AHFS Class:

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

Generic Name(s):

• Flurbiprofen Sodium

Flurbiprofen, a propionic acid derivative,7 is a prototypical nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and antipyretic activity.1,2,3,6,7

Inflammatory Diseases

Flurbiprofen is used for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis or osteoarthritis in adults.1,2,3,4,5,6,7,10 Efficacy for the management of signs and symptoms of these conditions has been established in controlled studies of 2-12 weeks in adults with osteoarthritis and 2 weeks to 12 months in adults with rheumatoid arthritis.2,3,4,5,6,7 Clinical evaluations in patients with rheumatoid arthritis or osteoarthritis have shown that flurbiprofen (e.g., 75-300 mg daily) is more effective than placebo2,7 and at least as effective as aspirin (e.g., 2-4 g daily),2,3,4,5,6,7 indomethacin (e.g., 75-150 mg daily),2,3,6,7 sulindac (e.g., 150-300 mg daily),2,3,7 naproxen (e.g., 500-750 mg daily),2,3,6,7,10 or ibuprofen (e.g., 2.4 g daily).2,6,7

Flurbiprofen also has been used in the management of ankylosing spondylitis†.2,6,8

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

Ophthalmic Uses

For ophthalmic uses of flurbiprofen, see 52:08.20.

General

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

Flurbiprofen is administered orally.1,13,14 Administration with food or antacids may alter the rate but not the extent of absorption.1,3,13

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

The usual dosage of flurbiprofen for the management of osteoarthritis or rheumatoid arthritis in adults is 200-300 mg daily given in 2-4 divided doses.1,3 Single doses of flurbiprofen should not exceed 100 mg, and the lowest effective dosage should be used.1,3 Limited evidence suggests similar efficacy whether the total daily dosage of flurbiprofen is administered in 2, 3, or 4 divided doses.2,9

Special Populations

Hepatic Impairment

Dosage reduction may be required in patients with hepatic dysfunction.1,3,15

CYP2C9 Poor or Intermediate Metabolizers

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that, in patients who are cytochrome P-450 isoenzyme 2C9 (CYP2C9) poor metabolizers, flurbiprofen should be initiated at a dosage that is 25-50% of the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to a dosage that is 25-50% of the maximum recommended dosage.520 Dosage should not be increased until steady-state concentrations are attained (at least 5 days following the initial dose in poor metabolizers).520 Alternatively, a drug that is not metabolized by CYP2C9 or is not substantially affected by CYP2C9 genetic variants in vivo should be considered.520 In addition, CPIC guidelines state that, in patients who are CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1, flurbiprofen may be initiated at the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to the maximum recommended dosage.520 Intermediate metabolizers with an AS of 1.5 may receive dosages recommended for normal metabolizers.520 (See Pharmacogenomic Considerations under Cautions.)

Contraindications

Known hypersensitivity to flurbiprofen or any ingredient in the formulation.1,15 History of asthma, urticaria, or allergic-type reactions precipitated by aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs).1 History of aspirin triad (aspirin sensitivity, asthma, and nasal polyps).1 In the setting of coronary artery bypass graft (CABG) surgery.508

Warnings/Precautions

Warnings

Cardiovascular Effects

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

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 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Flurbiprofen 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 flurbiprofen is used in such patients, the patient should be monitored for cardiac ischemia.508

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following 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.19,20,21,23,500,501,502,503,506 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.)

To minimize the potential risk of adverse cardiovascular events, NSAIAs should be used at the lowest effective dosage and for the shortest possible duration of therapy.1,500,508 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

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,16,502,508

Hypertension

Use of NSAIAs, including flurbiprofen, 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 NSAIAs, including flurbiprofen, should be used with caution in patients with hypertension.1 Blood pressure should be monitored closely during initiation of flurbiprofen therapy and throughout therapy.1

Heart Failure and Edema

Data from observational studies 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.1,508 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat these conditions (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).508 (See Drug Interactions.)

The manufacturer states that flurbiprofen 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 flurbiprofen 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

GI Effects

Risk of serious GI effects (e.g., bleeding, ulceration, perforation), which can occur at any time with or without warning signs or symptoms.1 Conditions or concomitant therapies that may increase risk include a history of GI bleeding or ulceration, treatment with anticoagulants or oral corticosteroids, longer duration of NSAIA therapy, smoking, alcohol dependence, poor general health, or older age (higher risk of fatal GI complications).1,15 Use with extreme caution in these patients.

Renal Effects

Renal papillary necrosis or other renal medullary changes may occur with long-term administration of NSAIAs, including flurbiprofen.1 Possibility of overt renal decompensation in patients dependent on renal prostaglandins for maintenance of renal perfusion.1 Patients at particular risk include those with heart failure, hepatic or renal dysfunction, or dehydration; those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist; and geriatric patients.1,18 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1

Sensitivity Reactions

Sensitivity reactions, including anaphylactoid reactions, are possible in patients without prior exposure to flurbiprofen.1 Immediate medical intervention and drug discontinuance are required.1 Cross-sensitivity may exist with other NSAIAs.1 (See Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.)

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.1202 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.1202 Symptoms may resemble those of an acute viral infection.1202 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1202 If such signs or symptoms develop, the NSAIA should be discontinued and the patient evaluated immediately.1202

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving flurbiprofen.1 These serious skin reactions may occur without warning.1 Discontinue flurbiprofen at the first appearance of rash or any other sign of hypersensitivity.1

General Precautions

Provide the medication guide for NSAIAs to the patient each time the drug is dispensed.1

Hepatic Effects

Borderline elevations in one or more liver function test result may occur in up to 15% of patients treated with NSAIAs, including flurbiprofen;1 clinically important (i.e., 3 times the upper limit of normal) elevations of serum ALT or AST reported in approximately 1% of patients receiving NSAIAs.1 Severe, sometimes fatal, reactions (e.g., jaundice, fulminant hepatitis, liver necrosis, hepatic failure) reported rarely in patients receiving NSAIAs.1 Discontinue drug if clinical manifestations of liver disease occur.1

Hematologic Effects

Anemia reported; platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT) usually not affected.1

Pharmacogenomic Considerations

In patients with the cytochrome P-450 isoenzyme 2C9 (CYP2C9) poor metabolizer phenotype, metabolism of flurbiprofen may be decreased substantially; half-life of flurbiprofen is prolonged and higher plasma concentrations of the drug may increase the likelihood and/or severity of adverse effects.520 Metabolism of flurbiprofen may be moderately reduced in CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1 and mildly reduced in those with an AS of 1.5.520 Higher plasma concentrations of the drug in intermediate metabolizers with an AS of 1 may increase the likelihood of adverse effects.520 The presence of other factors affecting clearance of the drug (e.g., hepatic impairment, advanced age) also may increase the risk of adverse effects in intermediate metabolizers.520 (See CYP2C9 Poor or Intermediate Metabolizers under Dosage and Administration.) The Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs should be consulted for additional information on interpretation of CYP2C9 genotype testing.520

Other Precautions

Ophthalmologic examinations recommended in patients experiencing blurred or diminished vision.1

May mask certain signs of infection; cannot be used as a substitute for corticosteroid therapy nor used to treat adrenal insufficiency.1

Specific Populations

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.1200,1202 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.1200,1202 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.1200,1202 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.1200,1202

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.1200,1202 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1200,1202 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1200,1202 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1200,1202 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.1202 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1202 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.1202

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 flurbiprofen, 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

There are no adequate and well-controlled studies of flurbiprofen in pregnant women.1201 In animal studies, embryofetal lethality was observed in pregnant rats and rabbits receiving flurbiprofen during the period of organogenesis at exposure levels of 0.03 and 0.5 times, respectively, the exposure at the maximum recommended human dose (MRHD) of 300 mg; no evidence of malformations was observed in rats, rabbits, or mice receiving flurbiprofen at dosages of 0.8, 0.5, or 0.2 times, respectively, the MRHD.1201 Reproduction studies revealed delayed parturition, prolonged labor, stillborn fetuses, and the presence of retained fetuses at necropsy in rats at flurbiprofen dosages that were lower than the MRHD.1201

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

Lactation

Flurbiprofen is distributed into milk in very small amounts (estimated to be 0.1 mg daily based on a daily maternal dosage of 200 mg).1,13,15 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for flurbiprofen and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1201

Fertility

Use of NSAIAs, including flurbiprofen, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1201 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.1201 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1201

Pediatric Use

Safety and efficacy not established in children younger than 18 years of age.1

Geriatric Use

Geriatric patients may experience a higher incidence of adverse GI effects (e.g., ulceration, bleeding, flatulence, bloating, abdominal pain) than younger patients and are at greater risk of developing renal decompensation with NSAIAs.1 Use flurbiprofen with caution and at the lowest effective dosage for the shortest possible duration.1

Renal Impairment

Use not recommended in patients with severe renal impairment.1 However, if flurbiprofen must be used in patients with advanced renal disease, closely monitor renal function.1

Common Adverse Effects

Adverse effects occurring in at least 1% of patients receiving flurbiprofen in clinical trials include edema, abdominal pain, constipation, diarrhea, dyspepsia/heartburn, liver enzyme elevations, flatulence, GI bleeding, nausea, vomiting, weight change, headache, nervousness, CNS stimulation (e.g., anxiety, insomnia, increased reflexes, tremor), CNS inhibition (e.g., amnesia, asthenia, depression, malaise, somnolence), rhinitis, vision changes, dizziness/vertigo, tinnitus, signs and symptoms of urinary tract infection, and rash.1

ACE Inhibitors and Angiotensin II Receptor Antagonists

Potential pharmacologic interaction (reduced antihypertensive effects).1,22

Beta-Adrenergic Blocking Agents

Potential pharmacologic interaction (reduced antihypertensive effects).1

Antidiabetic Agents

A slight reduction in blood glucose concentrations (without signs or symptoms of hypoglycemia) occurred when flurbiprofen was added to therapy in adults with diabetes mellitus receiving certain antidiabetic agents (e.g., glyburide, metformin, phenformin [no longer commercially available in the US] plus chlorpropamide or glyburide).1

Histamine H2-receptor Antagonists

Concomitant administration of cimetidine and flurbiprofen increased the AUC of flurbiprofen by 13%, which is not considered clinically important; ranitidine did not affect flurbiprofen pharmacokinetics when the drugs were administered concomitantly.1

Digoxin

Pharmacokinetic interaction unlikely.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 flurbiprofen.1 NSAIAs, including flurbiprofen, may reduce the natriuretic effects of furosemide and thiazides.1 Observe patient for signs of renal failure and for diuretic efficacy.1

Lithium

Pharmacokinetic interaction (decreased renal lithium clearance, increased plasma lithium concentration).1

Methotrexate

Potential pharmacokinetic interaction (enhanced toxicity of methotrexate resulting from inhibition of methotrexate renal elimination).1,12 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Methotrexate 10:00.) No interaction was observed in a study of 6 adults with arthritis receiving concomitant methotrexate (10-25 mg/dose) and flurbiprofen (300 mg daily); however, caution advised with concomitant administration of NSAIAs and methotrexate.1

Pemetrexed

Concomitant use of flurbiprofen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.1201 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.1201 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.1201 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 flurbiprofen and pemetrexed therapy.1201

Aspirin

Concomitant use of aspirin decreases serum flurbiprofen concentrations; clinical importance of this interaction is unknown.1,13,14 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.1 Because of the potential for increased adverse effects, concurrent use of flurbiprofen and aspirin generally is not recommended.1,15 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.16,502,508

Anticoagulants

The effects of warfarin and NSAIAs on GI bleeding are synergistic.1 Concomitant use of an NSAIA and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.1 Caution is advised if flurbiprofen is used concomitantly with warfarin or other anticoagulants.1

Because reduced CYP2C9 function is associated with an increased risk of major bleeding or supratherapeutic international normalized ratios (INRs) in patients receiving concomitant therapy with warfarin (a CYP2C9 substrate) and NSAIAs, some experts state that concomitant use of warfarin and NSAIAs should be avoided in patients who are CYP2C9 intermediate or poor metabolizers.520

Description

Flurbiprofen, a propionic acid derivative nonsteroidal anti-inflammatory agent (NSAIA), is structurally and pharmacologically related to fenoprofen, ibuprofen, and ketoprofen.2 Flurbiprofen has pharmacologic actions similar to those of other prototypical NSAIAs.2 The drug exhibits anti-inflammatory, analgesic, and antipyretic activity.1,2,7 Commercially available flurbiprofen is a racemic mixture of (+) S - and (-) R -enantiomers.1,13 As with other currently available chiral NSAIAs, the S -enantiomer of flurbiprofen appears to possess most of the anti-inflammatory activity, while both R - and S -enantiomers may possess analgesic activity.13 The exact mechanism of action of flurbiprofen has not been clearly established, but many of the actions appear to be associated principally with inhibition of prostaglandin synthesis.1,2 Like other NSAIAs, flurbiprofen inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase (COX), including both COX-1 and COX-2 isoenzymes.2 Flurbiprofen is one of the most potent NSAIAs in terms of prostaglandin inhibitory activity.2,7,13

Flurbiprofen is rapidly and almost completely absorbed following oral administration.1,2,3,13,14 Peak plasma concentrations are reached approximately 1.5-3 hours after ingestion.1,2 Flurbiprofen is greater than 99% bound to plasma proteins, principally albumin.1,2,13,14 Flurbiprofen is extensively metabolized.1,2,13,14 In vitro studies demonstrate that metabolism of flurbiprofen to its major metabolite, 4'-hydroxyflurbiprofen, occurs via the cytochrome P-450 (CYP) isoenzyme 2C9;1,11 studies in animals indicate that this metabolite has weak anti-inflammatory activity.1,2 Flurbiprofen does not appear to induce or inhibit its own metabolism.1,2,13,14 Following oral dosing, approximately 70% of the flurbiprofen dose is eliminated in urine as parent drug and metabolites, with less than 3% excreted unchanged in urine.1,3 The elimination half-lives of R - and S -flurbiprofen are approximately 4.7 and 5.7 hours, respectively.1

Advice to Patients

Importance of reading the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.1

Risk of serious cardiovascular toxicity (e.g., myocardial infarction, stroke).1,500,508 Importance of seeking immediate medical attention if signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) occur.1,500,508

Risk of GI ulceration or bleeding; importance of reporting any signs or symptoms of GI ulceration or bleeding.1

Importance of reporting signs or symptoms of hepatotoxicity, including nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, or flu-like symptoms.1

Risk of serious skin reactions, DRESS, and anaphylactoid and other sensitivity reactions.1 Advise patients to stop taking the drug immediately if they develop any type of rash or fever and to promptly contact their clinician.1202 Importance of seeking immediate medical attention if an anaphylactic reaction occurs.1202

Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.1,508

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 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 Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.1201

Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

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3. Anon. Flurbiprofen. Med Lett Drugs Ther. 1989; 31:31-2.

4. Lomen Pl, Lamborn KR, Porter GH et al. Treatment of osteoarthritis of the knee. A comparison of flurbiprofen and aspirin. Am J Med . 1986; 24(Suppl 3A):97-102.

5. Lomen PL, Turner LF, Lamborn KR et al. Flurbiprofen in the treatment of rheumatoid arthritis. A comparison with aspirin. Am J Med . 1986; 24(Suppl 3A):89-95.

6. Buchanan WW, Kassam YB. European experience with flurbiprofen. A new analgesic/anti-inflammatory agent. Am J Med . 1986; 24(Suppl 3A):145-52.

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8. Lomen PL, Turner LF, Lamborn KR et al. Flurbiprofen in the treatment of ankylosing spondylitis. A comparison with indomethacin. Am J Med . 1986; 24(Suppl 3A):127-32.

9. Brown BL, Daenzer CL, Hearron MS et al. Comparison of two dosing schedules of flurbiprofen for patients with rheumatoid arthritis. Twice-daily versus four-times-a-day schedules. Am J Med . 1986; 24(Suppl 3A):19-22.

10. Atkinson MH, Buchanan WW, Fitzgerald AA et al. A comparison of flurbiprofen and naproxen in the treatment of rheumatoid arthritis: a Canadian multi-centre study. Curr Med Res Opin . 1990; 12:76-85. [PubMed 2202552]

11. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol . 1998; 45:525-38. [PubMed 9663807][PubMedCentral]

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15. Pharmacia, Kalamazoo, MI: Personal communication.

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

17. 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.

18. 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.

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20. 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]

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

23. 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].

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