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93

Evaluations of New Drugs

Ketoprofen: A Review of Its Pharmacologic and


Clinical Properties
Thomas G. Kantor, M.D.

Ketoprofen (Orudis),a highly potent and safe nonsteroidal antiinflammatory drug


of the propionic acid derivative group, was synthesized in France by Rh6ne-
Poulenc chemists in 1967, 3 years after the prototype ibuprofen. Ketoprofen was
introduced in 1973 in France and the United Kingdom for antiinflammatory use.
Today the drug is available in about 80 countries and has recently been approved in
the United States for treatment of rheumatoid arthritis and osteoarthritis. The thera-
peutic experience with ketoprofen is estimated to have exc'eeded 3 million patient-
years. Double-blind trials have established its therapeutic equivalence with aspirin,
indomethacin, and ibuprofen in rheumatoid arthritis and with aspirin in osteoarthri-
tis. Ketoprofen has a short half-life, a simple metabolism, and a broad therapeutic
window, and does not accumulate with multiple doses. These features contribute to
a rapid onset of action, flexible dosing, and a reliable tolerance profile.
(Pharmacotherapy 1986;6(3):93-103)

OUTLINE Ketoprofen is a nonsteroidal antiinflammatory


drug (NSAID) belonging to the group of substituted
Pharmacology and Toxicology
2-phenylpropionicacids. Its structural formula (2-(3-
Antiinflammatory Effects
benzolpheny1)-propionicacid) is shown in figure 1 ;
Analgesic and Antipyretic Effects
its molecular weight is 254.29. Ketoprofen was syn-
Mechanism of Action
thesized by RhBne-Poulenc Research Laboratories,
Toxicology
Paris, in 1967 and was first approved for clinical use
Clinical Pharmacology in France and the United Kingdom in 1973. The drug
Pharmacokinetics and Metabolism is currently marketed throughout the world in a vari-
Drug Interactions ety of forms: capsules, injectable solutions, supposi-
tories, and a topical gel. A controlled-release capsule
Clinical Efficacy for once-daily administration (Oruvail) was intro-
Osteoarthritis duced in the United Kingdom. Extensive testing in
Rheumatoid Arthritis
Ankylosing Spondylitis
Acute Gouty Arthritis
Acute Painful Shoulder Syndrome
Juvenile Rheumatoid Arthritis
Clinical Safety
Conclusions
From the New York University School of Medicine, New York,
New York.
Address reprint requests to Thomas G. Kantor, M.D., Professor
Of Clinical Medicine, New York University School of Medicine, 550
First Avenue, New York, NY 10017.
These trials were sponsored by lves Laboratories, Inc., New
York, NY. Figure 1. Structural formula of ketoprofen
94 PHARMACOTHERAPY VOLUME6, NUMBER
3, MAY~JUNE
1986

the United States, confirming foreign clinical experi- As with all NSAIDs, the physiologic basis of keto-
ence, demonstrated that ketoprofen is effective in profen’s pharmacodynamic activities is presumed to
treatment of arthritis. Furthermore, the drug has a be interference with arachidonic acid metabolism
well-defined safety profile that offers significant ad- (Figure 2). Ketoprofen is one of the most powerful
vantages over aspirin in controlled studies. United inhibitors of cyclo-oxygenaseat concentrations well
States approval of clinical use of ketoprofen cap- within the range of therapeutic plasma levels (EC,, 2
sules in osteoarthritis and rheumatoid arthritis was pglL). The drug was 6 and 12 times more potent than
granted in January 1986. naproxen and indomethacin respectively in inhibiting
This review describes the pharmacology and prostaglandin synthesis in isolated guinea pig lung
pharmacokineticsof ketoprofen and summarizes the preparations perfused with arachidonic acid.g Ibu-
results of United States clinical trials conducted be- profen, phenylbutazone, and aspirin were 800-1 500
tween 1975 and 1984. Both published and unpub- times less potent than ket~profen.~ Although there
lished data are included to provide a comprehensive was a much narrower range of relative potencies in
summary of the available information. The unpub- antiinflammatory activity (carrageenin-induced ab-
lished trials are being summarizedfor publications in scess) among the NSAlDs tested, the rank order
a journal supplement; all of them have been subject- remained the same, indicating a correlation between
ed to review by the Food and Drug Administration. prostaglandin synthesis inhibition and antiinflamma-
Several reviews of the foreign clinical studies with tory a~tivity.~ Other studies showed potent inhibition
ketoprofen have been pubIished.l4 of prostaglandin synthesis by ketoprofen in ram and
rat seminal vesicle microsomes,lo.ll in rat and rabbit
Pharmacology and Toxicology renal medulla,’* and in human lung tissue.” Prosta-
glandin levels and associated paw edema after intra-
Antiinflammatory Effects plantar carrageenin injections were also reduced by
In several animal models (rats, mice, rabbits, guin- ketoprofen.l0
ea pigs, and pigeons) ketoprofen displayed potent In addition to its effects on cyclo-oxygenase,keto-
activity against acute inflammation (increased vas- profen inhibits the lipoxygenase pathway of the ara-
cular permeability, edema, and erythema), subacute chidonic acid c a ~ c a d e . ~This
l . l ~ pathway produces
inflammation (pleurisy, abscess, and granuloma for- noncyclized monohydroxy acids (HETE) and leuko-
mation), and chronic inflammation (experimental ar- trienes.12Of these, only leukotrienes (B4, C, and D,)
thritis and s y n o v i t i ~ )These
. ~ ~ tests showed ketopro- are thought to increase vascular permeability14;how-
fen to be 20 times more potent than ibuprofen, 80 ever, both HETE and leukotrienes synthesized with-
times more potent than phenylbutazone, and 160 in leukocytes are active in promoting leukocyte mi-
times more potent than aspirin in reducing inflamma- gration and The clinical relevance of
tion from carrageenin-induced abscesses in rat^.^^^ lipoxygenase inhibition remains to be established,
The drug’s potency was generally equivalent to that but it has been suggested that lipoxygenase inhibi-
of indomethacin in most models.5g Of significance, tors may attenuate cell-mediated inflammation and
in rat adjuvant arthritis, the minimally effective dos- thus retard the progression of tissue destruction in
age of ketoprofen (2.5 mg/kg/dj could be doubled to inflamed joints.
produce even greater efficacy (up to 70% inhibition), In addition to these properties, ketoprofen has oth-
while a similar dosage increase with indomethacin er pharmacologic effects that may be relevant to its
resulted in 100°/o m~rtality.~ antiinflammatory and analgesic activity. For exam-

Analgesic and Antipyretic Effects


Ketoprofen was a potent, peripherally acting anal-
gesic in 2 classic animal models of pain. In prevent- Arachidonic Acid Metabolism
ing pain from intraperitonealinjections of phenylben-
zoquinone, it was equivalent to indomethacinand 70 Membrane Phospholipids
times more potent than a ~ p i r i nIn. ~Randall and Selit-
to’s paw-compression test, ketoprofen was equiv- I Phospholipase
alent to indomethacin,* slightly more potent than na-
Slle 01 Inhibition Arachidonic Acid
proxen,8and 30 times more potent than a ~ p i r i nLike
.~ by Ketoprofen \
other NSAIDs, ketoprofen is inactive in assays mea-
suring centrally mediated analgesia (e.g., tail pinch-
i t ~ g ) It. ~did not reduce basal temperature, but de-
I Lipoxygenass J
creased antigen-induced hyperthermia in rats and I ) * I)%
rabbits to a greater extent than any other NSAID HETE Leukotrienes Prostaglandins Thromboxanes
tested, including indomethacin,naproxen, ibuprofen,
and phenylb~tazone.~
Figure 2. Schematic diagram of arachidonic acid metabo-
Mechanism of Action lism.
KETOPROFEN: A REVIEW Kantor 95

ple, it is a powerful inhibitor of brad~kinin,~


an impor- excretion are somewhat delayed in elderly subjects
tant chemical mediator of pain and inflammation. (65 years of age or ~ l d e r ) , ~resulting
~ . ‘ ~ in an increase
Also, it stabilizes lysosomal membranes against os- of the terminal half-life to 3-5 hours. Measurements
motic damage,18and prevents the release of lysoso- of the area under the curve after multiple dosing
ma1 enzymes that mediate tissue destruction in in- show that this half-life is short enough to prevent
flammatory reaction^.'^ toxic accumulation of the drug in elderly patients with
rheumatoid arthritkZ2Thus no routine dosage ad-
Toxicology justment seems to be necessary in these persons.
A similar minor prolongationin half-lifewas seen in
Acute oral toxic levels of ketoprofen (LD,) ranged
patients with impaired renal function (creatinine
from 360-575 mg/kg in mice and from 56-1 60 mg/kg clearance 20-60 m l / m i r ~or) ~alcoholic
~ cirrhosis.28In
in young adult rats (Charles River, CD). In guinea
patients with renal dysfunction, a close correlation
pigs and dogs, oral LD, values were greater than
between creatinine clearance and ketoprofen clear-
1000 mg/kg.8Drug toxicity was characterized by se-
ance was observed. Even among these patient pop-
dation, adynamia, diarrhea, and emesis (dogs only); ulations, the risk of excessive drug accumulation is
gastrointestinal lesions were present at autopsy.8
low.
Subacute toxicity studies using multiple doses were
Clinical evidence indicates that ketoprofen’seffect
performed in several mammalian species. Maximum
may be of longer duration than expected on the basis
daily dosages for studies of at least 1 year in duration
of the short plasma half-life. It is routinely prescribed
were 12.5 mg/kg/day in rats, 27 mgikglday in ba-
on a twice-daily regimen, particularly in Great Britain.
boons, and 32 mg/kg/day in mice.8 By comparison,
Double-blind trials demonstrated that its antiinflam-
the recommended dosage for humans (maximum
matory activity when taken twice daily at 50-1 50 mg
daily dose 300 mg) is 4.3 mg/kg/day (70-kg human).
per dose (except in juvenile rheumatoid arthritis, in
Rats exhibited toxic effects in the gastrointestinal
which it is 25 mg twice a day) is comparableto that of
and renal systems, a spectrum consistent with the piroxicam 20 m g / d a i l ~indomethacin
,~~ 50 mg twice
typical NSAID profile.8 Dogs were also highly sensi-
daily,30and Distalgesic (d-propoxyphene65 mg plus
tive to gastrointestinal effects; however, baboons acetaminophen 650 mg) 4 times a day3’ in osteoar-
had only minimal irritation of the gastrointestinal
thritis; diclofenac 50 mg twice a day in rheumatoid
tract.8 arthritis32;indomethacin 25 mg twice a day in juvenile
There was no evidence of carcinogenicityor muta-
rheumatoid arthritis33;benoxaprofen 600 mg daily in
genicity in standard screening assays, and the drug
ankylosing ~pondylitis~~; and ibuprofen 400 mg 3
appeared to have no effect on protein, or on DNA or
times a day in a mixed arthritic p ~ p u l a t i o nDelayed
.~~
RNA synthesis (unpublisheddata on file at lves Lab-
clearance from the synovial fluid, as mentioned
oratories, New York, NY). No embryotoxic or terato- above, or possibly a prolongedeffect on mediators of
genic effects have been demonstrated for ketopro- inflammation may underlie these clinical results.
fen and the drug has not been shown to affect fetal or
postpartumdeveloprnert8As with other NSAIDs, its
use during pregnancy should be avoided since in- Drug Interactions
creased maternal toxicity and dystocic effects have Despite being 99% protein ketoprofen
been observed in rats. does not appear to alter the pharmacokinetics of
other highly protein-bound drugs such as oral anti-
Clinical Pharmacology diabetic agents36or a n t i ~ o a g u l a n t sSingle-dose
.~~~~~
bioavailability was unchanged when ketoprofen was
Pharmacokinetics and Metabolism
given with food or with ar~tacid.~~,~, In addition, no
Human pharmacokinetic studies showed that oral- clinically significant interactions were detected be-
ly administered ketoprofen is rapidly absorbed, me- tween ketoprofen and digoxin4I or hydrochlorothia-
tabolized, and excreted. Absorption is more than zide (pharmacodynamicassessmentsafter 4 days of
90% completem; peak plasma levels are reached dosing in both studies). Concurrent administrationof
within 1-2 hours in most subjects.21Total bioavaila- aspirin reduced protein binding of ketoprofen, but
bility (AUC) is dose proportional in the range of this was offset by accelerated plasma clearance.42
75-200 mg. The plasma half-life is approximately 2 Although these offsetting effects resulted in no net
hours in healthy young Ketoprofencon- change in the plasma concentration of free ketopro-
centrations in the synovial fluid peak approximately 2 fen, the complex nature of the kinetic interaction
hours after the peak plasma levels and decrease might lead to unpredictable individual variations.
more slowly, so that synovial fluid levels exceed Therefore coadministration with aspirin is not recom-
plasma levels from 4 hours after dosing.22 mended. Concurrent administration of ketoprofen
In the blood stream, ketoprofen is 99% bound to did not affect salicylate pharmacokinetics; however,
protein (mostly albumin).23The drug follows a simple probenecid reduced both protein binding and clear-
metabolic pathway (primarily glucuronidation), lead- ance of ket0profen.O The latter appeared to be sec-
ing to the formation of an unstable glucuronic ester ondary to inhibition of glucuronidation of ketopro-
that is excreted in the urine.24Conjugation and renal fen and probenecid, both of which are transformed
96 PHARMACOTHERAPY VOLUME 3, MAYIJUNE
6, NUMBER 1986

Table 1. Ketoprofen in Osteoarthritis


Score Improvement from Baseline at First Visit ("lo)"
KET vs PLAb KET vs PLAc KET vs ASA
K 200 K 300 PLA K 200 K 300 PLA K 200 ASA
Efficacy variables (n=26) (n=25) (n=29) (n=55) (n=67) (n=55) (n=38) (n=38)
Morning pain 20.2d 22.3d 6.3 18.9' 25.5e - 0.4 23.7 12.9
Walking pain 27.6d 30.0d 8.9 19.3e 26.2e 7.1 25.4 12.7
Night pain 31.4' 14.0 15.8 16.2 29.2' 15.9 22.6 16.0
Pain index (on examination) 37.2 42.3 21.9 46.4d 46.0d 26.5 30.5 28.7
aFirst visit was after 1 week of treatment.
bFour-week trial.
=Six-weektrial.
dp < 0.01 versus control treatment.
ep < 0.001 versus control treatment.
'p i0.05 versus control treatment.
K 200 = ketoprofen 200 mgid; K 300 = ketoprofen 300 mgid; PLA = placebo; ASA = aspirin.
From references 45-47.

by the same biochemical pathway. Consequently, significant differences were found between the re-
combined treatment with these agents should be sponses of patients receiving the 200 and 300 mg
avoided. daily doses of ketoprofen.
Thyss et a144described several cases of impaired Comparedto aspirin 2600 mg/day, ketoprofen 200
clearance of methotrexate and serious toxic, even mgiday was significantly superior in controlling both
fatal, consequences after coadministration with ke- walking pain and morning pain at week 12. Aspirin
toprofen or diclofenac. Reduced clearance of metho- did not have any statistically significant advantages
trexate at high doses has been known in association over ketoprofen. The percentages of patients with
with aspirin45or ind~methacin.~~ It appears to be a marked or moderate improvement at the last visit
class phenomenon related to inhibitory effects of were similar in both groups, whether patients' ratings
NSAlDs on renal prostaglandins. With growing use (71% for ketoprofen; 67% for ASA) or investigators'
of methotrexate as a remittive agent in rheumatoid (67% for ketoprofen; 63% for ASA) were considered.
arthritis, the risk of this potentially life-threatening
interaction should receive wide recognition. Rheumatoid Arthritis
Separate studies compared ketoprofen to place-
Clinical Efficacy b0,50a~pirin,~'
ind~methacin,~'and ibuprofeP in
Osteoarthritis
Ketoprofenwas compared to placebo or aspirin in Table 2. Global Assessment of Improvement in Os-
3 separate double-blind, parallel trials in the United teoarthritis at End of Treatment
States. (In all double-blind studies, control agents
Percentage Improved
were given in capsule form rather than any commer- (markedly or moderately)
cial tablet preparation; therefore aspirin was neither Keto- Keto-
coated nor buffered.) The placebo-controlled trials profen profen
involved 301 patients and had a duration of 4 and 6 Duration Assess- 200 300
week^.^'^^^ The aspirin-controlled trial involved 85 of study ment mgid mg/d Placebo Aspirin
patients and lasted 12 weeks.49Ketoprofen doses (wks) by (n) (4 (n) (n)
were 200 or 300 mg/day in the placebo-controlled 445 (32) (32) (35) -
trials and 200 mg/day in the aspirin-controlled trial. Observer 7Za 72a 51 -
Within 1 week of treatment in each trial, ketoprofen Patient 72b 78' 46 -
provided relief from the painful symptoms of osteoar- 646 (63) (70) (66) -
thritis (Table 1). Relief was sustained over the entire Observer 54a 60a 32 -
course of each trial. In both placebo-controlledtrials, Patient 52 61a 35 -
1247 (42) - -
ketoprofen was significantly superior to placebo in Observer 67 - - (43)
global assessments both by patients and investiga- 63
Patient 71 - - 67
tors (Table 2) and in reducing walking pain and joint
tenderness after 1 week of treatment. In both trials, ap < 0.05.
bp < 0.01.
the rate of dropouts for lack of efficacy was signifi- "p < 0.1.
cantly lower and the percentage of patients with Probability values show significanceversus control group (chi-
marked or moderate improvement at the final visits square test across 5 classes Of improvement: marked, moderate,
were significantly higher in the ketoprofen group. N O minimal, none, and worse).
KETOPROFEN: A REVIEW Kantor 97

Table 3. Ketoprofen in Rheumatoid Arthritis


Score Improvement from Baseline at First Visit (Yo)"
KET vs PLA KET vs ASA KET vs IND
K 200 K 300 PLA K200 ASA KET IND
Efficacy variables (n=85) (n=87) (n=83) (n=87) (n=81) (n=64) (n=63)
Swollen joint index 35.1b 30.0b 18.4 11.4 10.8 37.8c 23.2
Tender joint index 43.1b 42.3b 26.0 25.4 25.9 34.2 35.5
Number of tender joints 48.6b 45.4b 23.4 40.4 37.2 45.8 55.5
(moderate and severe)
Global assessment by physician 20.0d 19.5d 7.5 27.2 21.6 30.1 25.8
Global assessment by patient 21.4d 22.5d 5.2 26.2 26.4 27.8 22.5
aThe first visit was at 2 weeks in the aspirin-controlled study, at 1 week in the other 2 trials.
bp < 0.01 vs control treatment.
'p < 0.05 vs control treatment.
dp < 0.001 vs control treatment.
K 200 = ketoprofen 200 mg/d; K 300 = ketoprofen 300 mg/d; KET = ketoprofen at variable doses; IND =
indomethacin; PLA = placebo; ASA = aspirin.

rheumatoidarthritis using a double-blind, parallel de- wider therapeutic margin than a~pirin.~' Trouble-
sign. In each trial the patients were required to meet some side effects from aspirin included gastrointesti-
American RheumatismAssociation (ARA) criteria for nal disturbances and salicylism (mostly tinnitus and
active disease after a pretrial washout period. Dis- hearing impairhent). In one placebo comparison,
ease-modifying antiarthritic agents (e.g., gold salts, the ketoprofen dosage was either 200 or 300
antimalarials) were permitted provided the dosage mg/day. No statistically significant differences in eff i-
remained constant throughout the study. cacy were observed between these levels, tested in
Ketoprofen provided rapid, long-lasting relief from 85 and 87 patients respectively.50It is therefore rec-
pain and swelling. In most variables, it was both clini- ommended that dosing be initiated at 225 mg/day;
cally and statistically superior to placebos0and equiv- individual patients may benefit from adding a fourth
alent to aspirins1and indometha~in.~~ Table 3 shows capsule to reach the recommendedmaximum of 300
the results obtained at the first visit in 5 key variables mg/day. The dosing recommendations for rheuma-
in 3 trials in rheumatoid arthritis; ketoprofen-treated toid arthritis and osteoarthritis do not differ.
patients had significant reductions from baseline in In the flexible-dose trials, the mean dose of keto-
the number of tender and swollen joints. Symptomat- profen was approximately 240 mg/day; most pa-
ic relief was maintained over the course of each trial tients used either 200 or 300 mg/day. The dose ra-
(6-54 wks). tios for the active controls were 16.4: 1 for aspirin
Each study analyzed patients having a predeter- and 1 :2 for indomethacin. The ratio for aspirin was
mined degree of improvement at the last visit in 4 lower than the scheduled 18: 1, probably because
selected variables (global assessments by patients side effects prevented patients in the aspirin group
and investigators, duration of morning stiffness, and from reaching the maximum dose permitted in the
grip strength). At the last visit, ketoprofen had a sta- protocol (5.4 g/d).
tistically significant advantage in both global assess- Ketoprofen was compared with ibuprofen in 103
ments and in duration of morning stiffness when patients.53The results of this double-blind, parallel
compared to placebo, and there was a trend toward study showed comparable efficacy for both drugs,
superiority for ketoprofen in grip strength (p < with ketoprofen having a slight therapeutic advan-
0.09).50When compared to indomethacin, a signifi- tage in mean score differences and in the percent-
cantly greater percentage of patients showed global age of patients improved according to global self-
improvement (investigator's rating) at the last visit assessment at the last visit (53% for ketoprofen vs
(82% vs 66%; p < 0.05).52 Patients' global ratings 41% for ibuprofen). The mean dose of ketoprofen
also showed a trend toward superiority for ketopro- was 225 mgiday and that of ibuprofen was 1717
fen (68% vs 52%; p < 0.08). mg/day. Gastrointestinalside effects were compara-
As expected, the number of dropouts for lack of ble in both groups; however, dizziness was reported
efficacy was significantly greater for placebo than for more frequently by the ibuprofen-treated patients.
k e t ~ p r o f e nIn
. ~ the
~ indomethacin trial, there were
more dropouts for lack of efficacy in the indometha- Ketoprofen was tested in the United States in 4
cin group (18.6%) than in the ketoprofen group additional indications, for which the marketing ap-
(1 1.6°/0).52 proval has not yet been granted.
Significantly more patients in the aspirin group
Ankylosing Spondylitis
dropped out due to adverse reactions (28.1% vs
12.2%; p < 0.01), indicating that ketoprofen has a Ketoprofen 200-300 mg/day (mean dose 245
98 PHARMACOTHERAPY VOLUME6,NUMBER3, MAYIJUNE
1986

mg/d) was compared to indomethacin 75-150 Clinical Safety


mg/day (mean dose 116 mg/d) in a double-blind
crossover trial involving 57 patients.54The treatment In United States clinical trials, the safety of keto-
period for each drug was 8 weeks and there was a profen was statistically evaluated in a total of 1545
drug-free washout period between the limbs of the patients, of whom 978 were treated in double-blind
study. Patients were not crossed over to the alter- trials. The comparatively benign side-effect profile
nate drug until they had suffered a well-defined flare seen was as expected from the vast foreign experi-
in symptoms. ence with the drug. The United States data were
Ketoprofen reduced mean pains scores by 50% or analyzed5*(data on file, lves Laboratories) to ad-
more in all pain variables and reduced the duration of dress areas of particular interest, such as safety in
morning stiffness from 3 hours to 1 hour. Improve- the elderly, effects on kidneys and liver, associations
ment was close to maximum after the first week of of adverse drug reactions (ADR) with duration of
treatment, particularly with respect to spontaneous treatment, or concomitant medications. No unusual
pain values and the investigator's global assess- reactions or disturbing patterns were noted in this
ment. No statistically significant differences between analysis, which also included the events deemed
ketoprofen and indomethacin were noted. unrelatedto trial treatments. No deaths were attribut-
ed to ketoprofen in the United States trials.
Acute Gouty Arthritis Most of the ketoprofen ADR were mild upper gas-
trointestinal complaints such as nausea, dyspepsia,
The 59 patients chosen for the multicenter study55 or epigastric discomfort. Less frequent were subjec-
demonstratedacute involvementof 1 or 2 joints, with tive nervous system symptoms (headache, drowsi-
onset of inflammation less than 48 hours prior to ness, dizziness) and complaints referable to the Iow-
enrollment and adequate initial severity of inflamma- er gastrointestinal tract (diarrhea, constipation,
tion. They were randomly assigned to either ketopro- flatulence). Treatment was discontinued for side ef-
fen 150 mg loading dose, then 100 mg 3 times a day fects in 13% of patients. Table 4 shows the most
or indomethacin 75 mg loading dose, then 50 mg 3 common side effects in the United States trials for
times a day for 7 days. Pain, tenderness, restriction ketoprofen,2 active controls (aspirin and indometha-
of motion, swelling, and redness were evaluated for cin), and placebo (before grouping; see footnote,
each affected joint. In addition, a global assessment Table 3).
of each affected joint was made by patients and in- In aspirin-controlledstudies, aspirin produced sig-
vestigators. nificantly more adverse effects than ketoprofen.
Acute gout attacks were rapidly and effectively When ADR were grouped into mutually related cate-
controlled by both drugs. The mean total score was gories such as upper and lower gastrointestinal dis-
reduced from 12.63 to 5.60 by ketoprofen on day 2 of tress, the following ADR groups were significantly
treatment. Both treatment groups produced statisti- more frequent in aspirin-treated patients: upper gas-
cally significant improvement compared to baseline trointestinal distress (p < 0.01), salicylism (p <
on days 2, 5, and 8.The results produced by indo- 0.001), rash (p < 0.05), pruritus (p < 0.05),upper
methacin were clinically and statistically indistin- respiratory inflammation (p < 0.05), and weight gain
guishable from those produced by ketoprofen. (p < 0.05).Compared to placebo, only upper gastro-
intestinal (13.2% vs 21.9%) and lower gastrointesti-
Acute Painful Shoulder Syndrome nal distress (1.6% vs 5.0%) were significantly more
The results of an open-label trial in 23 patients with frequent in patients receiving ketoprofen. No statisti-
bursitis or tendinitis indicated that ketoprofen pro- cally significant difference was found in the frequen-
vided rapid and effective symptomatic relief in both cy of any ADR between ketoprofen and either ibu-
conditions.56Improvements in joint mobility and on- profen or indomethacin.
set of pain relief were noted on day 1 of treatment by Examination of the safety data for serious gastro-
82% of patients. At the end of treatment (7 days), intestinal reactions in all patients treated with keto-
100% of the patients gave ketoprofen a good or very profen (excludingsingle-dose and short-term clinical
good global assessment. pharmacologic studies) (data on file, lves Laborato-
ries) revealed that peptic ulcer occurred in 2% (40 of
Juvenile Rheumatoid Arthritis
1987 patients), including cases of dubious causality.
Gastrointestinal hemorrhage without an identified ul-
The Pediatric Rheumatology Collaborative Study cer occurred in 14 patients. Serious gastrointestinal
Group performed a 4-week open-label pilot study in complications (peptic ulcer, melena) were more fre-
35 children with JRA. Ketoprofen was administered quent among the aspirin-treated patients (1.76%)
at doses increasing from 100-200 mg/m2/day.Glo- than those receiving ketoprofen (0.35%) in the
bal improvementwas noted in 62% by the observers matched populations. These observations dovetail
and in 68% by parents.57No double-blind pediatric with the results of studies showing more frequent
studies have been performed in the United States; and more severe pathologicchanges on gastroscop-
therefore, the use of ketoprofen in children is not ic examination5' and greater loss of radiolabeled red
recommended. blood cells from the gastrointestinal tract of aspirin-
KETOPROFEN: A REVIEW Kanfor 99

Table 4. Most Frequent Side Effects in Double-blind United States Trials


Patients with ADR (%)
Orudis Aspirin lndomethacin Placebo
Adverse reactions (n= 700) (n=197) (n=122) (n = 203)
CNS/sensory
Dizziness 3.6 6.6 5.7 1.5
Headache 9.3 7.6 27.0 5.4
Tinnitus 2.3 24.9 2.5 2.0
Gastrointestinal
Anorexia 3.0 1.5 0.8 2.0
Heartburn 2.9 6.1 4.1 1.5
Miscellaneous burning 2.9 8.1 - 1 .o
Indigestion 2.4 6.1 1.6 2.0
Epigastric distress 1.4 3.7 1.6 -
Stomach upset 0.9 5.6 0.8 0.5
Dyspepsia 0.9 1.o 3.3 -
Nausea 9.7 15.7 10.7 5.4
Epigastric pain 3.6 13.2 1.6 2.0
Abdominal pain 6.7 7.6 4.9 1.o
Constipation 3.6 7.6 8.2 8.4
Diarrhea 5.0 4.6 8.2 8.4
Flatulence 3.6 6.6 1.6 1.5
Skin
Rash, nonspecific 2.1 6.6 , 0.8 3.0
General
Edema, peripheral 2.1 1.5 0.8 0.5
For the purpose of overall statistical analysis, some of the above forms were grouped; e.g., upper gastrointestinal
distress cluster consisted of reports of nausea, heartburn, indigestion, epigastric pain, or distress (see text).
From reference 57.

treated paeitnst@
.S
' 6' Moreover, dropouts for gastroin- BUN. It was significant that patients with existing
testinal ADR were more frequent in the aspirin group mild renal dysfunction did not experience further de-
in aspirin-controlled trials in rheumatoid arthritis (ke- terioration in most instances (data on file, lves Labo-
toprofen 6.1%, ASA 1 2 . 3 O / 0 ) ~ and osteoarthritis (ke- ratories).
toprofen 4.8%, ASA 7.0°/').48 Much less common but more severe nephrotoxic
Transient depression of renal function (increased reactions that can be associated with NSAlDs are
blood urea nitrogen [BUN] and serum creatinine; flu- interstitial nephritis and renal papillary necrosis.62
id retention) is characteristic of NSAlDs.'j2 Since The etiology of this syndrome is not clearly defined;
prostaglandinssynthesized in the kidneys are potent however, it has been postulated that prostaglandin
vasodilators that serve to balance the effects of va- deficiency may lead to an unchecked hypersensitiv-
soconstrictive stimuli (norepinephrine, angiotensin ity reaction in susceptible individual~.~~ No cases of
11, renin) on renal blood preventing their organic renal injury were observed in the United
production will affect renal function in some situa- States trials with ketoprofen and only two cases of
tions. As expected, the presence of underlying path- interstitial nephritis related to ketoprofen have been
ologic conditions that cause renal ischemia, such as reported in the literature. One patient had a combina-
congestive heart failure, high renin state, cirrhosis, tion of tubular necrosis, interstitial nephritis, and du-
and renal disease, predispose patients to adverse odenal ulcer after 4 days of taking ketoprofen 100
renal effects during NSAID treatment.62*66 Elderly pa- mg/d intramuscularly, which resolved after a brief
tients receiving concomitant diuretic treatment are course of dialysis.6sThe second case involved a kid-
also susceptible.66 Renal functional changes in- ney that had been transplanted 7 years prior to the
duced by NSAIDs, whether asymptomatic or accom- incident.69The patient was receiving a triamterene-
panied by edema, are reversibleon withdrawal of the hydrochlorothiazide combination in addition to keto-
drug.% profen; thus the relationship of the adverse effect to
In the ketoprofen group, these transient renal ef- ketoprofen is questionable. This patient had to be
fects were observed in 7.9% of patients with and in maintained on dialysis indefinitely.
2.9% of patients without concomitant diuretic ther- In view of the experience with benoxaprofen, it is
apy (p < 0.05). Transient azotemia was reversible germane to point out that no evidence of hepatotox-
within 2 weeks of discontinuing ketoprofen. Three of icity related to ketoprofen was discovered in an ex-
1987 patients had treatment suspendedfor BUN and haustive review of laboratory and clinical data com-
Serum creatinine increases. Elevations in serum cre- piled in the United States clinical In one
atinine were much less frequent than increases in patient with an episode of reversible increase in
100 PHARMACOTHERAPY VOLUME6. NUMBER
3, MAY/JUNE
1986

transaminases, a causal role for ketoprofen could spondylitis, and acute gout; and to ibuprofen in rheu-
not be ruled out. The time course indicated that con- matoid arthritis. Improvement in arthritis variables
comitant estrogen treatment was a more likely was noted in pivotal studies after 1 week of treatment
cause. Moreover, reviews of the literat~re~’.~* stated and was sustained throughout the trials (6-54wks).
that no cases of liver injury attributable to ketoprofen Osteoarthritis and rheumatoid arthritis are presently
have been reported. European postmarketing sur- the only approved indications.
veillance identified several nonfatal cases of jaun- After extensive patient usage over 13 years, keto-
dice or abnormal liver function tests, but no firm profen has a reliable safety profile. Review of exten-
causal relationships were established and informa- sive data from United States clinical trials confirmed
tion on alternative causes is lacking. the foreign experience. Compared to aspirin, keto-
Similarly, no anaphylactoidor severe allergic com- profen produced significantly fewer gastrointestinal
plications were observed in the United States side effects and serious gastrointestinal complica-
Foreign clinical data demonstrated cross-sensitivity tions. Significant liver toxicity appears to be absent
to ketoprofen and other NSAlDs among aspirin- with ketoprofen, and organic renal injury is rare. Re-
intolerant patients,73 including one fatal case.74 versible renal functional changes, with or without
The so-called aspirin-intolerance syndrome (bron- edema, were seen with ketoprofen as with other
chospasm, urticaria, rhinitis) is presumably pharma- drugs of this class, but were rarely of clinical con-
cologically rather than immunologically mediated.75 cern. Ketoprofen appears to have a low potential for
No significant age-dependent relationships were allergic manifestations, aside from cross-reactivity in
evident in the analysis of safety data.58Similarly, aspirin-intolerant patients, which is a pharmacologi-
significant relationships between dose and adverse cally mediated feature of prostaglandin synthetase
reactions were not demonstrated except for upper inhibitors.
gastrointestinal distress, which was significantly With a short half-life in the elderly as well as in
more frequent at 300 than at 200 mglday (data on young adults, ketoprofen rapidly achieves steady
file, lves Laboratories). Adverse drug reactions did state in plasma and synovial fluid and provides
not appear to be time dependent, particularly in the prompt therapeutic action. Also, it is promptly
case of peptic ulcers and gastrointestinal hemor- cleared on termination of treatment. Testing has
rhage, both of which occurred randomly throughout shown good clinical tolerance in the elderly and even
the time course (data on file, lves Laboratories). in patients with impaired renal and hepatic function.
Thus no type of ADR was identified that seemed to Ketoprofen has entered the United States scene
reflect cumulative effects of the drug. Patients re- after a hiatus of 4 years since the approval of difluni-
ceiving concomitant corticosteroid therapy had a sig- sal, piroxicam, and benoxaprofen and since the ban
nificantly higher frequency of upper gastrointestinal of the latter. It seems very appropriate that a harbin-
distress than those receiving only ketoprofen(1 4.3% ger of a “new generation” (though “new” only in the
vs 5.5%). As stated above, patients receiving con- regulatory sense) is a drug well known and long used
comitant diuretics had a higher frequency of edema abroad, and one with a aura of predictability.
and transient elevation of BUN or creatinine levels
than those receiving only k e t o p r ~ f e n . ~ ~
Further evidence of the low toxicity of ketoprofen References
comes from the National Poison Information Service
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Folia Pharmacol Jpn 1974;70:543-69.
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30 Frank 0, Klemmayer K. Zur Behandlung der schweren Coxarthrose Scand J Rheumatol 1976:5(suppl 14):63-72.
mit Ketoprofen. Schweiz Rundschau Med (Praxis) 1974;63:1003-4. 60. Arsenault A, Lussier A. Gastrointestinalmicrobleeding under acetyl-
31. Dieppe PA, Jones HE, Bacon PA, Ring EFJ. The anti-inflammatory salicylic acid, ketoprofenand placebo. Eighth European rheumatology
effects of ketoprofen in osteoarthritis. Ninth European congress of congress, Helsinki, 1975. symposium on ketoprofen. Rheumatol Re-
rheumatology. Wiesbaden, 1979, ketoprofen symposium. Paris: habil 1976:15(suppl):87-93.
RhBne-Poulenc Sante, 1980:33-6. 61. Lussier A, Arsenault A. Gastrointestinalblood loss induced by keto-
32. Bendix T, Schmidt F, Rasmussen KJE, lbfelt HH. Diclofenac (Vol- profen, aspirin and placebo. Scand J Rheumatol 1976;5(suppl 14):
taren) and ketoprofen (Orudis) in rheumatoid arthritis: a randomized 73-5.
double-blind multicentre trial. Curr Ther Res 1983;33:192-200. 62. Henrich WL. Nephrotoxicity of nonsteroidalanti-inflammatoryagents.
33 Bhettay E, Thomson AJG. Double-blindstudy Of ketoprofenand lndo- Am J Kidney Dis 1983;2:478-84.
methacin in juvenile chronic arthritis. South Afr Med J 1978;54:276-8. 63. Zia P, Zipser A, Speckart P, et al. The measurements of urinary
34. Charlot J, Villaumey J. A comparative study of benoxaprofen and prostaglandin E in normal subjects and in high renin states. J Lab Clin
ketoprofen in ankylosing spondylitis. Eur J Rheumatol lnflamm 1982; Med 1978;92:415-22.
5277. 64. Walshe JJ, Venuto RC. Acute oliguric renal failure induced by indo-
35. Saxena RP, Saxena U. A comparative trial of ketoprofen and ibupro- methacin: possible mechanism. Ann Intern Med 1979;91:47-9.
fen in patients with rheumatic disease. Curr Med Res Opin 1978; 65. Epstein M, Llfschitz M, Preston S. Augementation of renal prostag-
54844. landin E (PGE) in decompensated cirrhosis (OC). Implicationsfor renal
36. Voigt U, Klassen E. Zur Prufung von Ketoprofen lnteraktionen mit function. Twelfth annual meeting of the American Society of Nephrolo-
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37 Double-blind parallel comparison study between the effects of Orudis 66. Dunn MJ, Zambraski EJ. Renal effects of drugs that inhibit prostag-
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102 PHARMACOTHERAPY VOLUME6, NUMBER
3, MAY~JUNE
1986

67.Torre VE. Present and future of the nonsteroidal anti-inflammatory have to be considered a big disadvantage since ibu-
drugs in nephrology. Mayo Clin Proc 1982;57:389-93.
68 Ducret F, Pointet P, Martin D, Villermet 6. lnsuffisance renale aigue profen is available inexpensively without prescrip-
rbversible induite par le kbtoprofene. Nephrologie 1982;3:105-6. tion.
69. Windeck R, Bock KD, Jakubowski H-D. Irreversible Versagen einer Carl E. Rosow, M.D., Ph.D.
transplantierten Niere, ausgelost durch Ketoprofen? Deutsch Med Wo-
chenschr 1983;108:720-1 Department of Anesthesia
70. Widmark RM, Vavre I. Liver safety of ketoprofen (Orudis) (abstr). J Massachusetts General Hospital
Clin Pharmacol 1984;24:401.
71. Mills PR, Sturrock RD. Clinical associations between arthritis and Boston, MA 02114
liver disease. Ann Rheum Dis 1982;41:295-307
72. Lewis JH. Hepatic toxicity of nonsteroidal anti-inflammatory drugs.
Clin Pharm 1984;3:12%38.
73. Frith P, Dolovich J, Hargreave FE. Life-threateningasthma, urticaria
and angioedema after ketoprofen. Lancet 1978;2:847-8. Commentary 2
74. Egede F. Fatalt forlobende astmatisk reaktion efter ketoprofen (Al- Nonsteroidal antiinflammatory drugs (NSAIDs)
rheumat, Orudis). Ugeskr Laeger 1979;141:1151-2.
75. Settipane GA. Adverse reactions to aspirin and related drugs. Arch continue to play a significant role in the treatment of
Intern Med 1981 ;I41:32&32. many rheumatic diseases. Currently, there are 13
76. Court H,Volans GN. Poisoning after overdose with nonsteroidal anti-
inflammatory drugs. Adverse Drug React Ac Pois Rev 1984;3:1-21 non-salicylate NSAlDs marketed in the United
States with the promise of more to be released in the
future. Although these agents have proven efficacy
in rheumatic disease, limitations to their use are evi-
dent. Significant side effects occur with these drugs
including gastrointestinal disturbances, renal disor-
ders, and CNS effects. In addition, variability in pa-
tient response is a well recognized phenomenon as-
sociated with these Therefore, trials of
several different NSAlDs in individual patients are
encouraged to attain optimal therapeutic response.
Commentaries To date, none of the NSAlDs available has proven
clearly superior to any other in the treatment of rheu-
matoid or osteoarthritis. Thus, caution is warranted
Commentary 1 in evaluating new NSAIDs. When commenting on
There seems little doubt that ketoprofen is both the burgeoning number of these drugs Kraag4sug-
safe and efficacious as an anti-inflammatoryanalge- gested that ". . . we should analyze the literature criti-
sic. There is some question in my mind as to its cally before readily prescribing a drug whose only
advantages over other available products. Studies advantage may be that it is new." In examining the
comparing ketoprofen with indomethacin, ibuprofen, available data pertinent to ketoprofen, this word of
and other newer non-steroidal anti-inflammatory an- caution seems appropriate.
algesics have not shown any noteworthy improve- Ketoprofen is the latest addition to the propionic
ment in therapeutic effect. All of the inhibitors of cy- acid derivatives which include ibuprofen, fenoprofen
clo-oxygenase must share, to a greater or lesser and naproxen. It has been utilized extensively in Eu-
degree, the same group of pharmacologic effects. rope and has recently been released in the United
The toxicity (GI, CNS, renal, hematologic), and not States. Dr. Kantor has presented data from US stud-
the efficacy, is the usual limiting factor in treatment. ies to support ketoprofen's efficacy in rheumatoid
In most controlled trials, GI intolerance is the most arthritis, osteoarthritis, ankylosing spondylitis and
frequent reason for discontinuationof treatment. The gout. Evaluations of ketoprofen's therapeutic effec-
propionic acid derivatives (ibuprofen, naproxen, fen- tiveness indicate it is more effective than placebo
oprofen, and ketoprofen) all produce about 5 to 15% and similar in efficacy to aspirin and other NSAIDs.
incidence of gastrointestinal complaints, but these Evidence from foreign studies support these re-
symptoms are usually less severe than those pro- sults." The most interesting aspect of ketoprofen's
duced by aspirin or indomethacin. The incidence of activity is the potential for dosage regimen flexibility.
other toxic effects appears to be similar within this The plasma half-lifeof ketoprofenis only 2 hours and
group, and all of these drugs are better tolerated than the usual recommended dosing regimen is three to
aspirin. four times daily. It has been suggested, however,
So why pick ketoprofen?The short half-life may or that ketoprofen'slong synovial fluid half-life may be a
may not be an advantage (less accumulation but more useful guide to the time course of action of the
lower patient compliance). We already have non- drug.gAccordingly, some initial studies indicate that
steroidal analgesics with short (ibuprofen), medium this drug may be efficacious when given in a twice
(naproxen), and long (piroxicam) half-lives. The Eu- daily regimen.*~lo~'lThus, a potential advantage of
ropean safety data are encouraging, since ketopro- ketoprofen could be a prolonged efficacy with less
fen seems to be relatively free of serious immunolo- drug accumulation and therefore decreased toxicity
gic, renal, hepatic, or bone marrow toxicity. Also when compared to twice daily agents with longer
encouraging is the fact that reported cases of over- plasma half lives. This, however, has yet to be prov-
dose have not been life-threatening. Finally, cost will en. Clearly, further evaluations of ketoprofen's eff i-