AHFS Class:

• Reversible COX-1/COX-2 Inhibitors 28:08.04.04

Generic Name(s):

• Ketoprofen

Ketoprofen is a prototypical nonsteroidal anti-inflammatory agent (NSAIA)1,2,3,4,30,53,93,205 that also exhibits analgesic and antipyretic activity.1,2,3,30,38,93

Ketoprofen is used for anti-inflammatory and analgesic effects in the symptomatic treatment of acute1,97,157 and chronic rheumatoid arthritis1,30,32,36,93,96,97,98,99,100,101,102,103,104,105,106,107,112,113,114,115,116,118,119,120,122,123,124,125,127,129,131,132,134,135,136,137,138,139,205 and osteoarthritis.1,30,32,96,97,104,105,106,131,132,138,147,148,150,153,154,156,157,165 Ketoprofen also is used to relieve mild to moderate pain1,121,160,166,171,173,174,235,236,238,239 and for the management of primary dysmenorrhea.1,50,161,164,234

Extended-release capsules of ketoprofen are not recommended for the management of acute pain.1

The potential benefits and risks of ketoprofen therapy as well as alternative therapies should be considered prior to initiating ketoprofen therapy.1 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1

Inflammatory Diseases

Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis

When used in the symptomatic treatment of rheumatoid arthritis,36,96,97,98,99,100,101,102,103,104,105,106,107,108,132,134,135,136,137,138,139,205 ketoprofen has relieved pain and stiffness;36,99,100,102,103,104,105,114,115,119,120,123,127,129,131,134,136,137,138,139,205 reduced swelling,102,118,205 tenderness,103,205 and the number of joints involved;115,118,119,129,133,137,138,139,145 and improved mobility99,100,129 and grip strength.102,103,114,115,119,125,127,132,136,138,139,145,155,205 In the symptomatic treatment of osteoarthritis, ketoprofen has relieved pain and stiffness104,105,131,132,138,147,148,205 and increased range of motion153,156,165 and functional activity.131,132,138,147,148,150,153,154,158 Ketoprofen appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process.7,18,19,96,104

Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual dosages of ketoprofen in the management of rheumatoid arthritis or osteoarthritis are greater than those of placebo100,103,113,114,115,119,120,148,149,153,154,155,162,204,205 and about equal to those of usual dosages of salicylates,1,102,113,118,122,123,124,125,157,205 fenoprofen,150 ibuprofen,1,113,134,135,136,137,138,205 indomethacin,1,100,101,127,131,132,133,157,155,205 naproxen,139,157,172 phenylbutazone,113,147,158 or piroxicam.151 In a controlled clinical study of 7-months' duration, 150 mg of ketoprofen daily was as effective as 4 g of aspirin daily in patients with rheumatoid arthritis.102

Patient response to oral NSAIAs is variable; patients who do not respond to or cannot tolerate one NSAIA might be successfully treated with a different agent.5,7,17,18,22,25,96,104 However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs.86,87,88,89,90,91,92 (See Cautions: Precautions and Contraindications.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction.244,273 Disease-modifying antirheumatic drugs (DMARDs) (e.g., abatacept, hydroxychloroquine, leflunomide, methotrexate, rituximab, sulfasalazine, tocilizumab, tofacitinib, tumor necrosis factor [TNF; TNF-α] blocking agents) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy.273 DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs.273 NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.244,273 (For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.)

Use of ketoprofen with aspirin is not recommended.1,13 There is inadequate proof that the combination is more effective than either drug alone,13 the potential for adverse reactions may be increased,13 and there is evidence that aspirin interacts with the pharmacokinetics of ketoprofen in a complex manner, the clinical importance of which has not been fully determined.1,52 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

Ketoprofen has been used with good results in preliminary, uncontrolled clinical studies for the management of juvenile rheumatoid arthritis†.140,141 Results of the studies suggest that the drug is generally effective in increasing grip strength and decreasing the number of painful, swollen, and tender joints and the duration of morning stiffness.140,141 Controlled studies are needed to further evaluate the efficacy and safety of ketoprofen in the management of juvenile rheumatoid arthritis.141 (See Cautions: Pediatric Precautions.)

Ankylosing Spondylitis

Ketoprofen has been used with good results in uncontrolled clinical studies for the symptomatic treatment of ankylosing spondylitis†.97,104,105,106,108,109,138,142,143,144,146,175,205 Results of the studies suggest that the drug may be effective in relieving night pain,108,142 morning stiffness,105,142,143,146,205 and pain at rest,105,108,142,143,146,205 and in improving mobility.108,142,143,146 Limited comparative studies suggest that the anti-inflammatory146,205 and analgesic effects143,146,205 of usual dosages of ketoprofen may be comparable to those of usual dosages of indomethacin205 and possibly less than those of usual dosages of phenylbutazone (no longer commercially available in the US).143,146

Other Inflammatory Conditions

Ketoprofen has been used in a limited number of patients for the symptomatic treatment of acute gouty arthritis†,205 acute painful shoulder† (bursitis and/or tendinitis),205 and Reiter's syndrome†.133

Pain

Ketoprofen is used for symptomatic relief of mild to moderate pain,1 such as postoperative166,239 (including that associated with dental surgery),121,160,171,173 postpartum,174,235 and orthopedic (including musculoskeletal strains or sprains)236 pain and visceral pain associated with cancer.238 Because of the relatively slow onset of action of ketoprofen extended-release capsules, this formulation is not recommended for the management of acute pain.1

When used to relieve mild to moderate acute pain, single ketoprofen doses of 25-100 mg are more effective than placebo173,174,235,236 and at least as effective as usual analgesic doses of other NSAIAs121,235 or mild opiate analgesics.173,174 In patients with oral surgery pain, 25- to 100-mg doses of ketoprofen have been reported to be more effective than 650-mg doses of aspirin121 or 90-mg doses of oral codeine sulfate.173 In patients with postpartum pain, 50- or 100-mg doses of ketoprofen have been reported to be more effective than 650-mg doses of aspirin235 and as effective as 90-mg doses of oral codeine sulfate.174 The duration of ketoprofen's analgesic effect appears to be longer than that of aspirin or codeine.121,173 Although ketoprofen doses of 25-150 mg have been shown to be effective for relief of mild to moderate pain, doses exceeding 25 mg generally have not been shown to provide substantially more relief; however, the onset may be faster and the duration more prolonged when the dose is increased to 50 mg.1 The analgesic effect is not increased substantially with doses exceeding 50-75 mg.1 IV† ketoprofen has been used for the relief of biliary pain†167 and renal colic†.169,170

Dysmenorrhea

Ketoprofen is used in the management of primary dysmenorrhea.1,50,161,164,234 In patients with primary dysmenorrhea, NSAIAs may relieve pain and reduce the frequency and severity of uterine contractions, possibly as a result of inhibition of prostaglandin synthesis.1,50,161,164,234

When used to relieve dysmenorrhea, 50-mg doses of ketoprofen administered up to 4 times daily, beginning with the onset of menses or pain, were more effective than placebo164 and as effective as 250-mg mefenamic acid doses up to 4 times daily.234 Ketoprofen dosages of 150 mg daily for 2-4 days monthly has been reported to provide relief of dysmenorrhea comparable to that of 75 mg of indomethacin daily for 2-4 days monthly.50,161 Overall relief provided by 75-mg doses of ketoprofen has been reported to be better than that provided by smaller doses of the drug in dysmenorrhea.1

Other Uses

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease† among patients who received an NSAIA for 2 years or longer.275,276 Similar findings have been reported from some other, but not all, observational studies.275,276,277,278,279,280

Administration

The potential benefits and risks of ketoprofen therapy as well as alternative therapies should be considered prior to initiating ketoprofen therapy.1

Ketoprofen is administered orally.1 Adverse GI effects may be minimized by administering the drug with meals,1,104 milk,1 or an antacid.1,97,102,115,116,142,149 Extended-release capsules of ketoprofen are not recommended for the management of acute pain.1 In addition, concomitant use of ketoprofen conventional and extended-release capsules is not recommended.1

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1 Dosage of ketoprofen must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.1

Inflammatory Diseases

Rheumatoid Arthritis and Osteoarthritis

For the symptomatic treatment of acute or chronic rheumatoid arthritis or osteoarthritis, the usual initial adult dosage of ketoprofen as conventional capsules is 75 mg 3 times daily or 50 mg 4 times daily.1 For the symptomatic treatment of chronic rheumatoid arthritis or osteoarthritis, the usual initial adult dosage of ketoprofen as extended-release capsules is 200 mg once daily.1 Lower initial dosages (e.g., 50 mg 3 times daily) may be preferred in relatively small or debilitated adults.1,209 The manufacturer recommends that ketoprofen therapy be initiated at low dosages in geriatric patients (i.e., those older than 75 years of age) because their renal function is usually decreased.1 Subsequent dosage should be adjusted according to the patient's response and tolerance.1

Although well-controlled clinical studies did not show that the average response was greater with 300 mg daily than with 200 mg daily, some patients may have a better response with 300 mg daily.1 Since ketoprofen dosages of 300 mg daily are associated with an increased frequency of adverse GI effects and headache, particularly in women, an adequate increase in clinical benefit should be evident to justify potential increased risks associated with this dosage.1 Dosages exceeding 300 mg (as conventional capsules) and 200 mg (as extended-release capsules) daily have not been adequately studied and are not recommended by the manufacturers.1

Ankylosing Spondylitis

For the symptomatic treatment of ankylosing spondylitis†, dosages of ketoprofen similar to those used for rheumatoid arthritis or osteoarthritis have been employed.97,104,105,106,108,109,138,142,143,144,146,175,205

Pain and Dysmenorrhea

For relief of mild to moderate pain or dysmenorrhea, the usual adult dosage of ketoprofen as conventional capsules is 25 or 50 mg every 6-8 hours as necessary.1 Therapy should be initiated with relatively small dosages in small adults, debilitated or geriatric patients, and patients with renal or hepatic disease.1 Occasionally, some patients may benefit from increasing the individual doses to 75 mg; doses greater than 75 mg do not appear to provide substantial additional benefit.1 Dosages exceeding 300 mg daily are not recommended since they have not been adequately studied.1 The risk of adverse GI effects should be considered when relatively large dosages of ketoprofen are used.1

Dosage in Renal and Hepatic Impairment

Since ketoprofen and its metabolites are excreted mainly by the kidneys, the manufacturers recommend that the maximum daily dosage of the drug be reduced in patients with renal impairment.1,233 The maximum dosage of ketoprofen given as conventional or extended-release capsules in patients with mild renal impairment is 150 mg daily,1 while the maximum dosage in patients with more severe renal impairment (i.e., those with creatinine clearances less than 25 mL/minute per 1.73 m² or end-stage renal disease) is 100 mg daily (given as conventional or extended-release capsules).1 Use of ketoprofen in patients with severe renal impairment is not recommended; however, if ketoprofen is used in these patients, close monitoring is recommended.1 Patients with impaired hepatic function and serum albumin concentrations less than 3.5 g/dL should receive an initial ketoprofen dosage of 100 mg daily as conventional or extended-release capsules.1 The manufacturers also recommend that ketoprofen therapy be initiated at low dosages in patients with both hypoalbuminemia and renal impairment, since these patients may be at greater risk of developing adverse effects secondary to increased plasma concentrations of free ketoprofen.1 If the drug is used in patients with both hypoalbuminemia and impaired renal or hepatic function, the patients should be closely monitored.1

When ketoprofen is used for relief of mild to moderate pain or dysmenorrhea, the manufacturers recommend that therapy be initiated with relatively small dosages in patients with renal or hepatic disease.1

Adverse reactions to ketoprofen are usually mild and mainly involve the GI tract, particularly the upper GI tract;1,7,30,96,99,100,102,104,105,106,107,112,114,115,118,123,224,234 however, adverse effects may be severe enough to require discontinuance of the drug in about 5-15% of patients.98,99,100,104,105,107,125,127,135,205 Adverse GI effects and headache appear to be dose related and occur more frequently in women.1 Mild ketoprofen-induced adverse effects may be alleviated by dosage reduction.1

Cardiovascular Effects

Peripheral edema has occurred in about 2% of patients receiving ketoprofen.1,147 Other adverse cardiovascular effects, which occur in less than 1% of patients, include palpitation,1,105,131,136,147 hypertension,1,125 tachycardia,1 congestive heart failure,1 peripheral vascular disease,1 facial edema,1 and vasodilation.1 Postural hypotension,107 hot flushes,105 and chest pain146,147 have also been reported. Although a causal relationship to ketoprofen has not been established, cardiac arrhythmias and myocardial infarction have occurred during therapy with the drug.1

Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500,502,508 Use of NSAIAs also is associated with an increased risk of heart failure.500,508

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study.284,294,500 Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500,501,502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.500,502,505,506,508 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.500,502,506,508

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.505,508 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).500,508,511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.508,511

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased.508 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.508

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.288,289,290,294,500,501,502,503,506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.500,504,507,508 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.500,504,508 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.500,501,508 Fluid retention and edema also have been observed in some patients receiving NSAIAs.508

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,502,508

GI Effects

Adverse GI effects, which appear to be dose related and more frequently involve the upper GI tract,1 occur in about 10-30% of patients receiving ketoprofen.34,104,106,141,203,234 Adverse GI effects occasionally may be severe enough to require discontinuance of therapy.98,104,105,106,107,125,127,138,150,165,168,186 The frequency of adverse upper GI effects may be higher in patients receiving ketoprofen and corticosteroids concomitantly than in patients receiving ketoprofen alone.205 Adverse GI effects may be minimized by administering ketoprofen with meals,1,104 milk,1 or antacids.1,97,102,115,116,142

Dyspepsia is the most common adverse GI effect of ketoprofen,1,99,100,102,104,105,109,114,118,123,134,136,139,234 occurring in about 11% of patients.1 In controlled clinical studies, the incidence of ketoprofen-induced peptic ulcer, GI bleeding, or perforation was less than 1%; however, the incidence of peptic ulcer or GI bleeding increased to greater than 2% during long-term studies with the drug.1 Peptic ulcer occurs at a rate greater than 1% per year during prolonged ketoprofen therapy.1 Nausea,1,96,99,104,106,109,115,123,125,129,132,135,136,137,138,139,140,234 diarrhea,1,102,104,105,107,114,127,132,133,234 abdominal pain,1,104,115,127,135,136,137,138,140,234 constipation,1,99,104,105,107,109,118,132,135,143 and flatulence1,96,109,137,147,149,155 occur in more than 3% of patients receiving the drug.1 Vomiting,1,104,105,109,125,135,136,137,139 anorexia,1,107,109,135,137,147 and stomatitis1,105,132,146,149 occur in about 1-3% of patients.1 Other adverse GI effects, reportedly occurring in less than 1% of patients, include increased appetite,1 dry mouth,1,109,132,146 eructation,1 gastritis,1,99,107,133 rectal hemorrhage,1,191 melena,1,105,109,147 fecal occult blood,1 increased or excessive salivation,1 hematemesis,1,105,147 intestinal ulceration,1 microvesicular steatosis,1 and pancreatitis.1 Sore tongue,132 rectal burning,109 and sore gums136 have been reported rarely during ketoprofen therapy. Buccal necrosis and ulcerative colitis have also been reported, but a causal relationship to the drug has not been established.1

No difference in the development of adverse upper or lower GI effects was reported in crossover trials of patients receiving ketoprofen as the commercially available extended-release capsules (200 mg once daily) versus the conventional capsules (75 mg 3 times daily) for the treatment of rheumatoid arthritis or osteoarthritis.1 However, in a study of patients receiving ketoprofen for osteoarthritis of the hip, it was reported that extended-release capsules resulted in fewer adverse GI effects than the conventional capsules.168 Although not commercially available in the US, enteric-coated tablets,109,145,149 extended-release tablets,165,203,211 and suppositories127 of ketoprofen have been shown to produce fewer adverse GI effects than conventional ketoprofen capsules.

Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.241,242,245 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.1 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed on a long-term basis for the development of manifestations of such effects and advised of the importance of this follow-up.1,241,242 In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur.1,241,242 If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.1

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.241,242 In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.1,241,242 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.1 However, short-term therapy is not without risk.1 High dosages of any NSAIA probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs.241,242 Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.241,242

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors.1,233,270 In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status.1,233,270,281 Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis.233,270,273 In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.1

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy.244,270,273,274 (See Uses, in Misoprostol 56:28.28.) Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy.244,270,273 In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest.270 In addition, efficacy of usual dosages of H₂-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established.270 Therefore, most clinicians do not recommend use of H₂-receptor antagonists for the prevention of NSAIA-associated ulcers.270,273 Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs.273 However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori -negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk.282,283 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.282,283

Nervous System Effects

Headache1,99,102,104,105,106,109,118,123,127,129,234 and excitation (e.g., insomnia,1,150,155 nervousness,1,161 dreams,1,150 irritability,104,105,132,155 anxiety)161 occur in more than 3% of patients receiving ketoprofen.1 Headache appears to be dose related.1 Dizziness,1,104,106,109,118,127,131,132,138,234 malaise,1,132,136,147,150,155 depression,1,104,105,127,132,136,147,150,155 and other symptoms related to CNS depression (e.g., drowsiness,106,138,147,155,158,173,190 lassitude,147 fatigue,109 difficulty in concentration)109 occur in about 1-3% of patients.1 Other adverse nervous system effects, which occur in less than 1% of patients receiving ketoprofen,1 include amnesia,1,132 confusion,1 migraine,1 paresthesia,1 asthenia232 and vertigo.1,103,105,109,135,139,161 Although a causal relationship to ketoprofen has not been established, dysphoria,1 hallucination,1 nightmares,1,150 and personality disorder1 have been reported during therapy with the drug.1 Pseudotumor cerebri occurred in one child treated with ketoprofen for Bartter's syndrome† and was attributed to sodium and water retention induced by the drug.212

Renal and Genitourinary Effects

Ketoprofen has occasionally caused impairment of renal function, resulting in edema1,105,118,125,135,158,187,224 and/or increased BUN1,205,224 and serum creatinine concentrations.1,205 The frequency of these renal effects appears to be greater in patients receiving ketoprofen concomitantly with a diuretic than in those receiving the drug without a diuretic, occurring in about 8 and 3% of these patients, respectively.205,224 Signs and/or symptoms of urinary tract irritation (e.g., dysuria,131 frequency/urgency of micturition)146,147 have occurred in about 1-3% of patients.1 Menometrorrhagia,1 hematuria,1,107,141,153 renal failure,1,94,190,199,230 interstitial nephritis,1,192,224 and nephrotic syndrome1 have been reported in less than 1% of patients.1 Membranous glomerulonephritis, which resolved following discontinuance of ketoprofen and initiation of corticosteroid therapy, has been reported in at least one patient.237 As with other NSAIAs, nephritis has occurred following prolonged administration of ketoprofen in mice and rats.1 Acute renal tubulopathy has been reported in humans, but a causal relationship to the drug has not been established.1

Long-term administration of NSAIAs has resulted in renal papillary necrosis and other renal injury.1

Hepatic Effects

Severe hepatic reactions, including jaundice, have occurred rarely during ketoprofen therapy, but a causal relationship to the drug has not been established.1,205,209 Hepatic dysfunction, hepatitis, and cholestatic hepatitis have occurred in less than 1% of patients receiving the drug.1 Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs.1 Usual dosages of ketoprofen appear to be associated with a lower incidence of minor abnormalities in liver function test results than usual anti-inflammatory dosages of aspirin.95,224

Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs;1 meaningful (3 times the upper limit of normal) elevations of serum ALT (SGPT) or AST (SGOT) concentration have occurred in approximately 1% of patients receiving NSAIAs in controlled clinical studies.1,95,175 These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.1 Ketoprofen should be discontinued if signs or symptoms of a severe hepatic reaction occur.209,210 (See Cautions: Precautions and Contraindications.)

Ocular and Otic Effects

Visual disturbances have occurred in about 1-3% of patients during ketoprofen therapy.1 Other adverse ocular effects, including conjunctivitis,1,188 siccative conjunctivitis,1 eye pain,1 retinal hemorrhage,1 and pigmentary changes1 have occurred in less than 1% of patients receiving the drug.1

Tinnitus1,118,119,164 has occurred in about 1-3% and hearing impairment1,147 in less than 1% of ketoprofen-treated patients.1

Hematologic Effects

Anemia,1,141 purpura,1,132 hypocoagulability,1 agranulocytosis,1 hemolysis,1 and thrombocytopenia1 have occurred in less than 1% of patients receiving ketoprofen.1 If signs and/or symptoms of anemia appear in patients receiving the drug, hemoglobin concentration and hematocrit should be determined.1,209,210

Ketoprofen may inhibit platelet adhesion and aggregation and prolong bleeding time1,34,40,41,47,54 by approximately 3-4 minutes from baseline values,1 but this effect usually subsides within 24-36 hours after discontinuing the drug.40 Ketoprofen usually does not affect platelet count, prothrombin time, partial thromboplastin time, or thrombin time.1,40 Patients who may be adversely affected by a prolongation of bleeding time should be carefully observed during ketoprofen therapy.1,240 (See Cautions: Precautions and Contraindications.)

Dermatologic Effects

Rash1,96,104,105,127,132,135,155,190 occurs in about 1-3% of patients receiving ketoprofen.1 Other adverse dermatologic reactions, including pruritus,1,99,105,164 urticaria,1,107,155 erythema,134 eczema,1,134 alopecia,1 purpuric or bullous rash,1 exfoliative dermatitis,1 photosensitivity,1 skin discoloration,1 sweating,1,132,155 onycholysis,1 toxic epidermal necrolysis,1 erythema multiforme,1 and Stevens-Johnson syndrome,1 have occurred in less than 1% of patients.1

Other Adverse Effects

Adverse respiratory effects occurring in less than 1% of patients receiving ketoprofen include dyspnea,1 hemoptysis,1 epistaxis,1 pharyngitis,1 rhinitis,1 bronchospasm,1,105 and laryngeal edema.1 Other adverse effects of ketoprofen occurring in less than 1% of patients include impotence,1,132 chills,1 pain,1 infection,1 altered taste sensation,1 allergic reaction,1,189 anaphylaxis,1 muscle cramps,105,147,152 thirst,1 weight gain1,132,136,149 or loss,1 hyponatremia,1 and myalgia.1

Although a causal relationship to ketoprofen has not been established, gynecomastia,1,209 changes in libido, aggravation of diabetes mellitus, aseptic meningitis, septicemia, and shock have also been reported during therapy with the drug.1 Cholinergic crisis reportedly occurred following administration of a single 50-mg dose of ketoprofen in one patient with myasthenia gravis who was stabilized on long-term neostigmine therapy.201

Precautions and Contraindications

Patients should be advised that ketoprofen, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur.1,241,242,500,508 Patients also should be informed that, while NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases, and the drugs have a major role in the management of pain.1,241,242 Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without an NSAIA may represent an acceptable alternative to both the patient and clinician.241,242

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.1

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.1,288,289,290,294,500,502,508 (See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.1,500,508 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.1,500,508 Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.1,500,508 Ketoprofen should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if ketoprofen is used in such patients, the patient should be monitored for cardiac ischemia.508

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,284,502,508 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.1 Because of the potential for increased adverse effects, patients receiving ketoprofen should be advised not to take aspirin.1

Use of NSAIAs, including ketoprofen, can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events.1 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.1,508,509 NSAIAs, including ketoprofen, should be used with caution in patients with hypertension.1 Blood pressure should be monitored closely during initiation of ketoprofen therapy and throughout therapy.1

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that ketoprofen should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if ketoprofen is used in such patients, the patient should be monitored for worsening heart failure.508 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.508 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).508 (See Drug Interactions.)

The risk of potentially serious adverse GI effects should be considered in patients receiving ketoprofen, particularly in patients receiving chronic therapy with the drug.241,242,247 (See Cautions: GI Effects.) Ketoprofen should be used with caution and under close supervision in patients with a history of GI disease.1,99,105,200,202 Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug,1,247,255 patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.1

Ketoprofen should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration,1 and such patients should receive an appropriate ulcer preventive regimen.233,243,250,270,274 All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely1,250 for signs and symptoms of ulcer perforation or GI bleeding. To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed.1 For patients who are at high risk, therapy other than an NSAIA should be considered.1

Elevations in serum ALT may be the most sensitive indicator of NSAIA-induced liver dysfunction.1,26,27,48,83,93 Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving ketoprofen should be evaluated for evidence of the development of a more severe hepatic reaction.1 Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs.1 Although such reactions appear to be rare with ketoprofen,1,205 the drug should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).209,210

Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration and the drugs should be used concomitantly with caution.246,253

Ketoprofen should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy), since the drug may inhibit platelet function.1,5,6,9,15,27,240 If signs and/or symptoms of anemia occur during therapy with ketoprofen, hemoglobin concentration and hematocrit should be determined.1,209,210

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.1 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.1,9,15,26,48,83,95,177,198,199,208,210,214,215,216 Patients at greatest risk of this reaction are those with impaired renal function,1,15,48,83,177,198 heart failure,1,26,48,83,177,198 or hepatic dysfunction;1,15,26,48,83,177,198 those with extracellular fluid depletion (e.g., patients receiving diuretics);1,16,26,48,83,177,198,224 those taking an ACE inhibitor1 or angiotensin II antagonist286 concomitantly; and geriatric patients.1,48,177 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.1 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1

Ketoprofen has not been evaluated in patients with severe renal impairment, and the manufacturer states that use of ketoprofen is not recommended in patients with advanced renal disease.1 If ketoprofen is used in patients with severe renal impairment, close monitoring of renal function is recommended.1

Anaphylactoid reactions have been reported in patients receiving ketoprofen.1 Patients receiving ketoprofen should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.1

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving ketoprofen.1,142 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.1 Ketoprofen should be discontinued at the first appearance of rash or any other sign of hypersensitivity.1

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1201 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1201 Symptoms may resemble those of an acute viral infection.1201 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1201 If such signs or symptoms develop, ketoprofen should be discontinued and the patient evaluated immediately.1201

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.1

Because NSAIAs have caused adverse ocular effects, patients who experience visual disturbances during ketoprofen therapy should have an ophthalmologic examination.209,210,211

If corticosteroid therapy is discontinued or dosage is decreased during ketoprofen therapy, it should be done gradually and patients should be observed for adverse effects including adrenocortical insufficiency or symptomatic exacerbation of the inflammatory condition being treated.1

The possibility that the antipyretic and anti-inflammatory effects of ketoprofen may mask the usual signs and symptoms of infection or other diseases should be considered.83,177,209,210

The manufacturers state that ketoprofen is contraindicated in patients with known hypersensitivity to the drug.1 In addition, NSAIAs, including ketoprofen, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, rarely fatal, anaphylactic reactions to NSAIAs have been reported in these patients.1,26,48,83,86,89,90,91,92,177 Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization.88,89,90,91,92 Because patients with asthma may have aspirin-sensitivity asthma, ketoprofen should be used with caution in patients with asthma.1 In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad.1 For a further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.

Ketoprofen is contraindicated in the setting of CABG surgery.508

Pediatric Precautions

Although ketoprofen has been used with good results in preliminary, uncontrolled clinical studies for the management of juvenile rheumatoid arthritis† in children 2-16 years of age,140,141 safety and efficacy of the drug in children younger than 18 years of age have not been established.1

Geriatric Precautions

Because elimination of ketoprofen may be prolonged in geriatric individuals, ketoprofen dosage should be adjusted carefully in geriatric patients (e.g., initiate therapy with a low dose).1 (See Dosage and Administration: Dosage.) Geriatric individuals appear to tolerate GI ulceration or bleeding less well than other individuals, and many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involved geriatric individuals.1 (See Cautions: GI Effects.)

Approximately 30% of patients in clinical studies that evaluated use of ketoprofen (conventional or extended-release preparations) for osteoarthritis or rheumatoid arthritis were 65 years of age or older.1 No overall difference in efficacy was observed between geriatric individuals and younger adults.1

Mutagenicity and Carcinogenicity

No evidence of ketoprofen-induced mutagenesis was seen in the Ames microbial mutagen test or several other tests.1,211

No evidence of carcinogenic potential was seen in mice receiving oral ketoprofen dosages up to 32 mg/kg daily (about 0.5 times the maximum daily recommended human dosage based on body surface area) for 24 months.1,209 Following oral administration of ketoprofen self-medicate with dosages up to 12.5 mg/kg daily for 91 weeks in rats, an increased incidence of tumors was not observed;1,209,211 however, the study was not acceptable because of poor survival rates.1

Pregnancy, Fertility, and Lactation

Pregnancy

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.1200,1201 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.1200,1201 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.1200,1201 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.1200,1201

Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.1202

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1200,1201 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1200,1201 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1200,1201 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1200,1201 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1200,1201 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.1201 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1201 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.1201

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1201 In animal studies, inhibitors of prostaglandin synthesis, such as ketoprofen, were associated with increased pre- and post-implantation losses.1201 Prostaglandins also have an important role in fetal kidney development.1201 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1201

In animal reproduction studies in mice and rats, no teratogenic or embryotoxic effects were observed at ketoprofen dosages up to approximately 0.2 times the maximum recommended human dosage of 185 mg/m² daily.1201 In rabbits, maternally toxic dosages were associated with embryotoxicity but not with teratogenicity.1201

The effects of ketoprofen on labor and delivery in humans currently are not known,1 but the drug has delayed parturition in rats when administered in doses of 6 mg/kg (about 0.2 times the maximum daily recommended human dosage based on body surface area) before the onset of labor.1

Fertility

Use of NSAIAs may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1203 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.1203 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1203

Reproduction studies in male rats using ketoprofen dosages up to 9 mg/kg daily have not revealed evidence of impaired fertility, but decreases in the number of implantation sites occurred in female rats receiving dosages of 6 or 9 mg/kg daily.1

Lactation

It is not known whether ketoprofen is distributed into human milk;1 4-5% of circulating plasma concentrations of the drug are distributed into the milk of lactating dogs.1 In rats, perinatal development was not adversely affected in nursing offspring whose mothers received ketoprofen doses of 9 mg/kg (approximately 0.3 times the maximum daily recommended human dosage based on body surface area).1 The manufacturers recommend that ketoprofen not be used in nursing women.1

Protein-bound Drugs

Because ketoprofen is highly protein bound, it could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs.52,78 Although only a few protein-binding interactions with ketoprofen have been observed to date,52,78 patients receiving ketoprofen concomitantly with other highly protein-bound drugs should be observed for adverse effects of combined therapy.209,210,211 Since formal drug interaction studies have generally been performed using ketoprofen dosages of 50 mg 4 times daily, the possibility of increased interaction should be kept in mind when ketoprofen is administered in single doses greater than 50 mg or in dosages greater than 200 mg daily concomitantly with highly protein-bound drugs.1

Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

There is some evidence that concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists may reduce the blood pressure response to the antihypertensive agent.1,291

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic.1 Concomitant use of ketoprofen and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.1

In a short-term controlled study in healthy adults, ketoprofen did not substantially alter the hypoprothrombinemic effect of warfarin when the drugs were administered concomitantly.1 However, prolongation of prothrombin time and GI bleeding in a geriatric patient whose warfarin anticoagulation had been stabilized occurred following initiation of ketoprofen therapy.240 Because ketoprofen may cause GI bleeding,1,105,140,200,202 inhibit platelet aggregation,1,34,40,41,47,54 and prolong bleeding time,1,34,40,41,47,54 the drug should be used with caution and the patient carefully observed if the drug is used concomitantly with any anticoagulant (e.g., warfarin)1,240 or thrombolytic agent (e.g., streptokinase).39

Digoxin

In patients with congestive heart failure, concomitant administration of ketoprofen with digoxin did not alter serum concentrations of digoxin.1

Diuretics

Patients receiving diuretics may have an increased risk of developing renal failure secondary to decreased renal blood flow resulting from prostaglandin inhibition by NSAIAs, including ketoprofen.1,16,26,48,83,177,222 (See Cautions: Precautions and Contraindications.) In addition, NSAIAs may interfere with the natriuretic response to diuretics whose activity depends in part on prostaglandin-mediated alterations in renal blood flow (e.g., loop diuretics).8 Concomitant administration of ketoprofen and hydrochlorothiazide has resulted in decreased urinary excretion of potassium and chloride compared with hydrochlorothiazide alone.1 Patients receiving concomitant NSAIA and diuretic therapy should be monitored for signs of renal failure and for efficacy of the diuretic.1

Nonsteroidal Anti-inflammatory Agents

Following concomitant administration of ketoprofen and aspirin in healthy individuals, protein binding of ketoprofen is decreased and its plasma clearance is substantially increased;1,52 however, the net effect on free plasma ketoprofen concentrations appears to be minimal.52 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.1 Because of the potential for increased adverse effects, patients receiving ketoprofen should be advised not to take aspirin.1 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.284,502,508

Ketoprofen and salicylates appear to interact in a complex manner, the clinical importance of which remains to be determined.52 Salicylate also appears to reduce conjugation of ketoprofen and renal elimination of ketoprofen conjugates, and enhance conversion of ketoprofen to nonconjugated metabolites.52 Ketoprofen does not appear to affect salicylate pharmacokinetics.52

Probenecid

When probenecid is administered concomitantly with ketoprofen, total and free plasma concentrations of ketoprofen are substantially increased as a result of decreased protein binding of ketoprofen, decreased total apparent plasma clearance of ketoprofen, and decreased apparent plasma clearance of free ketoprofen.78 In addition, probenecid appears to inhibit conjugation of ketoprofen and renal excretion of ketoprofen conjugates.78 The manufacturers state that concomitant use of ketoprofen and probenecid is not recommended.1

Methotrexate

Severe, sometimes fatal, toxicity has occurred following administration of an NSAIA,210,216,217,218,219,221,231 including ketoprofen,24 concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis. The toxicity was associated with elevated and prolonged blood concentrations of methotrexate.1,24,210,216,217,218,219,221,231 The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination.24,210,216,217,218,219,221,231 When ketoprofen was administered at least 12 hours after completion of high-dose methotrexate IV infusion, there was no evidence of methotrexate toxicity or an alteration in methotrexate pharmacokinetics.24 Additional studies are needed to evaluate the interaction between ketoprofen and methotrexate.210,216,217,218,219,221 Caution is advised if methotrexate and an NSAIA are administered concomitantly.1 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Methotrexate 10:00.)

Pemetrexed

Concomitant use of NSAIAs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.1203 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.1203 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.1203 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant NSAIA and pemetrexed therapy.1203

Lithium

Like other NSAIAs, ketoprofen has been reported to increase serum lithium concentrations.209,229 NSAIAs appear to decrease renal clearance of lithium.209,229 The mechanism involved in the reduction of lithium clearance by NSAIAs is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium.254 When ketoprofen therapy is initiated in patients receiving lithium or when dosage of ketoprofen is adjusted or the drug is discontinued in these patients, plasma lithium concentrations should be monitored and the patient should be observed for signs and symptoms of lithium intoxication.209,229

Laboratory Test Interferences

In vitro at a concentration of 60 mcg/mL, ketoprofen has caused falsely elevated blood glucose concentrations when the glucose oxidase and peroxidase method using diammonium azinobisethyldihydrobenzothiazole sulfonic acid (ABTS) as a chromogen was employed.84 At this concentration in vitro, the drug has also caused falsely elevated serum iron concentrations using the Ramsay method, falsely decreased serum iron concentrations with a method using bathophenanthroline disulfonate as a chromogen reagent, and falsely elevated serum bilirubin concentrations with a method using dimethylsulfoxide (DMSO) as a reagent.84 Since the in vitro concentration tested substantially exceeds the usual peak plasma concentrations of ketoprofen attained in humans, the clinical importance of these interferences is not known.209,211

Acute Toxicity

Limited information is available on the acute toxicity of ketoprofen.1,10,31,53

Pathogenesis

The acute lethal dose of ketoprofen in humans is not known.10 Individuals have survived reported ingestions of up to 5 g of the drug.1,10 The oral LD₅₀ of ketoprofen is 2000, 1300, 360, 160, and 145 mg/kg in dogs,31 guinea pigs,31 mice,31,33,53 rats,31,33,53 and rabbits,31 respectively. The IV LD₅₀ of the drug is 450 mg/kg in guinea pigs,31 and the subcutaneous LD₅₀ is 550 and 100 mg/kg in mice and rats, respectively.31

Manifestations

Drowsiness,1,10 vomiting,1,10 and abdominal pain10 have been reported in a few individuals following acute overdosage of ketoprofen.1,10 In a 12-year-old female who intentionally ingested an unknown amount of ketoprofen, hydrocodone, and acetaminophen, tonic-clonic seizures and metabolic acidosis resulted; the patient recovered within 18 hours of ingestion.1

Treatment

In acute ketoprofen overdosage, general measures should include immediately emptying the stomach by inducing emesis or by gastric lavage, followed by initiation of supportive and symptomatic treatment.1 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.45

Pharmacology

Ketoprofen has pharmacologic actions similar to those of other prototypical NSAIAs.1,30,31,33,34,35,42,43,53,205 The drug exhibits anti-inflammatory, analgesic, and antipyretic activity.1,31,33,41,43,53,205,220 The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis.1,31,34,42,43,205 Ketoprofen inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway.264,265,266,267,268,269,270 Ketoprofen, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.264,265,266,267,268,269,270 Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.264,265,266,267,268,269,270

Anti-inflammatory, Analgesic, and Antipyretic Effects

The anti-inflammatory, analgesic, and antipyretic effects of ketoprofen and other NSAIAs, including selective inhibitors of COX-2 (e.g., celecoxib), appear to result from inhibition of prostaglandin synthesis.5,6,11,15,18,19,31,42,43,49,205,264,265,266,267,268,269,270 While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.264,265,266,267,268,269,270

Ketoprofen also stabilizes lysosomal membranes in vitro34,44,205 and in vivo,34 inhibits leukotriene synthesis in vitro at high concentrations,1,211,225,226 and exhibits antibradykinin activity in vivo.1,31,53 On a weight basis, the anti-inflammatory potency of ketoprofen has been shown to be similar to that of indomethacin30,31,32,33,43,53,205 and naproxen31 and about 20, 80, or 160 times that of ibuprofen,31,43,205 phenylbutazone,31,43,205 or aspirin,33,43,205 respectively, as determined by inhibition of carrageenan-induced inflammation in rats.

On a weight basis, the analgesic potency of ketoprofen was similar to that of indomethacin and about 70 times that of aspirin as determined by antagonism of phenylbenzoquinone-induced writhing in mice.31,33,53,205 On a weight basis, as determined by the paw pressure test in rats, the analgesic potency of ketoprofen was similar to that of naproxen31 or indomethacin31,33 and about 6,31 15,31 or 3033 times that of ibuprofen, phenylbutazone, or aspirin, respectively.

Ketoprofen lowers body temperature in animals with antigen-induced fever.31,33,53 Although the mechanism of antipyretic effect of NSAIAs is not known, it has been suggested that suppression of prostaglandin synthesis in the CNS (probably in the hypothalamus) may be involved.5,21,209,210,211 In rats, the antipyretic activity of ketoprofen 1.2 mg/kg was similar to that of aspirin 135 mg/kg.33

Genitourinary and Renal Effects

In some patients, ketoprofen has relieved symptoms associated with primary dysmenorrhea, probably by inhibiting the synthesis and/or actions of prostaglandins.50,161,234 Whether the increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or COX-2 remains to be determined.27

Ketoprofen has been reported to adversely affect renal function.1,94,190,199,205,209,230 (See Cautions: Renal and Genitourinary Effects.) Although the exact mechanism of adverse renal effects of NSAIAs has not been determined, the effects may be related to inhibition of renal prostaglandin synthesis.9,15,16,18,19,46,192,193,198,199

GI Effects

Ketoprofen can cause gastric mucosal damage which may result in ulceration and/or bleeding.1,32,181,182,183,184,185,186,245 (See Cautions: GI Effects.) These gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.264,265,266,267,268,269,270 Other factors possibly involved in NSAIA-induced gastropathy include local irritation, promotion of acid back-diffusion into gastric mucosa, uncoupling of oxidative phosphorylation, and enterohepatic recirculation of the drugs.264,265,266,267,268,269,270

Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.268 Although the exact mechanism by which NSAIAs may inhibit colon carcinogenesis remains to be determined, it has been suggested that inhibition of prostaglandin synthesis may be involved.268

Hematologic Effects

Ketoprofen can inhibit platelet aggregation and may prolong bleeding time.1,34,40,41,47,54 Like other prototypical NSAIAs,5,9,15,28 the effects of ketoprofen on platelets appear to be associated with inhibition of the synthesis of prostaglandins produced by COX-1.40,47,54,268 Unlike the irreversible action of aspirin on platelets and the resultant prolonged effect on platelet aggregation, ketoprofen has a transient effect on platelet function and platelet aggregation usually returns to normal within 24-36 hours following discontinuance of the drug.40 In one in vitro study, on a molar basis, ketoprofen inhibited thrombin-induced platelet aggregation to a greater extent than did indomethacin.54

Pharmacokinetics

Absorption

Ketoprofen is rapidly and almost completely absorbed from the GI tract.1,55,57,58,59 The absolute bioavailability of commercially available conventional and extended-release ketoprofen capsules is approximately 90%.1 Food and milk decrease the rate of absorption of conventional capsules of the drug, resulting in delayed and reduced peak plasma concentrations, but the extent of absorption is not affected.1

Following single 50-mg oral doses of ketoprofen as conventional capsules, average peak plasma ketoprofen concentrations of 4.1 mcg/mL occur after about 1 hour in the fasted state compared with 2.4 mcg/mL after 2 hours in the nonfasted state.1 Concomitant administration of an aluminum and magnesium hydroxides antacid1 or an aluminum phosphate antacid63,66 does not appear to affect absorption of the drug as conventional capsules.1,63,66

Following oral administration of a single 50-, 100-, or 150-mg dose of ketoprofen as conventional capsules in fasting, healthy individuals or rheumatoid arthritis patients, average peak plasma ketoprofen concentrations of 3.2-4.8,1,60,61,64,71 5.5-10.1,1,58,62,63,64,66,71 and 13.169 mcg/mL, respectively, occur within about 1 hour (range: 0.5-2 hours).1,58,60,61,62,64,66,69,71 The area under the plasma concentration-time curve (AUC) increases linearly with single ketoprofen doses of 75-200 mg.1 There is considerable interindividual and intraindividual variation in plasma concentrations attained with a given dosage.57,60,63,64

Commercially available extended-release capsules of ketoprofen (Oruvail^®) contain the drug as hundreds of coated pellets.1 The dissolution of the pellets is pH-dependent, with optimum dissolution occurring at pH 6.5-7.5; no dissolution occurs at pH 1.1 The pellets are designed to release the drug in the higher pH environment of the small intestine, avoiding dissolution in the more acidic gastric fluid.1

Ketoprofen is well absorbed from the extended-release formulation; however, an observable increase in plasma ketoprofen concentration does not occur until approximately 2-3 hours following administration.1 Peak plasma concentrations usually are reached 6-7 hours following oral administration of the extended-release formulation.1 Administration of the extended-release formulation with a high-fat meal delayed the time to maximum plasma concentrations by 2 hours; however, neither the total bioavailability nor the maximum plasma concentration was affected.1 The effect of antacids on concomitantly administered extended-release ketoprofen capsules has not been studied;1 however, the administration of antacids or other drugs that may increase gastric pH would not be expected to change the rate or extent of absorption of ketoprofen from the extended-release formulation.1

Following oral administration of a single 200-mg dose of ketoprofen as an extended-release capsule in fasting individuals, mean peak plasma concentration was 3.1 mg/L;1 in non-fasting individuals, the mean peak plasma concentration was 3.4 mg/L.1 Time to peak plasma concentration was approximately 7 hours in fasting individuals and 9 hours in non-fasting individuals.1

Steady-state plasma concentrations of ketoprofen generally are reached within 24-48 hours following continuous dosing1,57,60,63 and average 1.7-2.3 mcg/mL with ketoprofen dosages of 50 mg 4 times daily.57,60,62 Although the relationship between plasma ketoprofen concentrations and therapeutic effect has not been precisely determined, a therapeutic range of 0.4-6 mcg/mL has been suggested.60,62

Trough concentrations of ketoprofen at 24 hours following administration of the drug as a single 200-mg extended-release capsule, 50-mg conventional-release capsules 4 times daily for 12 hours, or 75-mg conventional-release capsules 3 times daily for 12 hours were 0.4 mg/L, 0.07 mg/L, or 0.13 mg/L, respectively.1

Clinical studies in patients with rheumatoid arthritis or osteoarthritis suggest that the therapeutic effects of ketoprofen may persist longer than expected on the basis of its plasma elimination half-life.138,151,205,207 Following oral administration of a single 50-mg dose of ketoprofen in patients with dental or postpartum pain†, analgesic activity is evident within 1-2 hours and persists for approximately 3-4 hours.173,174

Distribution

Distribution of ketoprofen into human body fluids and tissues has not been fully characterized.1,57,64,67,71,75 Ketoprofen is distributed into synovial fluid,57,64,67,68,71,227 with peak synovial fluid concentrations about 30% of those attained in plasma;57,64,71 by 4-6 hours after administration, synovial fluid concentrations of the drug exceed those in plasma.64,71,227 Following oral administration of a single 50-mg dose of ketoprofen, peak synovial fluid ketoprofen concentrations of approximately 0.9 mcg/mL occur within about 3 hours.57,64,71 The drug is also rapidly and readily distributed into the CNS, with CSF concentrations of free drug approximately equivalent to those in plasma.75 Following oral administration in healthy adults, ketoprofen reportedly has an apparent volume of distribution at steady state (V_ss) of about 8 L.61 Following oral62 or IV1 administration of the drug, the apparent volume of distribution (V_d) is approximately 0.1 L/kg.1,62 V_d appears to be increased in patients with alcoholic cirrhosis.2

Ketoprofen is approximately 99% bound to plasma proteins,1,75 mainly albumin.1 In geriatric patients and patients with alcoholic cirrhosis, protein binding of the drug appears to be reduced.1 In a group of patients with alcoholic cirrhosis, the fraction of free ketoprofen was double that of a group of age-matched healthy individuals.1 The reduced degree of protein binding in patients with alcoholic cirrhosis probably results from hypoalbuminemia.1

It is not known whether ketoprofen is distributed into milk in humans.1 In dogs, ketoprofen is distributed into milk in concentrations about 4-5% of simultaneous maternal plasma drug concentrations.1

Elimination

Plasma concentrations of ketoprofen appear to decline in a biphasic manner.61 Following single or multiple oral doses as conventional capsules in healthy adults, the elimination half-life of the drug has averaged 1.1-4 hours.1,58,60,62,68,80,82 Elimination half-life following administration of ketoprofen 200 mg extended-release capsules averaged 5.4 hours.1 This prolongation is attributed to delayed absorption from the extended-release preparation; intrinsic clearance is unchanged.1 Following administration of the drug as conventional capsules in geriatric individuals, the elimination half-life was prolonged by 26%; following administration of the drug as 200 mg extended-release capsules in geriatric individuals, the elimination half-life was prolonged by 54%.1

The elimination half-life of ketoprofen is also prolonged in patients with renal impairment, but in patients with moderate renal impairment (i.e., creatinine clearance of 20-60 mL/minute), the half-life following administration of the drug as conventional capsules is still within the reported normal range, averaging about 3.5 hours.1,72 In patients with moderate to severe renal impairment, elimination half-life of ketoprofen is prolonged to approximately 5-9 hours.1 No studies of the extended-release formulation have been reported in patients with renal impairment.1

The exact metabolic fate of ketoprofen is not clearly established, but the drug is rapidly and extensively metabolized in the liver,1,2,45,59 principally via conjugation with glucuronic acid.1,55,59,60,62,73,74 The glucuronide conjugate of ketoprofen is pharmacologically inactive,1,211 and no active metabolites of the drug have been identified to date.1

Following oral administration, ketoprofen and its metabolites are excreted mainly in urine.1,57,59,60,61,62,70,72,80,228 The drug and its metabolites are also excreted in feces following oral administration,1,59 but fecal excretion has not been fully characterized.59 Results of animal studies suggest that ketoprofen may undergo enterohepatic circulation,228 but studies to determine whether this occurs in humans have not been performed to date.1,209,211 Following a single oral dose of ketoprofen in healthy adults, about 50-90% of the dose is excreted in urine1,57,59,60,61,62,70,72,80,211,228 and about 1-8% in feces59,228 within 1-5 days; most urinary excretion occurs within 12-24 hours,1,57,58,59,60,62 and most fecal excretion occurs within 24-48 hours.59 It appears that ketoprofen is excreted in urine almost completely as metabolites, principally as ketoprofen glucuronide, and that only a small amount is excreted as unchanged drug (possibly less than 1%).70,79 Since ketoprofen glucuronide apparently undergoes hydrolysis in the bladder prior to excretion and in urine samples stored at room temperature or frozen, results of early pharmacokinetic studies probably substantially overestimated the fraction excreted as unchanged drug.70,79 Other unidentified, conjugated metabolites are also excreted in urine.70

Following oral administration in healthy individuals, total apparent plasma clearance of ketoprofen averages approximately 1-1.3 mL/minute per kg.1,69,72 Total apparent plasma clearance of the drug is decreased in patients with reduced renal function.1,72 In a group of patients with creatinine clearances of 20-60 mL/minute, total apparent plasma clearance averaged 0.7 mL/minute per kg (range: 0.5-0.9 mL/minute per kg).72 Total apparent plasma clearance is also similarly decreased in geriatric individuals.1,69

Chemistry and Stability

Chemistry

Ketoprofen, a propionic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,30,53,93,205 The drug is structurally related to fenoprofen, ibuprofen, and naproxen.2,3,30,38,93 Unlike these other propionic acid derivatives, ketoprofen has a benzoyl substituent at the meta position of α-phenylpropionic acid.3,38

Ketoprofen occurs as a white1,2,4,34 to off-white,1,4 fine to granular1,34 powder and is practically insoluble in water1,2,4,34 and freely soluble in alcohol1,2,4 at 20°C. The pK_a of the drug is 5.9 in a 3:1 solution of methanol and water.37

Stability

Ketoprofen conventional and extended-release capsules should be stored in tight,1 light-resistant2 containers at room temperature (approximately at 25°C);1,2 ketoprofen capsules should be protected from excessive heat and humidity.1 Commercially available ketoprofen conventional capsules have an expiration date of 3 years following the date of manufacture.2

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Wyeth. Orudis^® and Oruvail^® (ketoprofen) capsules and extended-release capsules prescribing information. Philadelphia, PA; 2006 Mar.

2. Wyeth Laboratories Inc. Product information form for American Hospital Formulary Service on Orudis^®. Philadelphia, PA; 1985.

3. Windholz M, ed. The Merck index. 10th ed. Rahway, NJ: Merck & Co, Inc; 1983:573,712,762,920,1294.

4. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 28th ed. London: The Pharmaceutical Press; 1982:261-2.

5. Moncada S, Roderick JF, Vane JR. Prostaglandins, prostacyclin, thromboxane A2, and leukotrienes. In: Gilman AG, Goodman L, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:660-73.

6. Atkinson DC, Collier HOJ. Salicylates: molecular mechanism of therapeutic action. Adv Pharmacol Chemother . 1980; 17:233-88. [PubMed 7004141]

7. Hart FD. Rheumatic disorders. In: Avery GS, ed. Drug treatment: principles and practice of clinical pharmacology and therapeutics. 2nd ed. Sydney: ADIS Press; 1980:846-88.

8. Brater DC. Drug-drug and drug-disease interactions with nonsteroidal anti-inflammatory drugs. Am J Med . 1986; 80(Suppl 1A):62-77. [PubMed 3511686]

9. Wolf RE. Nonsteroidal anti-inflammatory drugs. Arch Intern Med . 1984; 144:1658-60. [PubMed 6235791]

10. Court H, Volans GN. Poisoning after overdose with non-steroidal anti-inflammatory drugs. Adv Drug React Ac Pois Rev . 1984; 3:1-21.

11. Abramson S, Edelson H, Kaplan H et al. Inhibition of neutrophil activation by nonsteroidal anti-inflammatory drugs. Am J Med . 1984; 10:3-6.

12. McElnay JC, D'Arcy PF. Displacement of albumin-bound warfarin by anti-inflammatory agents in vitro. J Pharm Pharmacol . 1980; 32:709-11. [PubMed 6107346]

13. Pawlotsky Y, Louboutin JY, Chales G et al. Interactions ketoprofene-aspirine. (French; with English abstract.) Sem Hop Paris . 1983; 59:3218-20.

14. Lewis GR, Jacobs SG, Vavra I. Effect of ketoprofen on serum digoxin concentrations. Curr Ther Res . 1985; 38:494-9.

15. Robinson DR. Prostaglandins and the mechanism of action of anti-inflammatory drugs. Am J Med . 1983; 10:26-31.

16. O'Brien WM. Pharmacology of nonsteroidal anti-inflammatory drugs: practical review for clinicians. Am . J Med. 1983; 10:32-9.

17. Harris ED Jr. Evaluation of pathophysiology and drug effects on rheumatoid arthritis. Am J Med . 1983; 10:56-61.

18. Hart FD, Huskisson EC. Non-steroidal anti-inflammatory drugs: current status and rational therapeutic use. Drugs . 1984; 27:232-55. [PubMed 6368185]

19. Simon LS, Mills JA. Nonsteroidal antiinflammatory drugs. N Engl J Med . 1980; 302:1179-85. [PubMed 6988717]

20. Ferreira SH, Lorenzetti BB, Correa FMA. Central and peripheral analgesic action of aspirin-like drugs. Eur J Pharmacol . 1978; 53:39-48. [PubMed 310771]

21. Bernheim HA, Block LH, Atkins E. Fever: pathogenesis, pathophysiology, and purpose. Ann Intern Med . 1979; 91:261-70. [PubMed 223485]

22. Wilkens RF. The use of nonsteroidal anti-inflammatory agents. JAMA . 1978; 240:1632-5. [PubMed 691156]

23. Capetola RJ, Rosenthale ME, Dubinsky B et al. Peripheral antialgesics: a review. J Clin Pharmacol . 1983; 23:545-56. [PubMed 6363465]

24. Thyss A, Milano G, Kubar J et al. Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet . 1986; 1:256-8. [PubMed 2868265]

25. Ylikorkala O, Dawood YM. New concepts in dysmenorrhea. Am J Obstet Gynecol . 1978; 130:833-47. [PubMed 25021]

26. McNeil Pharmaceutical. Tolectin^® DS and Tolectin^® prescribing information. Spring House, PA; 1985 Aug.

27. Flower RJ, Moncada S, Vane JR. Analgesic-antipyretics and anti-inflammatory agents; drugs employed in the treatment of gout. In: Gilman AG, Goodman L, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Co; 1985:674-715.

28. Moncada S, Vane JR. Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N Engl J Med . 1979; 300:1142-7. [PubMed 219340]

29. Standing Advisory Committee for Haematology of the Royal College of Pathologists. Drug interaction with coumarin derivative anticoagulants. BMJ . 1982; 285:274-5. [PubMed 6807448]

30. Brogden RN, Speight TM, Avery GS. Ketoprofen: a preliminary report of its pharmacological activity and therapeutic efficacy in rheumatic disorders. Drugs . 1974; 8:168-75. [PubMed 4611741]

31. Julou L, Guyonnet JC, Ducrot R et al. Ketoprofen (19.583 R.P.) (2-(3-benzoylphenyl)-propionic acid): main pharmacological properties—outline of toxicological and pharmacokinetic data. Scand J Rheumatol . 1976; 14(Suppl):33-44.

32. Anon. Naproxen (Naprosyn) and ketoprofen (Orudis). Drug Ther Bull . 1974; 12:25-7. [PubMed 4616814]

33. Julou L, Guyonnet JC, Ducrot R et al. Some pharmacological and toxicological studies on ketoprofen. Rheumatol Rehabil . 1976; 15(Suppl):5-10.

34. Fossgreen J. Ketoprofen: a survey of current publications. Scand J Rheumatol . 1976; 14(Suppl):7-32.

35. Simon LS, Mills JA. Nonsteroidal antiinflammatory drugs. N Engl J Med . 1980; 302:1237-43. [PubMed 6988723]

36. Renier JC, Boasson M. Etude de l'acide (benzoyl-3 phenyl)-2 propionique en rhumatologie (a propos de 27 observations). Arch Med Ouest . 1973; 5:485-92.

37. Liversidge GG. Ketoprofen. In: Florey K, ed. Analytical profiles of drug substances. Vol 10. New York: Academic Press; 1981:443-71.

38. Hamor GH. Nonsteroidal anti-inflammatory agents. In: Foye WO, ed. Principles of medical chemistry. 2nd ed. Philadelphia, PA: Lea & Febiger; 1981:561-80.

39. Hoechst-Roussel. Streptase^® prescribing information. Sommerville, NJ: 1982 Apr.

40. Gandini R, Cunietti E, Pappalepore V et al. Effects of intravenous high doses of ketoprofen on blood clotting, bleeding time and platelet aggregation in man. J Int Med Res . 1983; 11:243-6. [PubMed 6617983]

41. Marmo E, Ottavo R, Giordano L et al. Analisi sperimentale di alcuni aspetti farmacodinamici del ketoprofene lisina. (Italian; with English summary.) Arch Sci Med . 1980; 137:387-404.

42. Kubota T, Komatsu H, Kawamoto H et al. Studies on the effects of anti-inflammatory action of benzoyl-hydrotropic acid (ketoprofen) and other drugs, with special reference to prostaglandin synthesis. Arch Int Pharmacodyn Ther . 1979; 237:169-76. [PubMed 485681]

43. Guyonnet JC, Julou L. Relationship between the inhibitory activity on “RCS” and prostaglandins synthesis and the anti-inflammatory activity of ketoprofen and several other non-steroidal anti-inflammatory agents. Rheumatol Rehabil . 1976; 15(Suppl):11-4.

44. Migne J, Vedrine Y, Bourat G et al. Action of ketoprofen on hepatic lysosome in the rat. Rheumatol Rehabil . 1976; 15(Suppl):15-9.

45. Gosselin RE, Smith RP, Hodge HC et al. Clinical toxicology of commercial products. 5th ed. Baltimore: The Williams & Wilkins Co; 1984:I-10.

46. Fiore CE, Petralito A, Mazzarino MC et al. Effects of ketoprofen on the calciuric and uricosuric activities of calcitonin in man. J Endocrinol Invest . 1981; 4:81-4. [PubMed 7240673]

47. Migne J, Santonja R, Kunz S. Etude comparee de l'activite antiagregante plaquettaire de plusieurs anti-inflammatoires. (French; with English summary.) Sem Hop Paris . 1983; 59:3197-203.

48. The Upjohn Company. Motrin^® prescribing information. Kalamazoo, MI; 1985 Jul.

49. Deraedt R, Jouquey S, Benzoni J et al. Inhibition of prostaglandin biosynthesis by non-narcotic analgesic drugs. Arch Int Pharmacodyn Ther . 1976; 224:30-42. [PubMed 13749]

50. Dawood MY. Dysmenorrhoea and prostaglandins: pharmacological and therapeutic considerations. Drugs . 1981; 22:42-56. [PubMed 6790261]

51. O'Reilly RA. Anticoagulant, antithrombotic, and thrombolytic drugs. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacologic basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:1338-59.

52. Williams RL, Upton RA, Buskin JN et al. Ketoprofen-aspirin interactions. Clin Pharmacol Ther . 1981; 30:226-31. [PubMed 7249506]

53. Julou L, Guyonnet JC, Ducrot R et al. Etude des proprietes pharmacologiques d'un nouvel anti-inflammatoire, l'acide (benzoyl-3 phenyl)-2 propionique (19583 R.P.). J Pharmacol (Paris) . 1971; 2:259-86.

54. Migne J, Santonja R, Kunz S. Etude comparee de l'activité anti-agregante plaquettaire de plusieurs anti-inflammatoires. Therapie . 1973; 28:861-76. [PubMed 4368089]

55. Populaire P, Terlain B, Pascal S et al. Comportement biologique: taux sériques, excrétion et biotransformation de l'acide (benzoyl-3 phényl)-2 propionique ou ketoprofene chez l'animal et chez l'homme. (French; with English abstract.) Ann Pharm Fr . 1973; 31:735-49.

56. Blanchard JC, Schneider YJ, Tulkens P et al. Cellular uptake and subcellular distribution of two non-steroidal anti-inflammatory drugs: indomethacin and ketoprofen. Arch Int Pharmacodyn Ther . 1979; 240:4-16. [PubMed 507996]

57. Grahame R, Billings R, Reeback J et al. Blood level studies on ketoprofen. Rheumatol Rehabil . 1978; 17(Suppl):64-70.

58. Sala G, Silvestri N, Castegnaro E et al. Pharmacokinetic and therapeutic effects of ketoprofen. Farmaco . 1978; 33:455-60.

59. Delbarre F, Roucayrol JC, Amor B et al. Pharmacokinetic study of ketoprofen (19.583 R.P.) in man using the tritiated compound. Scand J Rheumatol . 1976; 5(Suppl 14):45-52.

60. Lewellen ORW, Templeton R. The pharmacokinetics of ketoprofen in man during and after repeated oral dosing (50 mg q.i.d.) with Orudis. Scand J Rheumatol . 1976; 5(Suppl 14):53-62. [PubMed 1257710]

61. Upton RA, Williams RL, Guentert TW et al. Ketoprofen pharmacokinetics and bioavailability based on an improved sensitive and specific assay. Eur J Clin Pharmacol . 1981; 20:127-33. [PubMed 7262174]

62. Ishizaki T, Sasaki T, Suganuma T et al. Pharmacokinetics of ketoprofen following single oral, intramuscular and rectal doses and after repeated oral administration. Eur J Clin Pharmacol . 1980; 18:407-14. [PubMed 7439263]

63. Brazier JL, Tamisier JN, Ambert D et al. Bioavailability of ketoprofen in man with and without concomitant administration of aluminium phosphate. Eur J Clin Pharmacol . 1981; 19:305-7. [PubMed 7286034]

64. Mitchell WS, Scott P, Kennedy AC et al. Clinico-pharmacological studies on ketoprofen ("Orudis'). Curr Med Res Opin . 1975; 3:423-30.

65. Upton RA, Buskin JN, Guentert TW et al. Ketoprofen kinetics based on a new high-pressure liquid chromatographic assay. Clin Pharmacol Ther . 1979; 25:251-2.

66. Tamisier JN, Brazier JL, Ambert D et al. Etude de la biodisponibilite du ketoprofene (Profenid) administre par voie orale en association avec un protecteur gastrique (phosphate d'alumine, Phosphalugel). (French; with English abstract.) Sem Hop Paris . 1983; 59:3214-7.

67. Kohler G, Mohing W, Lutz D et al. Teneur en principe actif du sang, du liquide synovial, de la membrane synoviale et des tissus osseux, musculaires et adipeux avoisinants chez des malades atteints de polyarthrite rhumatoide et ayant recu une injection intramusculaire unique de ketoprofene ou d'acide acetylsalicylique (trois heures apres injection). (French; with English abstract.) Sem Hop Paris . 1983; 59:3210-3.

68. Kennedy AC. Pharmacocinetique du ketoprofene dans le liquide synovial. (French; with English abstract.) Sem Hop Paris . 1983; 59:3208-9.

69. Advenier C, Roux A, Gobert C et al. Pharmacokinetics of ketoprofen in the elderly. Br J Clin Pharmacol . 1983; 16:65-70. [PubMed 6882624]

70. Upton RA, Buskin JN, Williams RL et al. Negligible excretion of unchanged ketoprofen, naproxen, and probenecid in urine. J Pharm Sci . 1980; 69:1254-7. [PubMed 7452451]

71. Kennedy AC. Synovial-fluid pharmacokinetics of ketoprofen. Rheumatol Rehabil . 1976; 15(Suppl):20-1.

72. Stafanger G, Larsen HW, Hansen H et al. Pharmacokinetics of ketoprofen in patients with chronic renal failure. Scand J Rheumatol . 1981; 10:189-92. [PubMed 7291952]

73. Houghton GW, Dennis MJ, Rigler ED et al. Urinary pharmacokinetics of orally administered ketoprofen in man. Eur J Drug Metab Pharmacokinet . 1984; 9:201-4. [PubMed 6519121]

74. Verbeeck RK, Wallace SM, Loewen GR. Reduced elimination of ketoprofen in the elderly is not necessarily due to impaired glucuronidation. Br J Clin Pharmacol . 1984; 17:783-4. [PubMed 6743473]

75. Netter P, Lapicque F, Bannwarth B et al. Diffusion of intramuscular ketoprofen into the cerebrospinal fluid. Eur J Clin Pharmacol . 1985; 29:319-21. [PubMed 4076328]

76. Queneau P, Decousus H, Ollagnier M et al. Chronocinetique du ketoprofene administre per os et en perfusion veineuse continue. (French; with English summary.) Rev Rhum . 1985; 52:403-8.

77. Houghton GW, Dennis MJ, Rigler ED et al. Comparative pharmacokinetics of ketoprofen derived from single oral doses of ketoprofen capsules or a novel sustained-release pellet formulation. Biopharm Drug Dispos . 1984; 5:203-9. [PubMed 6487749]

78. Upton RA, Williams RL, Buskin JN et al. Effects of probenecid on ketoprofen kinetics. Clin Pharmacol Ther . 1982; 31:705-12. [PubMed 7075118]

79. Kaye CM, Sankey MG, Holt JE. A high-pressure liquid chromatographic method for the assay of ketoprofen in plasma and urine, and its application to determining the urinary excretion of free and conjugated ketoprofen following oral administration of Orudis to man. Br J Clin Pharmacol . 1981; 11:395-8. [PubMed 7259935]

80. Verbeeck RK, Blackburn JL, Loewen GR. Clincial pharmacokinetics of non-steroidal anti-inflammatory drugs. Clin Pharmacokinet . 1983; 8:297-331. [PubMed 6352138]

81. Braverman AM, Ghosh D, Kaye CM et al. The pharmacokinetics of ketoprofen in geriatric subjects given a single oral dose of a controlled release formulation. Br J Clin Pharmacol . 1985; 20:298P.

82. Wallis WJ, Simkin PA. Antirheumatic drug concentrations in human synovial fluid and synovial tissue: observations on extravascular pharmacokinetics. Clin Pharmacokinet . 1983; 8:496-522. [PubMed 6360465]

83. Merck Sharp & Dohme. Indocin^® prescribing information. West Point, PA; 1985 Oct.

84. Jelie-Ivanovic Z, Majkie-Singh N, Spasoc S et al. Interference by analgesic and antirheumatic drugs in 25 common laboratory assays. J Clin Chem Clin Biochem . 1985; 23:287-92. [PubMed 3874926]

85. Weutersz TB (Wyeth Laboratories; Philadelphia, PA). Letter to members of P&T committees; 1986.

86. Weinberger M. Analgesic sensitivity in children with asthma. Pediatrics . 1978; 62(Suppl):910-5. [PubMed 103067]

87. Settipane GA. Adverse reactions to aspirin and related drugs. Arch Intern Med . 1981; 141:328-32. [PubMed 7008734]

88. Pleskow WW, Stevenson DD, Mathison DA et al. Aspirin desensitization in aspirin-sensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J Allergy Clin Immunol . 1982; 69(1 Part 1):11-9. [PubMed 7054250]

89. VanArsdel PP Jr. Aspirin idiosyncrasy and tolerance. J Allergy Clin Immunol . 1984; 73:431-3. [PubMed 6423718]

90. Stevenson DD. Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol . 1984; 74(4 Part 2):617-22. [PubMed 6436354]

91. Stevenson DD, Mathison DA. Aspirin sensitivity in asthmatics: when may this drug be safe? Postgrad Med . 1985; 78:111-3, 116-9. (IDIS 205854)

92. Settipane GA. Aspirin and allergic diseases: a review. Am J Med . 1983; 74(Suppl):102-9. [PubMed 6344621]

93. Anon. Ketoprofen. Med Lett Drugs Ther . 1986; 28:61-2. [PubMed 3713638]

94. Atkinson LK, Goodship THJ, Ward MK. Acute renal failure associated with acute pyelonephritis and consumption of non-steroidal anti-inflammatory drugs. BMJ . 1986; 292:97-8. [PubMed 3080108]

95. Widmark RM, Vavra I. Liver safety of ketoprofen (Orudis). J Clin Pharmacol . 1984; 24:401.

96. Hart FD, Huskisson EC, Answell BM. Non-steroidal anti-inflammatory analgesics. In: Hart FD, ed. Drug treatment of the rheumatic diseases. 2nd ed. Balgowlah, NSW Australia: ADIS Press; 1982:7-60.

97. Renier JC, Boasson M. Clinical use of ketoprofen: a retrospective study. Rheumatol Rehabil . 1976; 15(Suppl):81-2. [PubMed 132695]

98. Sany J, Serre H. A study of ketoprofen in rheumatoid arthritis. Rheumatol Rehabil . 1976; 15(Suppl):67-70. [PubMed 935737]

99. Spongsveen K, Aune A, Brath HK et al. An interim report on an open multicentre long-term study of ketoprofen (Orudis) in rheumatic diseases. Rheumatol Rehabil . 1978; 17(Suppl):71-7.

100. Zutshi D, Mason M. Ketoprofen in rheumatoid arthritis: its tolerance and therapeutic effect. Scand J Rheumatol . 1976; 5(Suppl 14):77-84. [PubMed 935826]

101. Fossgreen J, Kirchheiner B, Petersen FO et al. Clinical evaluation of ketoprofen (19.583 R.P.) in rheumatoid arthritis. Scand J Rheumatol . 1976; 5(Suppl 14):93-8.

102. Peltola P. Long-term treatment with ketoprofen in rheumatoid arthritis. Scand J Rheumatol . 1976; 5(Suppl 14):115-7.

103. Cathcart BJ, Vince JD, Gordon AJ et al. Studies on 2-(3-benzoylphenyl) propionic acid (Orudis). Ann Rheum Dis . 1973; 32:62-5. [PubMed 4568350]

104. Baker PG, Goulton J. Ketoprofen (Orudis) twice daily dosage in arthritis and tissue injuries: a general practice study. J Int Med Res . 1979; 7:344-50. [PubMed 499641]

105. Mason J, Bolton MS. A general practice assessment of Alrheumat (ketoprofen) in the treatment of rheumatic conditions. Br J Clin Pract . 1977; 31:127-34. [PubMed 337997]

106. Willans MJ, Digby JW, Topp JR et al. Long-term treatment of arthritic disease with ketoprofen (Orudis): a Canadian multi-centre evaluation. Curr Ther Res . 1979; 25:35-45.

107. Willans MJ, Wehner SE, Bourgouin J et al. Double-blind study of ketoprofen capsules and enteric-coated tablets in the maintenance treatment of patients with rheumatoid arthritis. Curr Ther Res . 1985; 38:870-9.

108. Acqaviva B, Cayla J, Delcambre B et al. Etude clinique du bi-profenid en pratique rhumatologique. (French; with English abstract.) Sem Hop Paris . 1983; 59:3229-34.

109. Russell AS, Labelle JL. A double-blind crossover study of ketoprofen enteric-coated and ketoprofen non-enteric-coated tablets in patients with ankylosing spondylitis, osteoarthritis and rheumatoid arthritis. Curr Ther Res . 1983; 33:185-91.

112. Marcolongo R, Rubegni M, Provvedi D et al. A double-blind, interpatient comparison of plain and slow-release ketoprofen in osteoarthritis. Int J Clin Pharmacol Ther Toxicol . 1984; 22:377-81. [PubMed 6381334]

113. Grahame R. Ketoprofen-clinical efficacy. Rheumatol Rehabil . 1976; 15(Suppl):22-5.

114. O'Brien WM, Grunwaldt E. Ketoprofen in the treatment of rheumatoid arthritis. Scand J Rheumatol . 1976; 5(Suppl 14):105-10.

115. Howard DLG. A double-blind crossover evaluation of ketoprofen (Orudis) and placebo in rheumatoid arthritis with assessment of long-term tolerance. J Int Med Res . 1978; 6:300-5. [PubMed 357231]

116. Howard DLG. A double-blind crossover evaluation of ketoprofen (Orudis) and placebo in rheumatoid arthritis with assessment of long-term tolerance. Curr Ther Res . 1978; 23:678-84.

117. Sacchetti G, Camera P, Paolo Rossi A et al. Injectable ketoprofen vs acetylsalicylic acid for the relief of severe cancer pain: a double-blind, crossover trial. Drug Intell Clin Pharm . 1984; 18:403-6. [PubMed 6373214]

118. Lussier A, Camerlain M, Menard H et al. A double-blind cross-over evaluation of ketoprofen and aspirin in rheumatoid arthritis. Scand J Rheumatol . 1976; 5(Suppl 14): 99-104.

119. O'Brien WM, Sakofsky HY, Schmid FR et al. A controlled double-blind study of ketoprofen versus aspirin in the treatment of rheumatoid arthritis. Curr Ther Res . 1977; 21:689-96.

120. Kennedy AC. Ketoprofen in the treatment of rheumatoid arthritis. Rheumatol Rehabil . 1976; 15(Suppl):34-6.

121. Cooper SA, Gelb S, Goldman EH et al. An analgesic relative potency assay comparing ketoprofen and aspirin in postoperative dental pain. Adv Ther . 1984; 1:410-8.

122. Peltola P. A double-blind cross-over study of ketoprofen and phenylbutazone in rheumatoid arthritis. Scand J Rheumatol . 1976; 5(Suppl 14):111-3.

123. Sydnes O, Brath HK, Haerum LB et al. Clinical evaluation of ketoprofen (Orudis) in rheumatoid arthritis. Scand J Rheumatol . 1976; 5(Suppl 14):119-22. [PubMed 935823]

124. Ricciardi S, Filosa E. Il ketoprofen nelle reumoartropatie in eta geriatrica: ricerca a doppio cieco. (Italian; with English abstract.) Clin Ter . 1977; 83:593-608.

125. Sydnes OA, Brath HK, Haerum LB et al. Clinical evaluation of ketoprofen (Orudis) in rheumatoid arthritis: results of a multi-centre double-blind trial against phenylbutazone. Rheumatol Rehabil . 1976; 15(Suppl):43-9. [PubMed 1082624]

126. Huskisson EC. Rheumatoid arthritis. In: Hart FD, ed. Drug treatment of the rheumatic diseases. 2nd ed. Balgowlah, NSW Australia: ADIS Press; 1982:124-130.

127. Griffin AJ, Grahame R, Bloch M et al. Ketoprofen: double-blind cross-over study with indomethacin administered as a combined suppository/capsule regime in patients with rheumatoid arthritis: a preliminary report. Rheumatol Rehabil . 1978; 17(Suppl):84-9.

128. Huskisson EC. Osteoarthritis (Osteoarthrosis). In: Hart FD, ed. Drug treatment of the rheumatic diseases. 2nd ed. Balgowlah, NSW Australia: ADIS Press; 1982:131-4.

129. Viara M, Franchi R, Liverta C et al. Ketoprofen and indomethacin in the treatment of rheumatoid arthritis: a double-blind cross-over trial. Eur J Clin Pharmacol . 1975; 8:205-8. [PubMed 786679]

130. Hart FD. Gout: treatment of the acute attack. In: Hart FD, ed. Drug treatment of the rheumatic diseases. 2nd ed. Balgowlah, NSW Australia: ADIS Press; 1982:135-8.

131. El-Ghobarey AF, Rennie JAN, Hadidi T et al. A comparative trial of large doses of ketoprofen and indomethacin in the treatment of rheumatoid arthritis. Curr Med Res Opin . 1976; 4:432-5. [PubMed 793780]

132. Gyory AN, Bloch M, Burry HC et al. Orudis in management of rheumatoid arthritis and osteoarthrosis of the hip: comparison with indomethacin. Br Med J . 1972; 4:398-400. [PubMed 4564764]

133. Juvakoski T, Lassus A. A double-blind cross-over evaluation of ketoprofen and indomethacin in Reiter's disease. Scand J Rheumatol . 1982; 11:106-8. [PubMed 7046034]

134. Montrone F, Fumagalli M, Pellegrini P et al. A double-blind cross-over evaluation of ketoprofen (Orudis) and ibuprofen in the management of rheumatoid arthritis. Rheumatol Rehabil . 1979; 18:114-8. [PubMed 377448]

135. Calin A, Bennett RM, Sukhupunyaraksa S et al. Double-blind, multi-centre parallel trial of ketoprofen and ibuprofen in the treatment of rheumatoid arthritis. J Rheumatol . 1977; 4:153-7. [PubMed 328880]

136. Mills SB, Bloch M, Bruckner FE. Double-blind cross-over study of ketoprofen and ibuprofen in management of rheumatoid arthritis. Br Med J . 1973; 4:82-84. [PubMed 4583184]

137. Huskisson EC, Woolf DL, Balme HW et al. Four new anti-inflammatory drugs: responses and variations. Br Med J . 1976; 1:1048-9. [PubMed 773499]

138. Saxena RP, Saxena U. A comparative trial of ketoprofen and ibuprofen in patients with rheumatic disease. Curr Med Res Opin . 1978; 5:484-8. [PubMed 350500]

139. Wollheim FA, Lindroth Y, Sjoblom KG. A comparison of ketoprofen and naproxen in rheumatoid arthritis. Rheumatol Rehabil . 1978; 17(Suppl):78-83.

140. Bhettay E, Thomson AJG. Double-blind study of ketoprofen and indomethacin in juvenile chronic arthritis. S Afr Med J . 1978; 54:276-8. [PubMed 362571]

141. Brewer EJ, Giannini EH, Baum J et al. Ketoprofen (Orudis) in the treatment of juvenile rheumatoid arthritis: a segment I study. J Rheumatol . 1982; 9:144-8. [PubMed 7045361]

142. Charlot J, Villiaumey J. A comparative study of benoxaprofen and ketoprofen in ankylosing spondylitis. Eur J Rheumatol . 1982; 5:277-81.

143. Treadwell BLJ, Tweed JM. Ketoprofen (Orudis) in ankylosing spondylitis. N Z Med J . 1975; 81:411-3. [PubMed 1099489]

144. Renier JC, Fournier M, Loyau G et al. Spondylarthrite ankylosante: essai comparatif de deux anti-inflammatoires non-steroidiens, le pirprofene et le ketoprofene. (French; with English abstract.) Nouv Presse Med . 1982; 11:2494-6.

145. Willans MJ, Labelle JL, Forget JP. A double blind crossover study of ketoprofen enteric- and non-enteric-coated tablets in rheumatoid arthritis. Curr Ther Res . 1982; 31:913-21.

146. Jessop JD. Double-blind study of ketoprofen and phenylbutazone in ankylosing spondylitis. Rheumatol Rehabil . 1976; 15(Suppl):37-42. [PubMed 1082622]

147. Cardoe N. Double-blind cross-over study of ketoprofen and phenylbutazone in patients with chronic osteoarthrosis of the hip. Rheumatol Rehabil . 1976; 15(Suppl):27-33.

148. Hubault A, Caroit M, Forette B et al. Double-blind trial of ketoprofen compared with placebo in osteoarthrosis of the hip. Rheumatol Rehabil . 1976; 15(Suppl):52-6.

149. Russell AS, LeMorvan P. Double-blind comparison between ketoprofen capsules four times daily and enteric-coated tablets twice daily in patients with osteoarthritis. Curr Ther Res . 1985; 38:599-605.

150. Goulton J, Baker PG, Wilkinson MA. A multicentre hospital study of Orudis in osteoarthritis of the hip and knee. Br J Clin Pract . 1979; 33:26-8. [PubMed 435358]

151. Lang E, Steger W. A comparative study of efficacy and tolerability of ketoprofen and piroxicam. Br J Clin Pract . 1981; 35:267. [PubMed 7032566]

152. Martio J, Uuspaa V. Ketoprofen and pethidine in the treatment of post-operative pain following synovectomy: a double-blind trial on rheumatoid arthritis patients. Br J Clin Pract . 1981; 35:265. [PubMed 7032565]

153. Caroit M, Forette B, Hubault A et al. Double-blind study of ketoprofen against a placebo in osteoarthritis of the hip. Scand J Rheumatol . 1976; 5(Suppl 14):123-7.

154. Famaey JP, Colinet E. A double-blind trial of ketoprofen in the treatment of osteoarthritis of the hip. Scand J Rheumatol . 1976; 5(Suppl 14):129-32. [PubMed 824724]

155. Zutshi DW, Stern D, Bloch M et al. Ketoprofen: double-blind cross-over study with indomethacin in patients with rheumatoid arthritis. Rheumatol Rehabil . 1974; 13:10-6. [PubMed 4604659]

156. Serry MM. A low-dosage ketoprofen preparation in the management of osteoarthrosis of the knee joint. J Int Med Res . 1980; 8:388-90. [PubMed 7439515]

157. Ring EFJ, Dieppe PA, Bacon PA. The thermographic assessment of inflammation and anti-inflammatory drugs in osteoarthritis. Br J Clin Pract . 1981; 35:263-4. [PubMed 7032564]

158. Bresnihan FP, Grahame R, Burry HC. Ketoprofen in the management of osteoarthritis of the hip: comparison with phenylbutazone. Rheumatol Rehabil . 1974; 13:125-31. [PubMed 4608933]

159. van der Bijl P. Non-steroidal anti-inflammatory drugs (NSAID's) as analgesics in dentistry—a review. Tydskr Tandhelkd Ver S Afr . 1983; 38:419-26.

160. Benoit P, Michelet FX, Pinsolle J et al. Interet therapeutique d'un nouvel anti-inflammatoire: le ketoprofene en chirurgerie maxillo-faciale et en stomatologie. Rev Odontostomatol Midi Fr . 1980; 38:177-85. [PubMed 6939044]

161. Kauppila A, Puolakka J, Ylikorkala O. The relief of primary dysmenorrhea by ketoprofen and indomethacin. Prostaglandins . 1979; 18:647-53. [PubMed 531231]

162. Zutshi DW, Marr S, Bloch M et al. Double-blind cross-over study of Orudis and placebo in fifty patients with rheumatoid arthritis. Rheumatol Rehabil . 1973; 12:62-7. [PubMed 4582347]

163. Anon. Nonsteroidal anti-inflammatory drugs for rheumatoid arthritis. Med Lett Drugs Ther . 1980; 22:29-31. [PubMed 7366532]

164. Gleeson S, Sorbie J. Efficacy of ketoprofen in treating primary dysmenorrhea. Can Med Assoc J . 1983; 129:842-4. [PubMed 6351994]

165. Toft B, Christophersen J, Christensen N et al. A double-blind, crossover study of a sustained-release tablet of ketoprofen and normal ketoprofen capsules in the treatment of patients with osteoarthritis. Curr Med Res Opin . 1985; 9:708-12. [PubMed 3907991]

166. Turek MD, Baird WM, Larouche SJ et al. Comparison of ketoprofen, acetaminophen plus codeine and placebo in post-operative analgesia. Clin Pharmacol Ther . 1986; 39:232.

167. Magrini M, Rivolta G, Movilia PG et al. Successful treatment of biliary colic with intravenous ketoprofen or lysine acetylsalicylate. Curr Med Res Opin . 1985; 9:454-60. [PubMed 3928264]

168. Morley KD, Bernstein RM, Hughes GRV et al. A comparative trial of a controlled-release formulation of ketoprofen ("Oruvail') and a conventional capsule formulation of ketoprofen ("Orudis') in patients with osteoarthritis of the hip. Curr Med Res Opin . 1984; 9:28-34. [PubMed 6723349]

169. Ryckelynck JP, Landru I, Dapogny C et al. Traitement de la colique nephretique par le ketoprofene: a propos de 39 episodes chez 37 patients. LARC Med . 1984; 4:453-4. [PubMed 6503567]

170. Magrini M, Pavesi G, Liverta C et al. Intravenous ketoprofen in renal colic: a placebo-controlled pilot study. Clin Ther . 1984; 6:483-7. [PubMed 6432325]

171. Cofini S, Agopovich G, Arcuri C. Osservazioni cliniche sull'utilizzazione del ketoprofene in odontostomatologia. Riv Odontostomatol Implantoprotesi . 1984; 2:57-61.

172. Leopold M. A double-blind cross-over comparative study of ketoprofen versus naproxen in the treatment of osteo-arthritis of the knee. Scand J Rheumatol . 1980; 33(Suppl):22.

173. Mehlisch D, Frakes L, Cavaliere MB et al. Double-blind parallel comparison of single oral doses of ketoprofen, codeine, and placebo in patients with moderate to severe dental pain. J Clin Pharmacol . 1984; 24:486-92. [PubMed 6392354]

174. Kantor T, Cavaliere MB, Hopper M et al. A double-blind parallel comparison of ketoprofen, codeine, and placebo in patients with moderate to severe postpartum pain. J Clin Pharmacol . 1984; 24:228-34. [PubMed 6747019]

175. Serre H, Sany J. Etude clinique du ketoprofene en rhumatologie. Rhumatologie . 1973; (May):217-22.

176. Muller-Fassbender H, Reiter W, Eveld H. Open multicentre long-term trial (3 years) on efficacy and tolerance of ketoprofen (Orudis^® capsules) in rheumatology: final assessment. Curr Ther Res . 1984; 36:1221-7.

177. Syntex Puerto Rico, Inc. Naprosyn^® prescribing information. Humacao, PR; 1985 Jun.

178. Barthelemy C. Etude des effets secondaires du ketoprofene sur la muqueuse gastro-duodenale: comparaison de deux formes orales. (French; with English abstract.) Sem Hop Paris . 1983; 59:3258-60.

179. Ranlov PJ, Nielsen SP, Barenholdt O. Faecal blood loss during administration of acetylsalicylic acid, ketoprofen and two new ketoprofen sustained-release compounds. Scand J Rheumatol . 1983; 12:280-4. [PubMed 6604940]

180. Caruso I, Porro GB. Gastroscopic evaluation of anti-inflammatory agents. Br Med J . 1980; 280:75-7. [PubMed 7353130]

181. Pemberton RE, Strand LJ. A review of upper-gastrointestinal effects of the newer nonsteroidal antiinflammatory agents. Dig Dis Sci . 1979; 24:53-64. [PubMed 371938]

182. Magnusson B, Solvell L, Arvidsson B. A comparative study of gastrointestinal bleeding during administration of ketoprofen and naproxen. Scand J Rheumatol . 1977; 6:62-4. [PubMed 322269]

183. Lussier A, Arsenault A. Gastrointestinal blood loss induced by ketoprofen, aspirin and placebo (preliminary report). Scand J Rheumatol . 1976; 5(Suppl 14):73-6.

184. Rahbek I. Gastroscopic evaluation of the effect of a new anti-rheumatic compound, ketoprofen (19.583 R.P.), on the human gastric mucosa: a double-blind cross-over trial against acetylsalicylic acid. Scand J Rheumatol . 1976; 5(Suppl 14):63-72.

185. Peltola P. Ketoprofen experiences. Rheumatol Rehabil . 1978; 17(Suppl):109-11.

186. Arsenault A, Lussier A. Gastro-intestinal microbleeding under acetylsalicylic acid, ketoprofen and placebo. Rheumatol Rehabil . 1976; 15(Suppl):87-93. [PubMed 935738]

187. Ducret F, Pointet P, Martin D et al. Insuffisance renale aigue reversible induite par le ketoprofene. Nephrologie . 1982; 3:105-6. [PubMed 7121702]

188. Umez-Eronini EM. Conjunctivitis due to ketoprofen. Lancet . 1978; 2:737. [PubMed 80660]

189. Frith P, Dolovich J, Hargreave FE. Life-threatening asthma, urticaria, and angioedema after ketoprofen. Lancet . 1978; 2:847-8. [PubMed 81404]

190. Clerc D, Delfraissy JF, Salliere D et al. Insuffisance renale aigue sous ketoprofene et clometacine. (French; with English abstract.) Sem Hop Paris . 1983; 59:1613-5.

191. Avery GS, Heel RC, Speight TM. Appendix B: guide to adverse drug reactions. In: Avery GS, ed. Drug treatment: principles and practice of clinical pharmacology and therapeutics. 2nd ed. Sydney: ADIS Press; 1980:1224-51.

192. Carmichael J, Shankel SW. Effects of nonsteroidal anti-inflammatory drugs on prostaglandins and renal function. Am J Med . 1985; 78:992-9. [PubMed 2861741]

193. Caramelo C, Lopez-Novoa JM. Renal syndromes and nonsteroidal antiinflammatory drugs. N Engl J Med . 1984; 311:194. [PubMed 6738607]

194. Robert A. Cytoprotection by prostaglandins. Gastroenterology . 1979; 77:761-7. [PubMed 38173]

195. Blackshear JL, Davidman M, Stillman MT. Identification of risk for renal insufficiency from nonsteroidal anti-inflammatory drugs. Arch Intern Med . 1983; 143:1130-4. [PubMed 6860044]

196. Momma K, Hagiwara H, Konishi T. Constriction of fetal ductus arteriosus by non-steroidal anti-inflammatory drugs: study of additional 34 drugs. Prostaglandins . 1984; 28:527-36. [PubMed 6522619]

197. Miller TA, Jacobson ED. Gastrointestinal cytoprotection by prostaglandins. Gut . 1979; 20:75-87. [PubMed 367886]

198. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med . 1984; 310:563-72. [PubMed 6363936]

199. Adams DH, Michael J, Bacon PA et al. Non-steroidal anti-inflammatory drugs and renal failure. Lancet . 1986; 1:57-9. [PubMed 2867313]

200. Langman MJS, Morgan L, Worrall A. Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. BMJ . 1985; 290:347-9. [PubMed 3917814]

201. McDowell IFW, McConnell JB. Cholinergic crisis in myasthenia gravis precipitated by ketoprofen. BMJ . 1985; 291:1094. [PubMed 20742533]

202. O'Brien JD, Burnham WR. Bleeding from peptic ulcers and use of non-steroidal anti-inflammatory drugs in the Romford area. BMJ . 1985; 291:1609-10. [PubMed 3935207]

203. Guidoboni R. Uncontrolled clinical trial on gastric side effects of slow-release ketoprofen lysine. Curr Ther Res . 1983; 34:839-43.

204. Zipser RD, Henrich WL. Implications of nonsteroidal anti-inflammatory drug therapy. Am J Med . 1986; 80(Suppl 1A):78-84. [PubMed 3946427]

205. Kantor TA. Ketoprofen: a review of its pharmacologic and clinical properties. Pharmacotherapy . 1986; 6:93-102. [PubMed 3526298]

206. Bennett RM. Management of rheumatoid arthritis. Compr Ther . 1979; 5:23-35. [PubMed 487729]

207. Bendix T, Schmidt I, Rasmussen KJE et al. Diclofenac (Voltaren^®) and ketoprofen (Orudis^®) in rheumatoid arthritis: a randomized double-blind multicenter trial. Curr Ther Res . 1983; 33:192-9.

208. Henrich WL. Nephrotoxicity of nonsteroidal anti-inflammatory agents. Am J Kidney Dis . 1983; 2:478-84. [PubMed 6823966]

209. Wilson F. (Wyeth Laboratories, Philadelphia, PA): Personal communication; 1986 Aug.

210. Reviewers' comments (personal observations); 1986 Aug.

211. Teule M (Rhone-Poulenc Sante, Paris): Personal communication; 1986 Aug.

212. Larizza D, Colombo A, Lorini R et al. Ketoprofen causing pseudotumor cerebri in Bartter's syndrome. N Engl J Med . 1979; 300:796. [PubMed 423914]

213. Vale JA, Meredith TJ. Acute poisoning due to non-steroidal anti-inflammatory drugs: clinical features and management. Med Toxicol . 1986; 1:12-31. [PubMed 3537613]

214. Kimberly RP, Bowden RE, Keiser HR et al. Reduction of renal function by newer nonsteroidal anti-inflammatory drugs. Am J Med . 1978; 64:804-7. [PubMed 645744]

215. Corwin HL, Bonventre JV. Renal insufficiency associated with nonsteroidal anti-inflammatory agents. Am J Kidney Dis . 1984; 4:147-52. [PubMed 6475945]

216. Ellison NM, Servi RJ. Acute renal failure and death following sequential intermediate-dose methotrexate and 5-FU: a possible adverse effect due to concomitant indomethacin administration. Cancer Treat Rep . 1985; 69:342-3. [PubMed 3978662]

217. Singh RR, Malaviya AN, Pandey JN et al. Fatal interaction between methotrexate and naproxen. Lancet . 1986; 1:1390. [PubMed 2872507]

218. Day RO, Graham GG, Champion GD et al. Anti-rheumatic drug interactions. Clin Rheum Dis . 1984; 10:251-75. [PubMed 6150784]

219. Daly HM, Scott GL, Boyle J et al. Methotrexate toxicity precipitated by azapropazone. Br J Dermatol . 1986; 114:733-5. [PubMed 3718865]

220. Mikami T, Miyasaka K. Effects of several anti-inflammatory drugs on the various parameters involved in the inflammatory response in rat carrageenin-induced pleurisy. Eur J Pharmacol . 1983; 95:1-12. [PubMed 6583058]

221. Hansten PD, Horn JR. Methotrexate interactions: ketoprofen (Orudis). Drug Interact Newsl . 1986; 6(Updates):U5-6.

222. Hansten PD, Horn JR. Diuretics and non-steroidal anti-inflammatory drugs. Drug Interact Newsl . 1986; 6:27-9.

223. O'Brien WM, Grunwaldt E. Ketoprofen in the treatment of rheumatoid arthritis: double-blind, cross-over placebo comparison. Scand J Rheumatol . 1976; 5(Suppl 14):105-10.

224. Paulus HE, Vavra I. Safety profile of ketoprofen: the US clinical experience. In: Proceedings of the Ketoprofen Summit Conference, 16th World Conference of Rheumatology; Sidney, 1985. London: Medicine Communications International Ltd; 1986:43-56.

225. Walker JL. Interrelationships of SRS-A production and arachidonic acid metabolism in human lung tissue. Adv Prostaglandin Thromboxane Res . 1980; 6:115-9. [PubMed 6155760]

226. Walker JR, Harvey J. Actions of anti-inflammatory drugs on leukotriene and prostaglandin metabolism: relationship to asthma and other hypersensitivity reactions. Adv Inflammation Res . 1984; 6:227-38.

227. McCrea JD, Telford AM, Kaye CM et al. A comparison of plasma and synovial fluid profiles of standard and controlled-release formulations of ketoprofen in patients with rheumatoid arthritis. Curr Med Res Opin . 1986; 10:73-81. [PubMed 3519094]

228. Heusse D, Populaire P. The metabolic disposition of³H-ketoprofen in various species. Paper presented at Ketoprofen Symposium, 14th International Congress of Rheumatology; San Francisco, 1977.

229. Singer L, Imbs JL, Danion JM et al. Risque d'intoxication par le lithium en cas de traitement associé par les anti-inflammatoires non steroidiens. (French; with English abstract.) Therapie . 1981; 36:323-6.

230. Windeck R, Bock KD, Jakubowski HD. Irreversibles Versagen einer transplantierten Niere, ausgelöst durch Ketoprofen? (German; with English abstract.) Dtsch Med Wochenschr . 1983; 108:720-1.

231. Maiche AG. Acute renal failure due to concomitant action of methotrexate and indomethacin. Lancet . 1986; 1:1390. [PubMed 2872506]

232. Wyeth Laboratories Inc. Orudis^® (ketoprofen) product monograph. Philadelphia, PA; 1986 Jul.

233. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol . 1999; 26(suppl 56):18-24.

234. Hébert JG, Le Morvan P, Bourgouin J. Double-blind comparison of ketoprofen and mefenamic acid in the treatment of primary dysmenorrhea. Clin Ther . 1986; 8:329-35. [PubMed 3521860]

235. Sunshine A, Zighelboim I, Laska E et al. A double-blind, parallel comparison of ketoprofen, aspirin, and placebo in patients with postpartum pain. J Clin Pharmacol . 1986; 26:706-11. [PubMed 3540033]

236. Duranceau JA, Lacoste P, Bourgouin J et al. Double-blind comparison of ketoprofen and placebo in the treatment of sprains and strains. Clin Ther . 1986; 8:187-95. [PubMed 3698066]

237. Sennesael J, Van den Houte K, Verbeelen D. Reversible membranous glomerulonephritis associated with ketoprofen. Clin Nephrol . 1986; 26:213-5. [PubMed 3780072]

238. Thyss A, Viens P, Caldani C et al. Efficacíte antalgique dué ketopròfene en perfusion continue dans les douleurs rebelles paré metastases osseuses. Presse Med . 1987; 16:638. [PubMed 2952987]

239. Lopez Soriano F. Ketoprofen y nefopan en el tratamiento del dolor postoperatorio. Rev Esp Anestesiol Reanim . 1986; 33:291-3. [PubMed 3786880]

240. Flessner MF, Knight H. Prolongation of prothrombin time and severe gastrointestinal bleeding associated with combined use of warfarin and ketoprofen. JAMA . 1988; 259:353. [PubMed 3257277]

241. Palmer JF. Letter sent to Bathish J, of Wyeth-Ayerst Laboratories regarding labeling revisions about gastrointestinal adverse reactions to Orudis^® (ketoprofen). Rockville, MD: Food and Drug Administration, Division of Oncology and Radiopharmaceutical Drug Products; 1988 Sep.

242. Food and Drug Administration. Labeling revisions for NSAIDs. FDA Drug Bull . 1989; 19:3-4.

243. Searle. Cytotec^® (misoprostol) prescribing information. Skokie, IL; 1989 Jan.

244. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther . 2000; 42:57-64. [PubMed 10887424]

245. Soll AH, Weinstein WM, Kurata J et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med . 1991; 114:307-19. [PubMed 1987878]

246. Corticosteroid interactions: nonsteroidal anti-inflammatory drugs (NSAIDs). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:562.

247. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet . 1994; 343:769-72. [PubMed 7907735]

248. Langman MJS, Weil J, Wainwright P et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet . 1994; 343:1075-8. [PubMed 7909103]

249. Bateman DN. NSAIDs: time to re-evaluate gut toxicity. Lancet . 1994; 343:1051-2. [PubMed 7909094]

250. Hollander D. Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: prophylactic and therapeutic strategies. Am J Med . 1994; 96:274-81. [PubMed 8154516]

251. Schubert TT, Bologna SD, Nensey Y et al. Ulcer risk factors: interaction between Helicobacter pylori infection, nonsteroidal use, and age. Am J Med . 1993; 94:413-8. [PubMed 8475935]

252. Shorr RI, Ray WA, Daugherty JR et al. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med . 1993; 153:1665-70. [PubMed 8333804]

253. Piper SM, Ray WA, Daugherty JR et al. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med . 1991; 114:735-40. [PubMed 2012355]

254. Nonsteroidal anti-inflammatory drug interactions: lithium-diclofenac. In: Hansten PD, Horn JR. Drug Interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:607.

255. Bateman DN, Kennedy JG. Non-steroidal anti-inflammatory drugs and elderly patients: the medicine may be worse than the disease. BMJ . 1995; 310:817-8. [PubMed 7711609]

264. Hawkey CJ. COX-2 inhibitors. Lancet . 1999; 353:307-14. [PubMed 9929039]

265. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature . 1996; 384-644-8.

266. Riendeau D, Charleson S, Cromlish W et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol . 1997; 75:1088-95. [PubMed 9365818]

267. DeWitt DL, Bhattacharyya D, Lecomte M et al. The differential susceptibility of prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs; aspirin derivatives as selective inhibitors. Med Chem Res . 1995; 5:325-43.

268. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenase—a review. Prostaglandins Other Lipid Mediators . 1998; 56:341-61. [PubMed 9990677]

269. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med . 1999; 106(Suppl 5B):37-42S.

270. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med . 1999; 340:1888-99. [PubMed 10369853]

271. Morrison BW, Daniels SE, Kotey P et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled study. Obstet Gynecol . 1999; 94:504-8. [PubMed 10511349]

273. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines.. Guidelines for the management of rheumatoid arthritis:2002 update. Arthritis Rheum . 2002; 46:328-46. [PubMed 11840435]

274. Lanza FL, and the members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol . 1998; 93:2037-46. [PubMed 9820370]

275. in't Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med . 2001; 345:1515-21. [PubMed 11794217]

276. Breitner JCS, Zandi PP. Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer's disease? N Engl J Med . 2001; 345:1567-8. Editorial.

277. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology . 1996; 47:425-32. [PubMed 8757015]

278. Beard CM, Waring SC, O'sBrien PC et al. Nonsteroidal anti-inflammatory drug use and Alzheimer's disease : a case-control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc . 1998; 73:951-5. [PubMed 9787743]

279. in't Veld BA, Launer LJ, Hoes AW et al. NSAIDs and incident Alzheimer's disease: the Rotterdam Study. Neurobiol Aging . 1998; 19:607-11. [PubMed 10192221]

280. Stewart WF, Kawas C, Corrada M et al. Risk of Alzheimer's disease and duration of NSAID use. Neurology . 1997; 48:626-32. [PubMed 9065537]

281. Pharmacia. Daypro^® (oxaprozin) caplets prescribing information. Chicago, IL; 2002 May.

282. Chan FKL, Hung LCT, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med . 2002; 347:2104-10. [PubMed 12501222]

283. Graham DY. NSAIDs, Helicobacter pylori , and Pandora's box. N Engl J Med . 2002; 347:2162-4. [PubMed 12501230]

284. Food and Drug Administration. Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6.

285. Cush JJ. The safety of COX-2 inhibitors: deliberations from the February 16-18, 2005, FDA meeting. From the American College of Rheumatology web site. Accessed 2005 Oct 12. [Web]

286. Novartis Pharmaceuticals. Diovan^® (valsartan) capsules prescribing information (dated 1997 Apr). In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:2013-5.

287. Rosebraugh C (Director, Division of Nonprescription Clinical Evaluation). Supplemental labeling request. From FDA web site. Accessed Oct 2005. [Web]

288. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA . 2006; 296: 1633-44. [PubMed 16968831]

289. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ . 2006; 332: 1302-5. [PubMed 16740558]

290. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA . 2006; 296:1653-6. [PubMed 16968830]

291. Merck & Co. Clinoril^® (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.

294. Chou R, Helfand M, Peterson K et al. Comparative effectiveness and safety of analgesics for osteoarthritis. Comparative effectiveness review no. 4. (Prepared by the Oregon evidence-based practice center under contract no. 290-02-0024.) . Rockville, MD: Agency for Healthcare Research and Quality. 2006 Sep. Available from website. [Web]

500. Food and Drug Administration. Drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. RockvilleSilver Spring, MD; 2015 Jul 9. From the FDA web site. Accessed 2016 Mar 22. [Web]

501. Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet . 2013; 382:769-79. [PubMed 23726390]

502. Food and Drug Administration. FDA briefing document: Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee, February 10-11, 2014. From FDA web site [Web]

503. Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ . 2011; 342:c7086. [PubMed 21224324]

504. Gislason GH, Rasmussen JN, Abildstrom SZ et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med . 2009; 169:141-9. [PubMed 19171810]

505. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation . 2011; 123:2226-35. [PubMed 21555710]

506. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med . 2011; 8:e1001098. [PubMed 21980265]

507. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2013; 62:e147-239. [PubMed 23747642]

508. Teva. Ketoprofen capsules prescribing information. North Wales, PA; 2015 Jul.

509. Cumberland Pharmaceuticals Inc. Caldolor^® (ibuprofen) injection prescribing information. Nashville, TN; 2016 Apr.

511. Olsen AM, Fosbøl EL, Lindhardsen J et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation . 2012; 126:1955-63. [PubMed 22965337]

512. Olsen AM, Fosbøl EL, Lindhardsen J et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study. PLoS One . 2013; 8:e54309.

516. Bavry AA, Khaliq A, Gong Y et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med . 2011; 124:614-20. [PubMed 21596367]

1200. US Food and Drug Administration. FDA drug safety communication: FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid. 2020 Oct 15. From the FDA website. [Web]

1201. Mylan Pharmaceuticals. Ketoprofen extended-release capsules prescribing information. Morgantown, WV; 2020 Oct.

1202. Actavis Pharma. Sulindac tablets prescribing information. Parsippany, NJ; 2020 Oct.

1203. Jubilant Cadista Pharmaceuticals. Indomethacin extended-release capsules prescribing information. Salisbury, MD; 2020 Nov.