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
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 other inflammatory diseases includingankylosing spondylitis†, gout†, and psoriatic arthritis†.2, 6, 8, 24, 25
The American College of Rheumatology (ACR) guideline on the treatment of rheumatoid arthritis recommends initiation of a disease-modifying antirheumatic drug (DMARD) in DMARD-naïve patients with rheumatoid arthritis; methotrexate is recommended over other DMARDs for the initial treatment of patients with moderate-to-high disease activity, while hydroxychloroquine is recommended initially for patients with low disease activity.2001 Addition of a biologic or target-specific DMARD is recommended for patients who do not attain treatment goals on methotrexate monotherapy (“treat-to-target” approach).2001 The role of NSAIAs is not discussed in the current ACR guideline on rheumatoid arthritis.2001
Medical management of osteoarthritis of the hip, knee, and/or hand includes both pharmacologic therapy and nonpharmacologic (e.g., educational, behavioral, psychosocial, physical) interventions to reduce pain, maintain and/or improve joint mobility, limit functional impairment, and enhance overall well-being.2002 The ACR strongly recommends exercise, weight loss when necessary in patients with osteoarthritis of the knee and/or hip, self-efficacy and self-management programs, tai chi, cane use, hand orthoses, knee bracing, topical NSAIAs for osteoarthritis of the knee, oral NSAIAs, and intra-articular glucocorticoid injections for osteoarthritis of the knee or hip.2002 Other pharmacologic or nonpharmacologic interventions may be recommended conditionally.2002 Interventions and the order of their selection are patient specific.2002 Factors to consider when making decisions regarding therapy for osteoarthritis include patients' values and preferences, the presence of risk factors for serious adverse GI effects, existing comorbidities (e.g., hypertension, heart failure, other cardiovascular disease, chronic kidney disease), injuries, disease severity, surgical history, and access to and availability of the interventions.2002 Pharmacologic therapy should be initiated with treatments resulting in the least systemic exposure or toxicity.2002 For some patients with limited disease, topical NSAIAs may be an appropriate initial choice for pharmacologic therapy; for other patients, particularly those with osteoarthritis of the hip or with polyarticular involvement, oral NSAIAs may be more appropriate.2002
Dispensing and Administration Precautions
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, 26 Flurbiprofen tablets should be stored at room temperature (20-25°C).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.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
Dosage reduction may be required in patients with hepatic dysfunction.1, 3, 15
Dosage adjustment not necessary in mild renal impairment.1 Dosage reduction may be necessary in moderate or severe renal impairment.1
Use flurbiprofen with caution at the lowest effective dosage for the shortest possible duration.1
Pharmacogenomic Considerations
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
A boxed warning concerning the increased risk of serious cardiovascular thrombotic events is included in the prescribing information for flurbiprofen.1 Clinical trials of NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs of up to 3 years' duration, have shown an increased 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.1 Based on available evidence, it is unclear if the risk of cardiovascular thrombotic events is similar for all NSAIAs.1 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.1 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.1
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.1, 505 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).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.511 Flurbiprofen should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risks of recurrent cardiovascular thrombotic events; if the drug is used in such patients, the patient should be monitored for cardiac ischemia.1
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.1 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.1
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 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular thrombotic events throughout therapy.1 Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.1
There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1
A boxed warning concerning the increased risk of serious adverse GI events is included in the prescribing information for flurbiprofen.1 Serious, sometimes fatal, adverse GI effects (e.g., bleeding, ulceration, or perforation of the esophagus, stomach, or small or large intestine) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.1, 27 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.1 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy.1 Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored even more closely for evidence of GI bleeding.1 In addition, patients should be advised about the signs and symptoms of ulceration and bleeding (e.g., epigastric pain, dyspepsia, melena, hematemesis) and to report these symptoms to their healthcare provider.1 If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.1 In patients receiving NSAIAs in clinical studies, upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.1 A longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.1 However, short-term therapy is not without risk.1
Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than 10-fold increased risk of developing GI bleeding than patients without these risk factors.1 In addition to a history of ulcer disease, other factors may increase the risk for GI bleeding, including concomitant use of oral corticosteroids, anticoagulants, aspirin, or selective serotonin-reuptake inhibitors (SSRIs); longer duration of NSAIA therapy; smoking; alcohol use; older a and poor general health status.1 Risk of GI bleeding also is increased in patients with advanced liver disease and/or coagulopathy.1 In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.1 To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed, and use of more than one NSAIA at a time should be avoided.1 In addition, use of NSAIAs should be avoided in patients at higher risk unless the benefits of therapy are expected to outweigh the increased risk of bleeding; for patients who are at high risk, as well as for those with active GI bleeding, alternative therapy other than an NSAIA should be considered.1
Severe (sometimes fatal) reactions including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure have been reported rarely in patients receiving NSAIAs.1
Elevations of ALT or AST (<3 times the upper limit of normal [ULN]) may occur in up to 15% of patients treated with NSAIAs; meaningful (≥3 times the ULN) elevations of serum ALT or AST concentration have occurred in approximately 1% of patients receiving NSAIAs in controlled clinical studies.1 Flurbiprofen should be discontinued immediately if signs or symptoms consistent with liver disease develop or if systemic manifestations (e.g., eosinophilia, rash) occur, and clinical evaluation of the patient should be performed.1
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.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 Blood pressure should be monitored closely during initiation of a NSAIA and throughout therapy.1
Results from Danish National Registry data indicate that use of NSAIAs in patients with chronic heart failure is associated with an increase in the risk of death, myocardial infarction, and hospitalization for heart failure.1 Fluid retention and edema also have been observed in some patients receiving NSAIAs.1
Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that flurbiprofen should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risks of worsening heart failure; if the drug is used, the patient should be monitored for worsening heart failure.1 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.1 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).1
Renal Toxicity and Hyperkalemia
Direct renal injury, including renal papillary necrosis, has been reported in patients receiving long-term NSAIA therapy.1 Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.1 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.1 Patients at greatest risk of this reaction are 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.1
Fluid depletion should be corrected prior to initiation of flurbiprofen therapy, and renal function should be monitored during therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.1 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1
Hyperkalemia has been reported in patients receiving NSAIAs, including in individuals without renal impairment; in those with normal renal function, this effect has been attributed to a hyporeninemic-hypoaldosteronism state.1
Anaphylactic reactions have been reported in patients receiving flurbiprofen with or without a known hypersensitivity to the drug and in patients with aspirin-sensitive asthma.1 Patients receiving NSAIAs should be informed of the signs and symptoms of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if a reaction develops.1
Exacerbation of Asthma Related to Aspirin Sensitivity
Patients with asthma but without known aspirin sensitivity who are receiving flurbiprofen should be monitored for changes in manifestations of asthma.1 In patients with asthma, aspirin sensitivity can manifest as severe, potentially fatal bronchospasm with chronic rhinosinusitis and nasal polyps and/or an intolerance to aspirin or other NSAIAs.1 Flurbiprofen is contraindicated in patients with aspirin-sensitive asthma.1
Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs.1 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.1 NSAIAs should be discontinued at the first appearance of rash or any other sign of hypersensitivity.1
Drug Reaction with Eosinophilia and Systemic Symptoms
Drug reaction with eosinophilia and systemic symptoms (DRESS), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1 DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling.1 Other clinical manifestations may include hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1 Symptoms may resemble those of an acute viral infection.1 Eosinophilia is often present.1 Clinical presentation is variable, and other organ systems may be involved.1 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1 If such signs or symptoms develop, flurbiprofen should be discontinued and the patient evaluated immediately.1
Fetal/Neonatal Morbidity and Mortality
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.1 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.1 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.1
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.1 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.1 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1
NSAIAs, including flurbiprofen, may increase the risk of bleeding.1 Flurbiprofen can inhibit platelet aggregation and may prolong bleeding time.1 Patients with certain coexisting conditions such as coagulation disorders and those receiving concomitant therapy with anticoagulants, antiplatelet agents, SSRIs, or SNRIs may be at increased risk and should be monitored for signs of bleeding.1
Anemia has been reported in patients receiving NSAIAs.1 Anemia may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.1 If signs and/or symptoms of anemia occur during therapy with flurbiprofen, hemoglobin concentration and hematocrit should be determined.1
Masking of Inflammation and Fever
The possibility that the antipyretic and anti-inflammatory effects of flurbiprofen may mask the usual signs and symptoms of infection or other diseases should be considered.1
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning, patients receiving long-term NSAIA therapy should have a CBC and chemistry profile performed periodically.1
Visual disturbances (e.g., blurred and/or diminished vision) have been reported; ophthalmic evaluation is recommended if visual changes occur.1
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.1 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.1 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.1
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.1 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1 Deaths associated with neonatal renal failure have been reported.1 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.1 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1 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.1
Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1 In animal studies, inhibitors of prostaglandin synthesis, such as flurbiprofen, were associated with increased pre- and post-implantation losses.1 Prostaglandins also have an important role in fetal kidney development.1 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1
There are no adequate and well-controlled studies of flurbiprofen in pregnant women.1 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.1 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.1
The effects of flurbiprofen on labor and delivery are unknown.1 In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased the incidence of stillbirth.1
Flurbiprofen is distributed into human milk in very small amounts (estimated to be 0.1 mg daily based on a daily maternal dosage of 200 mg).1 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.1
Females and Males of Reproductive Potential
Use of NSAIAs, including flurbiprofen, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1 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.1 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1
Safety and efficacy of flurbiprofen have not been established in pediatric patients.1
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
Use not recommended in patients with severe renal impairment; however, if flurbiprofen administration is necessary in patients with advanced renal disease, closely monitor renal function.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) may also increase the risk of adverse effects in intermediate metabolizers.520 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
The most common adverse effects (>3%) from clinical trials include abdominal pain, dyspepsia, nausea, diarrhea, constipation, headache, edema, and signs and symptoms suggesting urinary tract infection.1
ACE Inhibitors and Angiotensin II Receptor Antagonists
Potential pharmacologic interaction (reduced antihypertensive effects).1 Monitor blood pressure when flurbiprofen is used concomitant with ACE inhibitors and angiotensin II receptor antagonists.1
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; monitor patients.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
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).1
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 analgesic doses of aspirin generally is not recommended.1, 15
Beta-Adrenergic Blocking Agents
Potential pharmacologic interaction (reduced antihypertensive effects).1 Monitor blood pressure when flurbiprofen is used concomitant with β-adrenergic blocking agents.1
Concomitant use of flurbiprofen and cyclosporine may increase cyclosporine nephrotoxicity.1 Monitor for signs of worsening renal function during concomitant use.1
Concomitant use of flurbiprofen with digoxin has been reported to increase serum concentrations and prolong the half life of digoxin.1 Monitor serum digoxin levels during concomitant use.1
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 may reduce the natriuretic effects of furosemide and thiazides.1 Observe patients for signs of renal failure and for diuretic efficacy.1
Histamine H2-receptor Antagonists
Concomitant administration of cimetidine and flurbiprofen increased the AUC of flurbiprofen by 13%, which is not considered clinically important.1
Pharmacokinetic interaction (decreased renal lithium clearance, increased plasma lithium concentration).1 Monitor patients for signs of lithium toxicity during concomitant use.1
Potential pharmacokinetic interaction (enhanced toxicity of methotrexate resulting from inhibition of methotrexate renal elimination).1, 12 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
Concomitant use of flurbiprofen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.1 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.1 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.1 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.1
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
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.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 100 mg* | Flurbiprofen Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Genus Lifesciences. Flurbiprofen tablets prescribing information. Allentown, PA; 2024 Aug.
2. Brogden RN, Heel RC, Speight TM et al. Flurbiprofen: a review of its pharmacological properties and therapeutic use in rheumatic diseases. Drugs . 1979; 18:417-38. [PubMed 391529]
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.
7. Marsh CC, Schuna AA, Sundstrom WR. A review of selected investigational nonsteroidal anti-inflammatory drugs of the 1980s. Pharmacotherapy . 1986; 6:10-25. [PubMed 2937024]
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]
12. Frenia ML, Long KS. Methotrexate and nonsteroidal anti-inflammatory drug interactions. Ann Pharmacother . 1992; 26:234-7. [PubMed 1554938]
13. Davies NM. Clinical pharmacokinetics of flurbiprofen and its enantiomers. Clin Pharmacokinet . 1995; 28:100-14. [PubMed 7736686]
14. Kaiser DG, Brooks CD, Lomen PL. Pharmacokinetics of flurbiprofen. Am J Med . 1986; 24(Suppl 3A):10-13.
15. Pharmacia, Kalamazoo, MI: Personal communication.
19. 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]
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