AHFS Class:

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

Generic Name(s):

• Fenoprofen Calcium

Fenoprofen, a propionic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and antipyretic activity.

Fenoprofen is used to relieve mild to moderate pain and also is used for analgesic and anti-inflammatory effects in the symptomatic treatment of rheumatoid arthritis and osteoarthritis.

The potential benefits and risks of fenoprofen therapy as well as alternative therapies should be considered prior to initiating fenoprofen therapy.100 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.100

Pain

Fenoprofen is used to relieve mild to moderate postoperative, postpartum, orthopedic, and somatic pain.

There are few published studies comparing the effectiveness of fenoprofen with other analgesics. When used to relieve postoperative pain, a single 600 mg oral dose of fenoprofen has been reported to be as effective as a single 975 mg oral dose of aspirin. In a study in patients with postoperative, fracture-induced, or somatic pain, a 600 mg oral dose of fenoprofen appeared to be no more effective than a 200 mg dose, suggesting a plateau in the drug's analgesic effect above the recommended dose of 200 mg. In patients with postpartum pain associated with uterine cramping or episiotomy, 200 mg of oral fenoprofen has been reported to be at least as effective as 60 mg of oral codeine or codeine sulfate. In one study of patients with postoperative pain, the analgesic effect of a combination of oral propoxyphene napsylate (100 mg) and fenoprofen (200 mg) was no greater than that of fenoprofen alone.

Inflammatory Diseases

Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis

Fenoprofen is used for anti-inflammatory and analgesic effects in the symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis. When used in the treatment of rheumatoid arthritis, fenoprofen has relieved pain and stiffness; reduced swelling, tenderness, and the number of joints involved; and improved mobility and grip strength. In the treatment of osteoarthritis, fenoprofen has relieved pain and stiffness and improved mobility and knee joint function. Fenoprofen appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process.

Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual dosages of fenoprofen in the treatment of rheumatoid arthritis or osteoarthritis are greater than those of placebo and about equal to those of usual dosages of salicylates, ibuprofen, naproxen, or phenylbutazone (no longer commercially available in the US). In one study in patients with osteoarthritis, usual dosages of fenoprofen were somewhat more effective than usual dosages of sulindac. In the treatment of juvenile rheumatoid arthritis†, usual dosages of fenoprofen appear to be as effective as usual dosages of salicylates. Patient response to oral NSAIAs is variable; patients who do not respond to or cannot tolerate one drug might be successfully treated with a different agent. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs. (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.107,125 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.125 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.125 NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.107,125 (For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.)

Use of fenoprofen with aspirin is not recommended by the manufacturer. There is no proof that the combination is more efficacious than either drug alone, the potential for adverse reactions may be increased, and there is some evidence that aspirin decreases plasma fenoprofen concentrations. (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

Other Inflammatory Conditions

Fenoprofen has also been used with some success in the treatment of ankylosing spondylitis† and acute gouty arthritis†.

Other Uses

Fenoprofen has been used to reduce fever† associated with type A influenza, colds, pulmonary tuberculosis, or neoplasms.

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.128,129 Similar findings have been reported from some other, but not all, observational studies.128,129,130,131,132,133

Administration

The potential benefits and risks of fenoprofen therapy as well as alternative therapies should be considered prior to initiating fenoprofen therapy.100

Fenoprofen calcium is administered orally. Adverse GI effects may be minimized by administering fenoprofen with meals, milk, or antacids.

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.100 Dosage must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.

Dosage of fenoprofen calcium is expressed in terms of fenoprofen.

Pain

For the relief of mild to moderate pain, the usual adult dosage of fenoprofen is 200 mg every 4-6 hours as necessary.

Inflammatory Diseases

Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis

In the symptomatic treatment of rheumatoid arthritis or osteoarthritis, the usual initial adult dosage of fenoprofen is 400-600 mg 3 or 4 times daily.146,508 Subsequent dosage should be adjusted according to the patient's response and tolerance and should not exceed 3.2 g daily. The manufacturer states that, in general, patients with rheumatoid arthritis seem to require larger dosages of fenoprofen than do those with osteoarthritis. Symptomatic improvement usually begins in a few days, but an additional 2-3 weeks may be needed to determine response. In one study in the symptomatic treatment of juvenile arthritis†, initial daily doses of 900 mg/m² were administered; dosage was increased over 4 weeks to 1.8 g/m² daily.

Other Inflammatory Conditions

In the management of acute gouty arthritis†, 800 mg of fenoprofen has been given every 6 hours, after which the dosage was rapidly reduced, depending on patient response.

Fever

In the management of fever†, single oral doses of up to 400 mg of fenoprofen have been administered to adults.

Adverse reactions of fenoprofen mainly involve the GI tract and CNS; severe reactions may require discontinuing the drug.

Cardiovascular Effects

Peripheral edema, palpitations, tachycardia (including supraventricular tachycardia), atrial fibrillation, and ECG changes have been reported in patients receiving fenoprofen.

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.138,145,500 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.141,142,143,145,500,501,502,503,506 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.100,502,508

GI Effects

Adverse GI effects of fenoprofen occur in about 21% of patients and most frequently include dyspepsia, constipation, nausea, and vomiting. Abdominal pain or discomfort, anorexia, diarrhea, flatulence, dry mouth, occult blood in stool, and gastritis may also occur. Peptic ulcer and GI bleeding, sometimes severe, have also been reported. Aphthous ulcerations of the buccal mucosa, metallic taste, and burning tongue have been reported, although a causal relationship to fenoprofen has not been established. Although a causal relationship has not been directly determined, one case-control analysis suggests that NSAIAs may contribute to the formation of esophageal stricture in patients with gastroesophageal reflux.

The frequency of mild adverse GI effects with usual dosages of fenoprofen is reported to be less than that with usual dosages of aspirin. It is not known whether fenoprofen causes less peptic ulceration than does aspirin. The amount of GI bleeding, as determined by fecal blood loss and gastroscopic evaluation in healthy adults, has been reported to be less with 2.4 g of fenoprofen daily than with 3.9-4 g of aspirin daily. In one study, the frequency of adverse GI effects in patients receiving 2.4 g of fenoprofen daily was greater than that of patients receiving 500 mg of naproxen daily or 1.2 g of ibuprofen daily.

Adverse GI effects may be minimized by administering fenoprofen with meals, milk, or antacids. 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 concomitant use of anticoagulants or corticosteroids) should be monitored closely for signs and symptoms of ulcer perforation or severe GI bleeding.

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.104,105,108 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.100,104,105 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 chronically for the development of manifestations of such effects and advised of the importance of this follow-up.100,104,105 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. 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.100

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.104,105 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.104,105 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.100 However, short-term therapy is not without risk.100 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.104,105 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.104,105

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.124,127 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.124,127,134 Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis.124,125,127 In addition, most spontaneous reports of fatal GI effects have been in geriatric or debilitated patients.100

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.107,124,125,126 (See 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.107,124,125 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.124 In addition, efficacy of usual dosages of H₂-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established.124 Therefore, most clinicians do not recommend use of H₂-receptor antagonists for the prevention of NSAIA-associated ulcers.124,125 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.125 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.135,136 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.135,136

Nervous System Effects

Adverse nervous system effects commonly occur in patients receiving fenoprofen. The most frequent adverse nervous system effects of fenoprofen include headache and somnolence, which occur in about 8.5-8.7% of patients. Dizziness, tremor, confusion, insomnia, nervousness, asthenia, paresthesia, muscle weakness, fatigue, drowsiness, and malaise occur less frequently. Mental depression, disorientation, personality change, seizures, and trigeminal neuralgia have also been reported, although a causal relationship to fenoprofen has not been established.

Otic and Ocular Effects

Patients receiving fenoprofen have experienced tinnitus. Decreased hearing and blurred vision have also been reported. Diplopia and optic neuritis have been reported, although a causal relationship to the drug has not been established. Because NSAIAs have caused adverse ocular effects, patients who experience visual disturbances during fenoprofen therapy should have an ophthalmologic examination.

Hematologic Effects

Adverse hematologic effects of fenoprofen include purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and pancytopenia. Patients with low initial hemoglobin concentration who are receiving prolonged fenoprofen therapy should have hemoglobin concentrations determined regularly.

Fenoprofen may inhibit platelet aggregation and prolong bleeding time. Patients who may be adversely affected by a prolongation of bleeding time should be carefully observed during fenoprofen therapy.

Renal Effects

Dysuria, cystitis, hematuria, nephrotic syndrome, renal failure, oliguria, anuria, azotemia, allergic nephritis, nephrosis, and papillary necrosis have been reported in some patients receiving fenoprofen. Laboratory test abnormalities including proteinuria and elevations in BUN and serum creatinine concentrations have also occurred.

Fenoprofen use prior to detection of renal damage has been reported to range from a few weeks to several years. Nephrotic syndrome may be preceded by fever, rash, arthralgia, oliguria, and azotemia, and may progress to anuria. Renal biopsies have indicated a similar pathology in several patients with fenoprofen-induced acute renal failure and marked proteinuria. Histologic examinations have revealed infiltration of the interstitium with T cells, varying degrees of tubular damage, and extensive fusion of podocytes in otherwise normal glomeruli. The manufacturer states that early recognition of the syndrome and withdrawal of the drug have been followed by rapid recovery.

Hepatic Effects

Severe hepatic reactions (sometimes fatal) including jaundice and cholestatic hepatitis have occurred rarely during fenoprofen therapy. Elevations in serum aminotransferase (transaminase) concentrations, LDH, and alkaline phosphatase have also been reported; these changes persisted for several months and usually, but not always, declined despite continued administration of the drug. Hepatocellular hypertrophy has occurred in rats following chronic administration of high doses of fenoprofen.

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

Other Adverse Effects

Pruritus, rash, urticaria, increased sweating, dyspnea, and anaphylaxis have occurred during fenoprofen therapy. Stevens-Johnson syndrome, angioedema, toxic epidermal necrosis, exfoliative dermatitis, and alopecia have also been reported, although a causal relationship to the drug has not been established. Pulmonary edema, lymphadenopathy, mastodynia, pancreatitis, and fever have also been reported, although a causal relationship to fenoprofen has not been established.

Precautions and Contraindications

Patients should be advised that fenoprofen, 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.100,104,105,500,508 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.104,105 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.104,105

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.100

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.100,141,142,143,145,500,502,508 (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.100,500,508 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.100,500,508 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.100,500,508 Fenoprofen 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 fenoprofen 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.100,138,502,508 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.100 Because of the potential for increased adverse effects, patients receiving fenoprofen should be advised not to take aspirin.100

Use of NSAIAs 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.100 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.100,508 NSAIAs should be used with caution in patients with hypertension.100 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.100

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that fenoprofen 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 fenoprofen 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 fenoprofen, particularly in patients receiving chronic therapy with the drug.104,105 (See Cautions: GI Effects.) Fenoprofen should be used with caution in patients with a history of upper GI disease.100 Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.100

Fenoprofen should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration,100 and such patients should receive an appropriate ulcer preventive regimen.107,124,125,126 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 closely for signs and symptoms of ulcer perforation or GI bleeding.100 To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed.100 For patients who are at high risk, therapy other than an NSAIA should be considered.100

Fenoprofen should be used with caution in patients who may be adversely affected by prolongation of bleeding time (e.g., patients receiving anticoagulant therapy) and in those with low pretreatment hemoglobin concentration.100 If signs and/or symptoms of anemia occur during therapy with fenoprofen, hemoglobin concentration or hematocrit should be determined.100

Patients should be warned that fenoprofen calcium may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Since the safety of the drug in patients with impaired hearing has not been established, the manufacturer recommends that these patients have periodic testing of auditory function during prolonged fenoprofen therapy.

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

Patients receiving fenoprofen are at risk of developing adverse renal effects.100 Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.100 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.100 Patients at greatest risk of this reaction include those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II receptor antagonist concomitantly; and geriatric patients.100,140 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.100 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.100 Some clinicians recommend that renal function be monitored periodically in patients receiving long-term NSAIA therapy.

Fenoprofen has not been evaluated in patients with severe renal impairment, and the manufacturer states that use of the drug is contraindicated in patients with advanced renal disease.100

Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving fenoprofen should be evaluated for evidence of the development of a severe hepatic reaction. Although such reactions are rare, fenoprofen 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). Fenoprofen should be used under close medical observation in patients with impaired liver function.

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.100

Fenoprofen is not a substitute for corticosteroid therapy, and the drug is not effective in the management of adrenal insufficiency.100 Abrupt withdrawal of corticosteroids may exacerbate corticosteroid-responsive conditions.100 If corticosteroid therapy is to be discontinued after prolonged therapy, the dosage should be tapered gradually.100

The possibility that the antipyretic and anti-inflammatory effects of NSAIAs may mask the usual signs and symptoms of infection or other diseases should be considered.

Anaphylactoid reactions have been reported in patients receiving NSAIAs.100 Patients receiving fenoprofen 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.100

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs.100 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.100 Fenoprofen should be discontinued at the first appearance of rash or any other sign of hypersensitivity.100

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, fenoprofen should be discontinued and the patient evaluated immediately.1201

The manufacturers state that fenoprofen is contraindicated in patients with known hypersensitivity to the drug.100 In addition, NSAIAs 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, often fatal, anaphylactic reactions may occur in such patients.100 Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, NSAIAs should be used with caution in patients with asthma.100 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.100 For a further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.

NSAIAs are contraindicated in the setting of CABG surgery.508

Pediatric Precautions

Safety and efficacy of fenoprofen in children younger than 18 years of age have not been established.100

Geriatric Precautions

Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.100 NSAIAs, including fenoprofen, should be used with caution in patients 65 years of age or older.100

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 fenoprofen, 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

Reproduction studies in rats and rabbits receiving fenoprofen calcium dosages of 0.15 and 0.6 times, respectively, the maximum recommended human dosage of 3.2 g daily (based on body surface area comparisons) have not revealed evidence of developmental abnormalities.1201

The effects of fenoprofen on labor and delivery are unknown.1201 In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, increased the incidence of dystocia, delayed parturition, and decreased pup survival.1201

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

Lactation

Fenoprofen is distributed into milk. Because of the potential for serious adverse reactions from fenoprofen in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.100

Protein-bound Drugs

Because fenoprofen is highly protein bound, it theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Although no clinically significant drug interactions have been reported, patients receiving fenoprofen with any of these drugs should be observed for adverse effects.

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.100,144

Anticoagulants and Thrombolytic Agents

The effects of warfarin and fenoprofen on GI bleeding are synergistic.100 Concomitant use of fenoprofen and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.100

Because fenoprofen may cause GI bleeding and may inhibit platelet aggregation, the drug should be used with caution in patients receiving any anticoagulant or thrombolytic agent (e.g., streptokinase).

Nonsteroidal Anti-inflammatory Agents

Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.100 Because of the potential for increased adverse effects, patients receiving fenoprofen should be advised not to take aspirin.100 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.100,138,502,508

Administration of aspirin with fenoprofen may decrease plasma fenoprofen concentrations by about 50%, and decrease the plasma half-life of fenoprofen, possibly by displacing fenoprofen from binding sites or by enzyme induction; increased metabolism and/or excretion of fenoprofen may result. The clinical significance of this pharmacokinetic interaction has not been established.100

Diuretics

NSAIAs can reduce the natriuretic effects of furosemide or thiazide diuretics.100 This effect may be related to inhibition of renal prostaglandin synthesis.100 Patients receiving concomitant NSAIA and diuretic therapy should be monitored for signs of renal failure and for efficacy of the diuretic.100

Lithium

NSAIAs appear to decrease renal clearance of lithium.100 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.100 If fenoprofen and lithium are administered concomitantly, the patient should be observed for signs and symptoms of lithium toxicity.100

Methotrexate

Because of the possibility of enhanced toxicity of methotrexate, caution is advised if methotrexate and an NSAIA are administered concomitantly.100 (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

Phenobarbital

Chronic administration of phenobarbital may decrease plasma concentrations and plasma half-life of fenoprofen. The clinical significance of this interaction has not been established, but fenoprofen dosage may require adjustment if phenobarbital is added or withdrawn during fenoprofen therapy.

Laboratory Test Interferences

Fenoprofen calcium may cause false elevations in both free and total serum triiodothyronine (T₃) concentrations determined by the Amerlex-T^® assay;100,101,102,103 however, thyrotropin (thyroid-stimulating hormone, TSH), total thyroxine (T₄), and response to protirelin (thyrotropin releasing hormone) do not appear to be substantially affected.100,102,103 Although not clearly established, fenoprofen and/or its metabolite, 4'-hydroxyfenoprofen, appear to cross-react with the antibody used in the Amerlex-M^® assay.101,102,103 Limited data indicate that less marked false elevations in free and total T₃ concentrations determined by the Corning method also may occur in patients receiving the drug.102

Acute Toxicity

Limited information is available on the acute toxicity of fenoprofen.

Manifestations

An adult who ingested 60-72 g of fenoprofen in a suicide attempt developed nonoliguric renal failure and hypotension. The patient responded to supportive treatment which included IV furosemide to stimulate urine output and IV dopamine to increase blood pressure. Administration of furosemide does not lower plasma fenoprofen concentrations.

Coma, hypotension, metabolic acidosis, and respiratory depression occurred within 4 hours after ingestion of 24-36 g of fenoprofen by a 17-year-old girl.109 Subsequently, proteinuria and tachycardia with ST-segment and T-wave abnormalities developed.109 Manifestations of fenoprofen overdosage and toxicity resolved over 2 days in this patient following supportive and symptomatic treatment, which included correction of fluid imbalance and administration of dopamine.109

Treatment

In acute fenoprofen overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage, followed by administration of activated charcoal. 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. Supportive and symptomatic treatment should be initiated. Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis, and charcoal hemoperfusion do not enhance systemic elimination of fenoprofen.100

Pharmacology

Fenoprofen has pharmacologic actions similar to those of other prototypical NSAIAs. The drug exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis. Fenoprofen 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.118,119,120,121,122,123 Fenoprofen, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.118,119,120,121,122,123 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.118,119,120,121,122,123

Anti-inflammatory, Analgesic, and Antipyretic Effects

The anti-inflammatory, analgesic, and antipyretic effects of fenoprofen and other NSAIAs, including selective inhibitors of COX-2 (e.g., celecoxib), appear to result from inhibition of prostaglandin synthesis.118,119,120,121,122,123 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.118,119,120,121,122,123

Fenoprofen does not possess glucocorticoid or adrenocorticoid-stimulating properties.

There is no evidence that long-term therapy with fenoprofen results in tolerance to or physical dependence on the drug. The drug probably cannot suppress the abstinence syndrome in opiate-dependent patients.

Fenoprofen lowers body temperature in patients with fever. Although the mechanism of the 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.

Genitourinary and Renal Effects

Fenoprofen-induced inhibition of prostaglandin synthesis may result in decreased uterine tone and contractility. Prostaglandins E₂ and F_2α increase the amplitude and frequency of uterine contractions in pregnant women. Whether the increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or COX-2 remains to be determined. Administration of fenoprofen during late pregnancy may prolong gestation by inhibiting uterine contractions.

Fenoprofen has been reported to adversely affect renal function. (See Cautions: Renal Effects.) The extent to which inhibition of renal prostaglandin synthesis may be involved remains uncertain. It has been suggested that some of the fenoprofen-induced renal effects (e.g., acute interstitial nephritis) may result from disordered cell-mediated immunity and may be secondary to T-cell reactions at the glomeruli, tubules, and interstitium.

In one study, fenoprofen was reported to reduce serum uric acid concentrations, although the results of another study did not confirm this.

GI Effects

Fenoprofen can cause gastric mucosal damage which may result in ulceration and/or bleeding. (See Cautions: GI Effects.) These gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.118,119,120,121,122,123,124 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.120,124

Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.122 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.122

Hematologic Effects

Fenoprofen can inhibit collagen-induced platelet aggregation and may prolong bleeding time. Like aspirin and other prototypical NSAIAs, the effects of fenoprofen on platelets appear to be associated with the inhibition of the synthesis of prostaglandins produced by COX-1.122

Pharmacokinetics

In all studies described in the Pharmacokinetics section, the drug was administered as the calcium salt; dosage is expressed in terms of fenoprofen.

Absorption

Fenoprofen is rapidly and almost completely absorbed from the GI tract. When fenoprofen is taken with food, peak plasma drug concentrations are delayed and diminished. Administration of an aluminum and magnesium hydroxides antacid (Maalox^®) does not appear to alter absorption of fenoprofen. Following oral administration of a single 600-mg dose of fenoprofen to healthy fasting adults, peak plasma drug concentrations of approximately 50 mcg/mL are reached in 2 hours. The manufacturer states that steady-state plasma fenoprofen concentrations are reached approximately 2 hours after an oral dose and range from 40-70 mcg/mL in patients receiving 600 mg of fenoprofen 4 times daily.

Plasma fenoprofen concentrations required for anti-inflammatory or analgesic effect are not known; however, the analgesic and antipyretic effects of the drug appear to be linearly related to dose up to a dose of 200 mg, after which a plateau is reached. The onset of analgesic activity reportedly occurs within 15-30 minutes, and the duration of action is reported to be 4-6 hours.

Distribution

After therapeutic doses, fenoprofen is approximately 99% bound to albumin. Fenoprofen does not appear to cross the placenta. The drug is distributed into milk in concentrations less than 2% of simultaneous maternal plasma drug concentrations.

Elimination

The plasma half-life of fenoprofen has been reported to average 2.5-3 hours in healthy adults.

Fenoprofen is metabolized in the liver to 4'-hydroxyfenoprofen, which is probably inactive. Glucuronic acid conjugates of the drug and its metabolites are also formed. It appears that fenoprofen undergoes enterohepatic circulation.

Most of fenoprofen is excreted in urine within 24 hours, as unchanged drug (2-5%), 4'-hydroxyfenoprofen (2-5%), their glucuronide or other conjugates (90%), and small amounts of unidentified conjugates (2-5%). Renal tubular reabsorption of fenoprofen, but not its metabolites, may occur. A small amount of the drug is excreted in feces.

Chemistry and Stability

Chemistry

Fenoprofen, a propionic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA). The drug is structurally and pharmacologically related to ibuprofen and naproxen. Fenoprofen is commercially available as the calcium dihydrate salt; however, potency of the commercially available capsules and tablets is expressed in terms of fenoprofen. Fenoprofen calcium dihydrate occurs as a white, crystalline powder and is slightly soluble in water and sparingly soluble in alcohol. The pK_a of the drug is 4.5.

Stability

Fenoprofen calcium capsules and tablets should be stored in well-closed containers at a controlled room temperature.

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.

Only references cited for selected revisions after 1984 are available electronically.

100. Pedinol. Nalfon^® (fenoprofen calcium) capsules prescribing information. Farmingdale, NY; 2006 Jan.

101. Gurney JR, Mills RJ. Assessment of thyroid function: complications after treatment with fenoprofen. BMJ . 1986; 292:1560. [PubMed 3087516][PubMedCentral]

102. Tillman J, Leask JTS, Logue FC et al. Assessment of thyroid function: complications after treatment with fenoprofen. BMJ . 1986; 293:206. [PubMed 3089454][PubMedCentral]

103. Thornes HM, Carr D. Fenoprofen and free triiodothyronine measurement. Lancet . 1986; 2:101. [PubMed 2873356]

104. Palmer JF. Letter sent to Talbott MW of Eli Lilly and Company regarding labeling revisions about gastrointestinal adverse reactions to Nalfon^® (fenoprofen). Rockville, MD: Food and Drug Administration, Division of Oncology and Radiopharmaceutical Drug Products; 1988 Sep.

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

106. Searle. Cytotec (misoprostol) prescribing information. 1989 Jan.

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

108. 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]

109. Kolodzik JM, Eilers MA, Angelos MG. Nonsteroidal anti-inflammatory drugs and coma: a case report of fenoprofen overdose. Ann Emerg Med . 1990; 19:378-81. [PubMed 2321822]

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

111. 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]

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

113. Schubert TT, Bologna SD, Yawer N et al. Ulcer risk factors: interaction between Helicobacter pylori infection, nonsteroidal use, and age. Am J Med . 1993; 94:413-7. [PubMed 8475935]

114. Piper JM, 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]

115. 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][PubMedCentral]

116. Ciba Geigy, Ardsley, NY: Personal communication on diclofenac 28:08.04.

117. Reviewers' comments (personal observation) on diclofenac 28:08.04.

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

119. 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. [PubMed 8967954]

120. 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]

121. 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 inhibtors. Med Chem Res . 1995; 5:325-43.

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

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

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

125. 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]

126. 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]

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

128. 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]

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

130. 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]

131. 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]

132. 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]

133. 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]

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

135. 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]

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

137. US Food and Drug Administration. Proposed NSAID Package Insert Labeling Template 1. From the FDA website ([Web]). Accessed 10 Oct 2005.

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

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

140. 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.

141. 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]

142. 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][PubMedCentral]

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

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

145. 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 at: [Web].

146. Mylan Pharmaceuticals Inc. Fenoprofen calcium tablets prescribing information. Morgantown, WV; 2015 Jul.

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. Silver 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][PubMedCentral]

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][PubMedCentral]

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][PubMedCentral]

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. Xspire Pharma, LLC. Nalfon^® (fenoprofen calcium) capsules prescribing information. Ridgeland, MS; 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][PubMedCentral]

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. Xspire Pharma. Nalfon^® (fenoprofen calcium) tablets prescribing information. Ridgeland, MS; 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.