced pain intensity relative to baseline in
patients with osteoarthritis, rheumatoid arthritis
and ankylosing spondylitis. In addition, the analgesic efficacy of single doses of aceclofenac as
shown by VAS scores has been demonstrated in
previously reviewed[12] double-blind and placebocontrolled studies in patients with moderate to severe dental pain[47,48] and those having undergone
third molar extraction.[49] Analgesia was evident
from 1 hour after administration of a 100[47] or
150mg[49] dose. Aceclofenac 100mg was also su Adis International Limited. All rights reserved.
Dooley et al.
perior to paracetamol 650mg in the relief of postepisiotomy pain over an observation period of 6
hours in 2 studies in a total of 99 patients.[50,51] In
a more recent noncomparative study in 1338
women with dysmenorrhoea treated for the first 3
days of 2 consecutive cycles,[52] the efficacy of
aceclofenac 100mg twice daily was described as
excellent or good relative to baseline assessments by over 90% of patients and physicians.
In a study in 100 patients with acute lumbago,[53] alleviation of functional impairment with
and overall efficacy of aceclofenac were superior
to those seen with diclofenac. Both drugs were
given intramuscularly for the first 2 days (150 and
75mg twice daily for aceclofenac and diclofenac,
respectively), with oral administration (100mg
twice daily and 50mg 3 times daily) for the next 5
days. The physicians overall assessment of efficacy was good or better in more than 85% of
aceclofenac and 76% diclofenac recipients (p <
0.05). Lower back pain, as assessed on a VAS, decreased progressively from baseline (p < 0.01) with
both treatments over the 7 days of the study. In
addition, aceclofenac 100mg twice daily was associated with symptomatic relief of acute low back
pain in a noncomparative study in 67 patients.[54]
Aceclofenac 100mg twice daily has also been
assessed in patients with musculoskeletal trauma
(chiefly sprains and contusions), although only
noncomparative studies are available.[55,56] One of
these trials[56] enrolled 15 033 patients within 48
hours of injury, of whom 9616 were available for
assessment after 10 days treatment with aceclofenac 100mg twice daily. Proportions of patients
free from pain at rest and pain on movement increased from 14.93 to 87.25% and from 2.96 to
54.48%, respectively, during this time. In the absence of a control group, however, it is not possible
to comment on the relative contributions of natural
healing processes and the actions of the drug.
4.5 Pharmacoeconomic Considerations
A recent cost analysis has suggested that

aceclofenac compares favourably with a range of
other NSAIDs in terms of direct costs of treatment
Drugs 2001; 61 (9)
from a healthcare providers perspective when

costs associated with treatment of adverse events
and substitution of an alternative treatment after
NSAID discontinuation (iatrogenic costs) are
taken into account (in addition to drug acquisition
costs).[57] Data were obtained from 3239 patients
who participated in 12 of 13 randomised, doubleblind studies included in a meta-analysis carried
out primarily to assess the tolerability of aceclofenac[58] (see section 5 for more details). A
model was constructed around a decision tree that
reflected events related to NSAID use over a 3month treatment period, with costs being attached
to each final outcome. Pathways that could be followed by each patient included noncompliance or
compliance, lack of efficacy or efficacy, and adverse events or no adverse events experienced. Adverse events were specified and were classified as
mild to moderate (treatment continued) or severe
(treatment stopped); the model allowed for up to 4
adverse events per patient. All probabilities applied to the model were estimated on the basis of
the results of the 12 clinical studies. Patients were
treated for osteoarthritis, rheumatoid arthritis or
ankylosing spondylitis, and comparator NSAIDs
were diclofenac (50mg 3 times daily), naproxen
(500mg twice daily), piroxicam (20mg daily), indomethacin (50mg 2 or 3 times daily), tenoxicam
(20mg once or twice daily) and ketoprofen (50mg
3 times daily).
Resource use associated with each adverse
event was estimated from the results of a survey of
10 rheumatologists that yielded data on specific
treatments used for adverse events, numbers of
medical visits, length of hospital stay (where relevant), diagnostic tests and therapies substituted
for aceclofenac and comparator drugs (where necessary). The time needed to identify lack of efficacy and to change treatments was also accounted
for. Median values were calculated for each cost
and expressed in $US for the year 1996. NSAID
daily acquisition costs were taken as the average
value, weighted according to the market share of
each brand used, of the market price of each drug
in Spain. Nondrug costs were based on hospital
1369
accounting data where available. The iatrogenic

cost factor (ICF) was calculated as the sum of
NSAID cost (acquisition and administration) and
iatrogenic cost (cost of adverse event treatment and
substitution therapy) divided by the NSAID cost.
A lower ICF indicated a treatment option with lower
additional costs associated with adverse events
and/or substitution of alternative treatments.
Total costs (NSAID cost plus iatrogenic cost)
per patient were higher with aceclofenac 200
mg/day than with the comparator NSAID in most
individual studies; analysis of 95% confidence intervals (95% CIs) showed these cost differences to
be statistically significant in 6 of the 12 trials. Calculation of mean total costs across studies grouped
by comparator drug, however, showed statistically
similar overall total costs for aceclofenac and all
other agents except piroxicam (for which only 1
comparison was available). ICFs of aceclofenac
were lower than those of comparator agents in all
studies, with statistical significance being attained
in 2 of 3 comparisons with diclofenac, 3 of 3 with
indomethacin, 1 of 2 with naproxen, and 1 of 2 with
tenoxicam. In the single comparisons available for
ketoprofen and piroxicam, the ICF of aceclofenac
was statistically significantly lower than that of the
former, but not the latter. Calculation of mean ICF
ratios and 95% CIs for studies grouped by comparator drug (as before) showed a statistically significantly difference in favour of aceclofenac against
all comparators except piroxicam.
5. Tolerability
This section presents data obtained from the
manufacturers prescribing information,[34] from
double-blind comparative trials in patients with
rheumatoid arthritis,[9,41-43] osteoarthritis[1,3,35-37]
or ankylosing spondylitis,[11,45,46] and from a nonblind comparative trial in patients with osteoarthritis[38] (see section 4 for study details). In addition,
tolerability data have been included from a nonrandomised, nonblind comparison of aceclofenac
100mg twice daily with diclofenac sustained release 75mg twice daily for 12 months in 10 142
patients with rheumatic disease (most patients had
Drugs 2001; 61 (9)
1370
osteoarthritis),[59] and from a meta-analysis of 13

randomised, double-blind comparisons with other
NSAIDs in 3574 patients.[58] Baseline characteristics of the patients involved in one of these
studies,[59] which was carried out in accordance
with Safety Assessment of Marketed Medicines
(SAMM) guidelines, were similar between the 2
treatment groups but the duration of disease was
longer (p = 0.019), and more patients had severe
disease (p < 0.001) and a history of dyspepsia (p =
0.025), at baseline in the aceclofenac group than in
the diclofenac group.
The manufacturers information indicates that
most adverse events associated with aceclofenac
are minor and reversible with treatment discontinuation, and that the GI system is predominantly
involved. The most common events (incidence
5%) include dyspepsia and abdominal pain.[34]
5.1 General Tolerability
The most common non-GI adverse events reported during aceclofenac therapy are dizziness,
vertigo, pruritus, rash and dermatitis. However, according to the manufacturers data, these events
occur in only small proportions of patients
(<5%).[34]
In a number of previously reviewed[12] placebocontrolled trials in patients with rheumatoid arthritis or osteoarthritis, aceclofenac showed a tolerability profile similar to that of placebo.
In individual clinical studies, the overall incidence of adverse events with aceclofenac 100mg
twice daily did not differ significantly from that
with ketoprofen 50mg 3 times daily,[42] piroxicam
20mg once daily,[1,35] diclofenac 50mg 3 times
daily[9,36] or tenoxicam 20mg once daily,[43,45] and
was lower than that with naproxen 500mg twice
daily [45 vs 55 events (p = 0.025),[37] and 32 vs 39%
of patients (no statistical analysis provided)[11]].
The overall incidence of adverse events was lower
with aceclofenac 100mg twice daily than with indomethacin 100mg daily (28 vs 38% of patients
reported 42 vs 75 events; p = 0.006) in 1 trial.[41] A
significantly (p = 0.032) greater number of major
adverse events leading to treatment withdrawal
Dooley et al.
was reported in the indomethacin group than in patients receiving aceclofenac. Overall adverse event
rates did not differ significantly between these 2
treatments in a second trial (30.3% of patients with
aceclofenac and 36.6% with indomethacin).[46]
Adverse events affecting the CNS (mainly headache and dizziness) were reported in significantly
fewer aceclofenac than indomethacin recipients
(2.6 vs 13.7%; p < 0.001).[46]
Results of a meta-analysis of 13 randomised,
double-blind, comparative 3- or 6-month studies in
a total of 3574 patients with osteoarthritis, rheumatoid arthritis or ankylosing spondylitis[58] have
shown patients receiving aceclofenac to be 1.38
times more likely than those receiving other
NSAIDs to be free of adverse events in general (2
= 18.31; p < 0.001). Comparators were diclofenac
50mg 3 times daily, naproxen 500mg twice daily,
piroxicam 20mg once daily, indomethacin 50mg
twice daily, tenoxicam 20mg daily and ketoprofen
50mg 3 times daily. Breslow-Day 2 testing
showed homogeneity of studies. Compliance with
aceclofenac (shown by completion of course of
study treatment) was also significantly better than
with other drugs (overall odds ratio = 1.37; p <
0.001).[58]
Rates of withdrawal from treatment due to adverse events did not differ significantly between aceclofenac and most comparator agents in the majority of trials examining this end-point.[9,35-37,43,45,46]
However, significantly fewer patients withdrew because of adverse events after aceclofenac than after
ketoprofen (2.3 vs 13.4%; p < 0.01)[42] or after diclofenac (8.2 vs 16.4%; p = 0.027)[3] in 2 studies.
The proportion of patients withdrawing from treatment because of adverse events was 29.5% lower
with aceclofenac than with comparator NSAIDs
overall in the meta-analysis of 13 trials (p =
0.002).[58]
The overall incidence of adverse events was significantly lower with aceclofenac 100mg twice
daily than with diclofenac sustained release 75mg
twice daily (p < 0.001) in the 12-month SAMM
study in 10 142 patients (fig. 2).[59] Adverse events
were most commonly associated with the GI and
Drugs 2001; 61 (9)
1371
Incidence (% of patients)
30
Aceclofenac
Diclofenac
25
**
20
15
**
**
10
5
*
in
ua
ra tion
te
s
ts
D
is
co
nt
ev
en
C
N
S
ts
G
Ie
ve
n
ad
ve
r
se Ov
ev era
en ll
ts
Fig. 2. Incidences of adverse events with aceclofenac and

diclofenac. Percentages of patients reporting adverse events
and of those withdrawing from study treatment during 12
months treatment with aceclofenac 100mg twice daily or
diclofenac sustained release 75mg twice daily. Results from a
nonrandomised, nonblind Safety Assessment of Marketed
Medicines (SAMM) study in 10 142 patients with rheumatic
disease.[59] * p = 0.007, ** p < 0.001 vs diclofenac.
central nervous systems. The incidence of CNS adverse events was significantly higher with aceclofenac than with diclofenac (p = 0.007) [fig. 2], although percentages of patients affected were low
in both groups (3 and 1.9%, respectively). No significant differences were observed in incidences of
events affecting other body systems. Adverse
events with both drugs were more common in older
patients (age not specified) and in females (events
reported by 25% of women and 21% of men). The
incidence of serious adverse events did not differ
significantly between aceclofenac and diclofenac
recipients (1.5 vs 1.9%), and similar percentages of
patients in each group required hospitalisation (1.2
vs 1.5%). Mortality was also similar between aceclofenac and diclofenac recipients (0.3 vs 0.8%),
and was observed most commonly in elderly patients (70 years of age). The rate of withdrawal
because of adverse events was significantly lower
with aceclofenac than with diclofenac (p < 0.001)
[fig. 2].[59]
In a nonblind comparison with nabumetone,[38]

proportions of patients experiencing adverse
events were similar with each treatment (35% with
aceclofenac and 40% with nabumetone). Furthermore, no significant differences were observed between the 2 treatments in the number of adverse
events reported (68 events with aceclofenac vs 72
with nabumetone). The most commonly reported
non-GI events were nausea/vertigo (3.6% in both
groups), respiratory symptoms (e.g. influenza,
dyspnoea, common cold: 5.1 and 2.9% with aceclofenac and nabumetone, respectively) and cardiovascular events (e.g. arterial hypertension, oedema:
3.6 and 2.2%).
Two cases[60,61] of hypersensitivity vasculitis in
recipients of aceclofenac have been reported previously,[12] and 5 new cases have been reported
since.[62] Palpable purpura developed in all 5 patients 1 to 50 days after starting aceclofenac 100 to
200 mg/day and subsided within 3 to 18 days of
drug withdrawal. Systemic involvement was not
apparent in any patient. A causal relationship with
aceclofenac was noted in 4 of the 5 cases, and was
confirmed by positive rechallenge in 1 patient.[62]
NSAID treatment is associated generally with
increases in systemic levels of hepatic enzymes in
some patients;[63] the manufacturers prescribing
information reports the incidence of this effect in
patients receiving aceclofenac to be 2.5%.[34] In
comparative clinical trials, incidences of raised
liver enzyme (ALT, AST, alkaline phosphatase or
-glutamyltranspeptidase) levels in blood with
aceclofenac were broadly similar to those observed
with diclofenac, indomethacin, naproxen, piroxicam or tenoxicam.[9,11,35-37,41,43,45,46] In 2 comparisons of aceclofenac with naproxen or piroxicam,[35,37] these elevations were nonsignificant or
were not sufficient for normal ranges to be exceeded.[35,37] There were no reports of serious hepatic adverse events in the SAMM study in 10 142
patients receiving aceclofenac or diclofenac.[59]
Elevated blood urea nitrogen and blood creatinine
levels have also been reported in patients receiving
aceclofenac.[34]
Drugs 2001; 61 (9)
1372
In trials in which elevations in hepatic enzyme

levels resulted in discontinuation of treatment,
withdrawal rates with aceclofenac were similar to
those with diclofenac (0.6 vs 3%[3] and 2 vs
4.1%[36]), tenoxicam (1.5 vs 0%)[45] and indomethacin (1.8 vs 0%).[41] In 1 trial,[36] the reason for
withdrawal was given as changes in laboratory parameters that included chiefly increases in serum
liver enzyme or creatinine levels.
It is difficult to assess the exact effect of
aceclofenac on hepatic function from the results of
these trials because many patients were receiving
other drugs (e.g. methotrexate). Furthermore, in 2
trials,[37,41] some patients had elevated levels of circulating liver enzymes at baseline. In a study in 12
elderly and 12 young volunteers who were given
aceclofenac alone (100mg twice daily for 7 days),[30]
statistically significant increases in circulating levels of AST (p = 0.002 vs baseline) and ALT (p =
0.047 vs baseline) were noted in elderly but not in
young study participants, although levels remained
within normal ranges in all but 1 young and 2 elderly volunteers.
5.2 Gastrointestinal Effects
In clinical trials, adverse events experienced after aceclofenac and comparator NSAIDs were most
commonly associated with the GI system. GI
events reported with aceclofenac include nausea,
diarrhoea, flatulence, gastritis, constipation, vomiting and ulcerative stomatitis (incidences below
5%[34]). As stated earlier, the most common GI
events are dyspepsia and abdominal pain.[34]
No significant differences in GI event rates
were apparent between aceclofenac and comparator
drugs in individual clinical trials; incidences
ranged from 8 to 28% after aceclofenac and from
15 to 36% after indomethacin, diclofenac, piroxicam, ketoprofen, tenoxicam or naproxen (fig.
3).[1,3,9,11,35-37,41-43,45,46] However, in 2 trials, withdrawal rates due to these events were significantly
lower with aceclofenac than with tenoxicam (0.7
vs 4%; p = 0.05)[43] or ketoprofen (1.1 vs 11%; p <
0.01).[42] In addition, the withdrawal rate was
lower with aceclofenac than with diclofenac (6 vs
Dooley et al.
11.5%; statistical analysis not reported) in 1 trial,[3]

and higher than that with naproxen (8.5 vs 2%; statistical analysis not reported) in another (fig. 3).[11]
Numerically similar withdrawal rates were observed for aceclofenac and indomethacin (1.3 vs
3.3%; statistical analysis not reported)[46] or
piroxicam (5.5% vs 2.8% and 5.6 vs 4.4%; statistical analyses not reported)[1,35] (fig. 3). Furthermore, in the trial discussed in section 5.1 in which
the overall withdrawal rate was significantly lower
after aceclofenac than after diclofenac treatment,
GI symptoms were a major cause of treatment
withdrawal in both treatment groups (no further
information provided).[3]
In general, the number of patients with faecal
blood loss did not differ significantly between aceclofenac and comparator agents, and ranged from 1.2
to 9% after aceclofenac and from 0 to 8.5% after
tenoxicam,[43,45] diclofenac,[3,9] piroxicam[35] or
indomethacin[46] in trials examining this end-point;
some patients had blood in their stools at baseline.[3,35,43] One patient receiving tenoxicam and no
aceclofenac recipients showed endoscopic evidence of duodenal or gastric ulceration in 2 studies
in which these agents were compared[43,45] (see
also section 2.2).
In the large nonblind SAMM trial,[59] GI events
were less common with aceclofenac 100mg twice
daily than with diclofenac sustained release 75mg
twice daily (p < 0.001) [fig. 2], and were mild to
moderate in both treatment groups. The incidences
of dyspepsia (5.4 vs 6.7%; p = 0.017), abdominal
pain (2.5 vs 4.4%; p < 0.001), diarrhoea (1.5 vs
3.6%; p < 0.001) and nausea (1.6 vs 2.4%; p = 0.01)
were significantly lower with aceclofenac than
with diclofenac.[59]
In the nonblind comparison with nabumetone,[38] the incidence of gastric intolerance appeared to be similar for aceclofenac 100mg twice
daily and nabumetone 1 to 2g daily (reported by 25
and 21 patients, respectively), but withdrawal rates
because of these events appeared to be higher with
aceclofenac (10.2 vs 5.1%). A between-treatment
statistical analysis was not reported.[38]
Drugs 2001; 61 (9)
1373
Aceclofenac
Comparator NSAID
GI events
ui
z
et
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.4
et
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.4
]
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5]
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7]
Pa
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. 11
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.3
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.9
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.4
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1]
ua
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Ba
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Withdrawals
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-R
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ui
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-M
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ar
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. [11
. [43
. [42
al
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-B
ez
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. [1]
5]
l. [3
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ie
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o
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. [9]
. [46
al
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. [3]
**
Pa
s
14
12
10
8
6
4
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Pe
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Incidence (% of patients)
40
35
30
25
20
15
10
5
0
Fig. 3. Rates of GI adverse events and treatment withdrawal in patients receiving aceclofenac. Incidence of GI events after administration of aceclofenac 100mg twice daily for 2 to 6 months in individual clinical studies in patients with osteoarthritis of the knee,
rheumatoid arthritis or ankylosing spondylitis in randomised, double-blind trials in 104 to 378 patients. Aceclofenac was compared
with indomethacin[41,46] diclofenac,[3,9,36] piroxicam,[1,35] ketoprofen,[42] tenoxicam[43,45] and naproxen.[11,37] Also shown are percentages of patients discontinuing study medication (withdrawals) because of adverse events affecting the GI system in clinical studies
comparing aceclofenac with indomethacin,[46] diclofenac,[3,9] piroxicam,[1,35] ketoprofen,[42] tenoxicam[43] or naproxen.[11] * p = 0.05,
** p < 0.01 vs comparator.
According to the meta-analysis in 3574 patients

described in section 5.1,[58] a significantly higher
proportion of patients receiving aceclofenac
100mg twice daily than of those receiving other
NSAIDs remained free from GI symptoms after 3
to 6 months treatment. The overall odds ratio indicated that aceclofenac recipients were 1.52 times
more likely than patients receiving other agents to
be free of GI adverse events (2 = 24.75; p < 0.001).
A recent 18-month analysis (reported as an abstract) in 142 776 Spanish patients showed aceclofenac to be associated with a lower incidence of
upper GI bleeding events than 10 other NSAIDs,
although demonstration of statistical significance
was not attempted as part of the analysis.[64] The
highest rates of upper GI bleeding were seen in
recipients of piroxicam, ketorolac, niflumic acid or
indomethacin.
Drugs 2001; 61 (9)
1374
6. Dosage and Administration

Aceclofenac is indicated for the relief of pain
and inflammation associated with rheumatoid arthritis, osteoarthritis or ankylosing spondylitis.
The recommended dosage is 100mg twice daily,
and adjustments are generally not necessary in elderly patients (see section 3.1) or in those with mild
renal impairment. As with other NSAIDs, monitoring is recommended in these 2 groups of patients,
and caution is advised in elderly patients, who are
more likely to have concomitant renal, hepatic or
cardiovascular impairment, or to be receiving concurrent medication, than the general population.
Dosage reductions are recommended in patients
with hepatic impairment, with a suggested initial
dosage of 100 mg/day.[34]
The use of aceclofenac is not recommended in
patients with active or suspected peptic ulcer or GI
bleeding, moderate or severe renal impairment,
sensitivity to aceclofenac or other NSAIDs, previous aspirin or NSAID-related allergic or anaphylactic reactions, or during pregnancy or breast feeding. Hepatitis may occur without prodromal symptoms, and if liver function tests are persistently
abnormal the use of aceclofenac should be discontinued. Aceclofenac may trigger attacks in patients
with hepatic porphyria, and reversible inhibition of
platelet aggregation may occur with the drug. Renal and hepatic function and blood counts should
be monitored in patients receiving long term treatment with aceclofenac.[34]
Drug interactions associated with aceclofenac
are similar to those observed with other NSAIDs.
Aceclofenac may increase plasma concentrations
of lithium, digoxin and methotrexate, increase the
activity of anticoagulants, inhibit the activity of diuretics, enhance cyclosporin nephrotoxicity, and
precipitate convulsions when coadministered with
quinolone antibiotics. Furthermore, hypo- or hyperglycaemia may result from the concomitant administration of aceclofenac and antidiabetic drugs, although this is rare. The coadministration of aceclofenac with other NSAIDS or corticosteroids
may result in increased frequency of adverse
events.[34]
Dooley et al.
7. Place of Aceclofenac in
the Management of Pain
and Rheumatic Disease
The treatment goals for osteoarthritis, rheumatoid arthritis and ankylosing spondylitis are generally similar, and are to stop or reduce joint inflammation and pain, maintain or improve functioning
and mobility, minimise disability, and prevent, delay or correct deformity.[1,2,36,41] Physical therapy
and other nonpharmacological treatments are very
important in the management of these rheumatic
diseases, and include exercise, weight reduction
and physiotherapy. Surgery may be necessary in
some patients with rheumatoid arthritis or osteoarthritis.[2,4,65,66] DMARDs are used in patients
with rheumatoid arthritis, but are ineffective in
those with osteoarthritis or ankylosing spondylitis
(with the exception of sulfasalazine in the latter
condition).[2,65] These treatments are also limited
in patients with rheumatoid arthritis by toxicity and
loss of disease control that may be seen within a
few years of starting treatment. Nevertheless, treatment with DMARDs is appropriate for most patients in the early stages of the disease.
Control of the symptoms of osteoarthritis may
be achieved with paracetamol, or with NSAIDs if
paracetamol is ineffective. Topical analgesics (e.g.
capsaicin or NSAIDs) can be used as add-on treatments or as alternatives in patients with contraindications to systemic NSAIDs. Intra-articular
steroids or hyaluronic acid may provide short term
relief in patients with osteoarthritis of the knee.
The flares, or increases in pain, associated with
this disease can be controlled with the short term
use of an opioid analgesic.[4,66]
Orally administered NSAIDs play an important
role in the symptomatic management of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. In general, they produce their anti-inflammatory and analgesic effects by inhibiting cyclooxygenase and thus preventing the production of
prostaglandins from arachidonic acid, although effects on other physiological systems (as seen with
aceclofenac; see section 2.1) may also be involved.
In addition, it has been suggested that some
Drugs 2001; 61 (9)
NSAIDs inhibit leukotriene production via lipoxygenase inhibition.[67]

Since long term NSAID treatment is indicated
for osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, the ideal agent should have
good efficacy and a low propensity to cause adverse events. In general, there does not appear to
be a significant difference in efficacy between the
individual NSAIDs. However, the interpatient
variability in responses to this class of drugs highlights the need to individualise NSAID treatment
(reviewed by Lane and Thompson.[66] and Creamer
and Hochberg[4]).
Aceclofenac is a phenylacetic acid derivative
that is an effective analgesic and anti-inflammatory agent with a good tolerability profile. In large
trials of 2 to 6 months duration, aceclofenac significantly reduced pain and improved functional
capacity and mobility relative to baseline in patients with osteoarthritis, rheumatoid arthritis or
ankylosing spondylitis, and reduced inflammation
in patients with rheumatoid arthritis (sections 4.1,
4.2 and 4.3). The analgesic and anti-inflammatory
efficacy of aceclofenac was generally equivalent
to that of comparator NSAIDs, with similar onset
of action. The drug has also been shown to be superior to placebo in the management of moderate
to severe dental pain, and to paracetamol 650mg
when given after episiotomy at a dose of 100mg
(section 4.4).
Clearly, NSAIDs are effective at reducing the
pain and inflammation associated with rheumatic
disease. However, it has been suggested that not all
NSAIDs have the same effect on cartilage maintenance and repair (reviewed by Stolz[68]). NSAIDs
may promote, inhibit or have no effect on cartilage
synthesis, thus influencing the clinical course of
conditions such as osteoarthritis in which cartilage
synthesis is already reduced. Aceclofenac decreases
production of IL-1 (which may be involved in
cartilage synthesis), and has been associated with
stimulation of cartilage matrix synthesis in vitro
(section 2.1). This effect merits investigation over
the long term in clinical studies.
1375
Aceclofenac is well tolerated, with most adverse events being mild and reversible and related
to the GI system. In individual comparative trials,
the overall incidence of adverse events after
aceclofenac was lower than after naproxen but generally similar to that of most other comparator
drugs. Meta-analysis of tolerability data from
randomised, double-blind studies, however, has
shown overall a significantly higher probability of
freedom from adverse events in patients taking
aceclofenac than in those taking a range of other
NSAIDs (section 5). In the large nonblind SAMM
trial (10 142 patients) discussed in section 5,[59] the
overall incidence of adverse events was significantly lower with aceclofenac than with a sustained release formulation of diclofenac. Aceclofenac appears in general to increase hepatic enzyme activity to a similar extent to other NSAIDs,
although the clinical significance of this is unclear.
GI tolerability may differ between the individual NSAIDs, and the risk of developing GI adverse
events is an important consideration when choosing an NSAID. The rate of GI adverse events, including faecal blood loss, was generally similar
with aceclofenac and comparator NSAIDs in individual clinical trials (section 5). However, these
effects generally resulted in significantly lower
withdrawal rates in patients receiving aceclofenac
than in ketoprofen or tenoxicam recipients.
Small trials using endoscopic assessments indicate that short term aceclofenac use induces less
gastric mucosal damage than diclofenac or
naproxen (section 2.2). Although the clinical relevance of such endoscopic data has been questioned
in the literature,[69] the SAMM study[59] showed a
significantly lower incidence of GI adverse events
with aceclofenac than with a sustained release formulation of diclofenac (section 5.2), even though
significantly more aceclofenac than diclofenac recipients had a history of dyspepsia at baseline. In
addition, as discussed in section 5.2, results of a
meta-analysis of studies involving a total of 3574
patients indicated that a significantly greater proportion of patients receiving aceclofenac remained
free from GI symptoms after 3 to 6 months treatDrugs 2001; 61 (9)
1376
ment than recipients of diclofenac, naproxen, piroxicam, indomethacin, tenoxicam or ketoprofen.[58]

Preliminary data obtained in a large number of
Spanish patients also suggest a lower incidence of
upper GI events in individuals receiving acecloenac than in recipients of other NSAIDs[64] (section
5.2). Of related interest are the in vitro findings
reported in section 2.1 that suggest high affinity of
aceclofenac for the COX-2 enzyme. It is anticipated that further clinical experience with aceclofenac in increasing numbers of patients will shed
further light on these promising findings.
Economic analysis of the use of aceclofenac in
12 of the 13 studies included in the meta-analysis
described above[58] has suggested that the favourable tolerability profile of the drug is reflected in
reductions in costs associated with managing adverse events relative to other NSAIDs from a
healthcare providers perspective (section 4.5).
This translated into similar overall costs of treatment for aceclofenac and a range of comparators,
including diclofenac, indomethacin, naproxen,
tenoxicam and ketoprofen over a 3-month period,
notwithstanding the acquisition cost of aceclofenac. To date, pharmacoeconomic data are confined to this meta-analysis of clinical trials, and
further investigations, preferably carried out in the
clinical setting over a longer period to show clearly
the cost of aceclofenac in terms of clinical outcomes relative to other agents (i.e. cost-effectiveness studies) would be of future interest. Studies
that take into account effects on indirect costs (e.g.
those associated with productivity) and quality of
life are also desirable.
In conclusion, trials of 2 to 6 months duration
have shown aceclofenac to be an effective agent in
the management of pain and rheumatic disease.
Data from in vitro studies indicate properties of
particular interest with respect to cartilage matrix
effects and selectivity for COX-2, and merit further
investigation. Aceclofenac is well tolerated, with
encouraging reports of improved general and GI
tolerability relative to other NSAIDs from a metaanalysis of double-blind trials and from large nonblind studies.
Dooley et al.
References
1. Torri G, Vignati C, Agrifoglio E, et al. Aceclofenac versus
piroxicam in the management of osteoarthritis of the knee: a
double-blind controlled study. Curr Ther Res 1994; 55 (5):
576-83
2. Berkow R, Fletcher AJ, editors. The Merck Manual. 16th ed.
Rahway, NJ: Merck Research Laboratories, 1992
3. Daz C, Rodrguez de la Serna A, Geli C, et al. Efficacy and
tolerability of aceclofenac versus diclofenac in the treatment
of knee osteoarthritis: a multicentre study. Eur J Rheumatol
Inflamm 1996; 16 (1): 17-22
4. Creamer P, Hochberg MC. Osteoarthritis. Lancet 1997 Aug 16;
350: 503-9
5. Gonzlez E, de la Cruz C, de Nicols R, et al. Long-term effect
of nonsteroidal anti-inflammatory drugs on the production of
cytokines and other inflammatory mediators by blood cells of
patients with osteoarthritis. Agents Actions 1994; 41: 171-8
6. Martel-Pelletier J, Cloutier J-M, Pelletier J-P. Effects of aceclofenac and diclofenac on synovial inflammatory factors in
human osteoarthritis. Clin Drug Invest 1997 Sep; 14: 226-32
7. Dingle JT. The effect of NSAIDs on human articular cartilage
glycosaminoglycan synthesis. Eur J Rheumatol Inflamm
1996; 16 (1): 47-52
8. Dingle JT, Parker M. NSAID stimulation of human cartilage
matrix synthesis: a study of the mechanism of action of
aceclofenac. Clin Drug Invest 1997 Nov; 14: 353-62
9. Pasero G, Marcolongo R, Serni U, et al. A multi-centre, double-blind comparative study of the efficacy and safety of
aceclofenac and diclofenac in the treatment of rheumatoid
arthritis. Curr Med Res Opin 1995; 13 (6): 305-15
10. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification
of rheumatoid arthritis. Arthritis Rheum 1988 Mar; 31 (3):
315-24
11. Pasero G, Ruju G, Marcolongo R, et al. Aceclofenac versus
naproxen in the treatment of ankylosing spondylitis: a doubleblind, controlled study. Curr Ther Res 1994; 55 (7): 833-42
12. Brogden RN, Wiseman LR. Aceclofenac: a review of its pharmacodynamic properties and therapeutic potential in the treatment of rheumatic disorders and in pain management. Drugs
1996 Jul; 52: 113-24
13. Cecchettin M, Cerea P, Torri G. Therapeutic efficacy of
aceclofenac and diclofenac in acute knee arthroses: a study of
E2-prostaglandin levels in synovial fluid and in serum. Clin
Trials J 1988; 25 (2): 144-51
14. Henrotin Y, de Laval X, Mathy-Hartet M, et al. In vitro effects
of aceclofenac and its metabolites on the production by
chondrocytes of inflammatory mediators. Inflamm Res. In press
15. Yamazaki R, Kawai S, Matsuzaki T, et al. Aceclofenac blocks
prostaglandin E2 production following its intracellular conversion into cyclooxygenase inhibitors. Eur J Pharmacol 1997
Jun 25; 329: 181-7
16. Yamazaki R, Kawai S, Matsumoto T, et al. Hydrolytic activity
is essential for aceclofenac to inhibit cyclooxygenase in rheumatoid synovial cells. J Pharmacol Exp Ther 1999; 289: 676-81
17. Garcia-Vicua R, Gonzlez-Alvaro I, Carmona L, et al.
Aceclofenac, a new NSAID, diminishes the neutrophil expression of cell adhesion molecules involved in interaction
with endothelium. Arthritis Rheum 1995; 38: S156
18. Akimoto H, Yamazaki R, Hashimoto S, et al. 4-Hydroxy
aceclofenac suppresses the interleukin-1-induced production
of promatrix metalloproteinases and release of sulfatedglycosaminoglycans from rabbit articular chondrocytes. Eur
J Pharmacol 2000; 401: 429-36
19. Yamazaki R, Kawai S, Mizushima Y, et al. A major metabolite
of aceclofenac, 4-hydroxy aceclofenac, suppresses the production of interstitial pro-collagenase/proMMP-1 and pro-
Drugs 2001; 61 (9)
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
stromelysin-1/proMMP-3 by human rheumatoid synovial

cells. Inflamm Res 2000; 49: 133-8
Grau M, Guasch J, Montero J, et al. Pharmacology of the potent
new non-steroidal anti-inflammatory agent aceclofenac.
Arzneimittelforschung 1991; 41: 1265-76
Ara A, Zapatero MI, Basi N, et al. Comparison of the antiinflammatory effect and gastrointestinal tolerability of
aceclofenac and diclofenac. Arzneimittelforschung 1996
Apr; 46: 398-400
Yanagawa A, Kudo T, Shimada J, et al. Endoscopic study of
the damaging action of diclofenac Na, aceclofenac and its
placebo on the gastric and duodenal mucosa [abstract]. Rheumatology in Europe 1995; 24 Suppl. 3: 220
Wassif W, Bjarnason I. A comparison of the effects of
aceclofenac and diclofenac on gastrointestinal blood loss. Br
J Clin Res 1992; 3: 109-14
Mundo F, Mitrani C, Snchez H, et al. Endoscopic assessment
of gastric mucosa injury with the use of non-steroidal antiinflammatory drugs: aceclofenac vs naproxen, single-blind,
controlled, prospective study [abstract]. Am J Gastroenterol
1996 Sep; 91: 1922
Lidbury P, Vojnovic I, Warner T. COX-2/COX-1 selectivity of
aceclofenac in comparison with celecoxib and rofecoxib in
the human whole blood assay [abstract]. Osteoarthritis Cartilage 2000; 8 Suppl. B: S40-1
de Leval X, Dogne JM, Delarge J, et al. Evaluation of classical
NSAIDs and COX-2 selective inhibitors on purified ovine
enzymes and human whole blood [abstract no. AB0223].
Proceedings of the European League Against Rheumatism
(EULAR); 2001 Jun 13-16; Prague
Blanco FJ, Maneiro E, de Toro FJ, et al. Effect of NSAIDs on
synthesis of IL-1 receptor antagonist (IL-1 Ra) by human
articular chondrocytes [abstract]. Osteoarthritis Cartilage
2000; 8 Suppl. B: S27
Yanagawa A, Endo T, Kusakari K, et al. Endoscopic evaluation
of aceclofenac-induced gastroduodenal mucosal damage: a
double-blind comparison with sodium diclofenac and placebo. Jpn J Rheumatol 1998; 8 (3): 249-59
Bort R, Ponsoda X, Carrasco E, et al. Metabolism of aceclofenac in humans. Drug Metab Dispos 1996 Aug; 24: 834-41
Creamer J. A comparison of the pharmacokinetics of single and
repeated doses of aceclofenac in young and elderly volunteers. Br J Clin Res 1992; 3: 99-107
Crema A, Crema F, Parnham MJ, et al. Effect of food on the
bioavailability of aceclofenac tablets in healthy volunteers.
Eur J Clin Res 1995; 7: 155-60
Wood SG, Fitzpatrick K, Brodie RR, et al. Pharmacokinetics
and metabolism of a new NSAID/analgesic aceclofenac in
man [abstract]. Pharm Res 1990; 7 (9): S-212
Honorato J, Caballero R, Giorgiani G, et al. Dose-analgesic
response study and aceclofenac plasma levels in humans.
Curr Ther Res 1990; 47 (4): 605-11
Preservex tablets. In: Walker G, editor. ABPI compendium of
data sheets and summaries of product characteristics 19992000. London: Datapharm Publications Ltd, 1999: 1680-1
Prez Busquier M, Calero E, Rodriguez M, et al. Comparison
of aceclofenac with piroxicam in the treatment of osteoarthritis. Clin Rheumatol 1997 Mar; 16: 154-9
Ward DE, Veys EM, Bowdler JM, et al. Comparison of aceclofenac with diclofenac in the treatment of osteoarthritis. Clin
Rheumatol 1995 Nov; 14: 656-62
Kornasoff D, Frerick H, Bowdler J, et al. Aceclofenac is a welltolerated alternative to naproxen in the treatment of osteoarthritis. Clin Rheumatol 1997 Jan; 16: 32-8
Gijn Baos JG. Efficacy and safety of nabumetone in the treatment of knee osteoarthritis: a comparative clinical trial versus
aceclofenac. Knee Arthrosis Nabumetone Study Group [in
Spanish]. Med Clin (Barc) 1997; 109 (4): 130-4
1377
39. Giorgianni G, Ottaviani C, Soliano A. Efficacy and tolerability

of aceclofenac versus ketoprofen in the treatment of rheumatoid arthritis. Curr Ther Res Clin Exp 1992; 51: 175-84
40. Ritchie DM, Boyle JA, McInnes JM, et al. Clinical studies with
an articular index for the assessment of joint tenderness in
patients with rheumatoid arthritis. Q J Med 1968; 37 (147):
393-406
41. Kornasoff D, Maisenbacher J, Bowdler J, et al. The efficacy
and tolerability of aceclofenac compared to indomethacin in
patients with rheumatoid arthritis. Rheumatol Int 1996 Mar;
15: 225-30
42. Martn-Mola E, Gijn-Baos J, Ansoleaga JJ. Aceclofenac in
comparison to ketoprofen in the treatment of rheumatoid arthritis. Rheumatol Int 1995; 15: 111-6
43. Perez-Ruiz F, Alonso-Ruiz A, Ansoleaga JJ. Comparative
study of the efficacy and safety of aceclofenac and tenoxicam
in rheumatoid arthritis. Clin Rheumatol 1996 Sep; 15: 473-7
44. Steinbrocker O, Traeger C, Battermann RC. Therapeutic criteria in rheumatoid arthritis. JAMA 1949; 140: 659-62
45. Villa Alczar LF, de Buergo MA, Lenza HR, et al. Aceclofenac
is as safe and effective as tenoxicam in the treatment of ankylosing spondylitis: a 3 month multicenter comparative trial.
J Rheumatol 1996 Jul; 23: 1194-9
46. Batlle-Gualda E, Figueroa M, Ivorra J, et al. The efficacy and
tolerability of aceclofenac in the treatment of patients with
ankylosing spondylitis: a multicenter controlled clinical trial.
J Rheumatol 1996 Jul; 23: 1200-6
47. Sainz-Olalla F. Analgesic efficacy of aceclofenac: double-blind
controlled study vs placebo in odontalgia. Curr Ther Res Clin
Exp 1988; 43 (5): 900-2
48. Bubani G. The analgesic activity and tolerability of aceclofenac in the treatment of odontalgia: a double-blind placebocontrolled evaluation. Clin Trials J 1988; 25 (4): 244-53
49. Puigvert Torrent A. Dose-response study of the analgesic activity of aceclofenac in odontalgia following extraction of the
third molar. Drug Invest 1990; 2 (2): 132-6
50. Yscla A. Aceclofenac and paracetamol in episiotomal pain.
Drugs Exp Clin Res 1988; 14 (7): 491-4
51. Movilia PG. Evaluation of the analgesic activity and tolerability
of aceclofenac in the treatment of post-episiotomy pain.
Drugs Exp Clin Res 1989; 15 (1): 47-51
52. da Fonseca AM, Bagnoli VR. A multicenter study of the efficacy and tolerability of aceclofenac in the treatment of primary dysmenorrhea [in Portuguese]. Rev Bras Med 1999; 56
(3): 169-73
53. Agrifoglio E, Benvenuti M, Gatto P, et al. Aceclofenac: a new
NSAID in the treatment of acute lumbago. Multicentre single
blind study vs diclofenac. Acta Ther 1994; 20 (1-2): 33-45
54. de Barros Filho TEP, Ortiz J, Gomes Vialle LR, et al. Study of
the efficacy and tolerability of aceclofenac in the management of low-back pain [in Portuguese]. Rev Bras Med 1999;
56 (1/2): 60-4
55. Kberle G, Couto Magalhaes AA, Jansen Paccola CA, et al.
Multicenter, open study of the use of aceclofenac 100 mg,
twice a day, in the treatment of muscular-skeletal traumas [in
Portuguese]. Rev Bras Med 1998; 55 (1/2): 63-9
56. Ishida A, Adames MK. Study of the efficacy and tolerability of
aceclofenac in the treatment of post-traumatic acute process
in orthopaedics and traumatology [in Portuguese]. Rev Bras
Med 1997; 54 (8): 687-93
57. Peris F, Martnez E, Badia X, et al. Iatrogenic cost factors
incorporating mild and moderate adverse events in the economic comparison of aceclofenac and other NSAIDs. Pharmacoeconomics 2001; 19 (7): 779-90
58. Peris F, Bird HA, Serni U, et al. Treatment compliance and
safety of aceclofenac versus standard NSAIDs in patients
with common arthritic disorders: a meta-analysis. Eur J
Rheumatol Inflamm 1996; 16 (1): 37-45
Drugs 2001; 61 (9)
1378
59. Huskisson EC, Irani M, Murray F. A large prospective open-label, multicentre SAMM study, comparing the safety of
aceclofenac with diclofenac in patients with rheumatic disease. Eur J Rheumatol Inflamm 2000; 17 (1): 1-7
60. Epelde F, Boada L. Leukocytoclastic vasculitis and hemoptysis
after treatment with aceclofenac [letter]. Ann Pharmacother
1995 Nov; 29: 1168
61. Nez M, Miralles ES, Harto A, et al. Hypersensitivity vasculitis associated with aceclofenac [letter]. J Dermatol Treat
1995; 6 (1): 54
62. Morros R, Figueras A, Capell D, et al. Hypersensitivity vasculitis related to aceclofenac [letter]. Br J Rheumatol 1997 Apr;
36: 503-4
63. Prescott LF. Effects of non-narcotic analgesics on the liver.
Drugs 1986; 32 Suppl. 4: 129-47
64. Llorente MJ. Specific types of nonsteroidal anti-inflammatory
drugs and relative risk of upper gastrointestinal bleeding [abstract]. Br J Rheumatol 1998; 37 Suppl. 1: 115
Dooley et al.
65. Speight TM, Holford N, editors. Averys drug treatment. 4th ed.
Auckland, New Zealand: Adis International Limited, 1997
66. Lane NE, Thompson JM. Management of osteoarthritis in the
primary-care setting: an evidence-based approach to treatment. Am J Med 1997 Dec 29; 103 Suppl. 6A: 25S-30S
67. Cashman JN. The mechanisms of action of NSAIDs in analgesia. Drugs 1996; 52 Suppl. 5: 13-23
68. Stolz J. Aceclofenac may offer advantages in arthritis management. Inpharma 1998 May 9; 1136: 3-4
69. Peterson WL, Cryer B. COX-1sparing NSAIDs is the enthusiasm justified? JAMA 1999; 282 (20): 1961-3
Correspondence: Christopher J. Dunn, Adis International

Limited, 41 Centorian Drive, Private Bag 65901, Mairangi
Bay, Auckland 10, New Zealand.
E-mail: demail@adis.co.nz
Drugs 2001; 61 (9)

Aceclofenac A Reappraisal of Its Use in The.12

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ADIS DRUG EVALUATION

Drugs 2001; 61 (9): 1351-1378

Aceclofenac is an orally administered phenylacetic acid derivative with effects

Adis International Limited. All rights reserved.

Drugs 2001; 61 (9)

decreased basal and IL-1stimulated production of this mediator in human

Aceclofenac is rapidly and completely absorbed after oral administration, with

Adis International Limited. All rights reserved.

Drugs 2001; 61 (9)

Aceclofenac (administered orally unless stated otherwise in all clinical studies

Adis International Limited. All rights reserved.

Drugs 2001; 61 (9)

Adis International Limited. All rights reserved.

Drugs 2001; 61 (9)

Adis International Limited. All rights reserved.

Drugs 2001; 61 (9)

arthritis of at least 3 joint areas

Inhibition of production of the inflammatory mediators IL-1a and

Rodent and canine models of acute and chronic inflammation[12]

2.1 Effects on Mediators of Inflammation

The anti-inflammatory effects of aceclofenac

tion, including some cell adhesion molecules from

production at concentrations of 1 to 30 mol/L.[14]

0.04 mol/L, respectively). All agents had a weak

2.1.2 Ex Vivo Studies in Patients

The inhibitory effects of aceclofenac on IL-1,

2.2 Other Effects

Oral aceclofenac alleviated pain induced by

Cmax and AUC values increased linearly after

Aceclofenac is metabolised to a major metabolite, 4-hydroxyaceclofenac, and to a number of

Aceclofenac decreases pain levels, reduces the

by investigators and patients by use of 5-point

Knee function scoree

Comparisons with diclofenac (D)

Comparisons with piroxicam (P)

Pain intensity scorea

Comparison with naproxen (N)

Drugs 2001; 61 (9)

Adis International Limited. All rights reserved.

Reductions in pain levels and improvements in

(from 61.3 to 44mm; p < 0.001 vs baseline) and

The anti-inflammatory and analgesic efficacy

smaller than with aceclofenac (table III). Overall

Aceclofenac 100mg twice daily reduced pain

Drugs 2001; 61 (9)

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Drugs 2001; 61 (9)

Adis International Limited. All rights reserved.

A 100mg bid (155)

Modified Schbers test C7 to iliac crestc or

I 25mg bid and

10.2/3.8 +1***/0.8*** 3.8

Adis International Limited. All rights reserved.

Drugs 2001; 61 (9)

scale; 0 = no pain to 3 = severe pain) by 55 to 79%

As discussed in the preceding sections (4.1, 4.2

A recent cost analysis has suggested that

from a healthcare providers perspective when

accounting data where available. The iatrogenic

osteoarthritis),[59] and from a meta-analysis of 13

Fig. 2. Incidences of adverse events with aceclofenac and

In a nonblind comparison with nabumetone,[38]

In trials in which elevations in hepatic enzyme

10.2/3.8 +1/0.8 3.8