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Flurbiprofen


Pronunciation

 (flure BI proe fen)


U.S. Brand Names

 Ansaid®; Ocufen®


Synonyms

 Flurbiprofen Sodium


Generic Available

 Yes


Canadian Brand Names

 Alti-Flurbiprofen; Ansaid®; Apo-Flurbiprofen®; Froben®; Froben-SR®; Novo-Flurprofen; Nu-Flurprofen; Ocufen®


Use

Oral: Treatment of rheumatoid arthritis and osteoarthritis

Ophthalmic: Inhibition of intraoperative miosis


Use - Dental

 Oral: Management of postoperative pain


Pregnancy Risk Factor

 C/D (3rd trimester)


Pregnancy Implications

 Teratogenic effects were not observed in animal studies, however, adequate and well-controlled studies have not been conducted in pregnant women. Exposure late in pregnancy may lead to premature closure of the ductus arteriosus.


Lactation

 Enters breast milk/not recommended


Contraindications

 Hypersensitivity to flurbiprofen or any component of the formulation; dendritic keratitis; pregnancy (3rd trimester); patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis)


Warnings/Precautions

 Fatal asthmatic and anaphylactoid reactions have occurred in patients with "aspirin triad." Use with caution in patients with CHF, hypertension, dehydration, decreased renal or hepatic function, history of GI disease (bleeding, ulcers, or previous GI symptoms with NSAID use), or those receiving anticoagulants and/or corticosteroids. Use lowest effective dose for shortest period possible; bleeding risk has been correlated to dose and duration of therapy. Gastrointestinal bleeding may occur without prior symptoms of gastrointestinal irritation. Elderly are at a high risk for adverse effects from NSAIDs. As many as 60% of elderly can develop peptic ulceration and/or hemorrhage asymptomatically.

Use of NSAIDs can compromise existing renal function especially when Clcr<30 mL/minute. CNS adverse effects such as confusion, agitation, and hallucination are generally seen in overdose or high-dose situations; however, elderly may demonstrate these adverse effects at lower doses than younger adults. Do not exceed 300 mg/day. Withhold for at least 4-6 half-lives prior to surgical or dental procedures.


Adverse Reactions

Ophthalmic: Frequency not defined: Ocular: Slowing of corneal wound healing, mild ocular stinging, itching and burning, ocular irritation, fibrosis, miosis, mydriasis, bleeding tendency increased

Oral:

>1%:

Cardiovascular: Edema

Central nervous system: Amnesia, anxiety, depression, dizziness, headache, insomnia, malaise, nervousness, somnolence

Dermatologic: Rash

Gastrointestinal: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, nausea, vomiting, weight changes

Hepatic: Liver enzymes elevated

Neuromuscular & skeletal: Reflexes increased, tremor, vertigo, weakness

Ocular: Vision changes

Otic: Tinnitus

Respiratory: Rhinitis

<1% (Limited to important or life-threatening): Anaphylactic reaction, anemia, angioedema, asthma, bruising, cerebrovascular ischemia, CHF, confusion, eczema, eosinophilia, epistaxis, exfoliative dermatitis, fever, gastric/peptic ulcer, hematocrit decreased, hematuria, hemoglobin decreased, hepatitis, hypertension, hyperuricemia, interstitial nephritis, jaundice, leukopenia, paresthesia, parosmia, photosensitivity, pruritus, purpura, renal failure, stomatitis, thrombocytopenia, toxic epidermal necrolysis, urticaria, vasodilation


Overdosage/Toxicology

 Symptoms of overdose include apnea, metabolic acidosis, coma, nystagmus, leukocytosis, and renal failure. Management of NSAID intoxication is supportive and symptomatic. Since many NSAIDs undergo enterohepatic cycling, multiple doses of charcoal may be needed to reduce the potential for delayed toxicities.


Drug Interactions

 Substrate of CYP2C8/9 (minor); Inhibits CYP2C8/9 (strong)

ACE inhibitors: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure.

Angiotensin II antagonists: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure.

Anticoagulants (warfarin, heparin, LMWHs) in combination with NSAIDs can cause increased risk of bleeding.

Antiplatelet drugs (ticlopidine, clopidogrel, aspirin, abciximab, dipyridamole, eptifibatide, tirofiban) can cause an increased risk of bleeding.

Cholestyramine and colestipol reduce the bioavailability of some NSAIDs; separate administration times.

Corticosteroids may increase the risk of GI ulceration; avoid concurrent use.

Cyclosporine: NSAIDs may increase serum creatinine, potassium, blood pressure, and cyclosporine levels; monitor cyclosporine levels and renal function carefully.

CYP2C8/9 substrates: Flurbiprofen may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

Gentamicin and amikacin serum concentrations are increased by indomethacin in premature infants. Results may apply to other aminoglycosides and NSAIDs.

Hydralazine's antihypertensive effect is decreased; avoid concurrent use.

Lithium levels can be increased; avoid concurrent use if possible or monitor lithium levels and adjust dose. Sulindac may have the least effect. When NSAID is stopped, lithium will need adjustment again.

Loop diuretics efficacy (diuretic and antihypertensive effect) is reduced. Indomethacin reduces this efficacy, however, it may be anticipated with any NSAID.

Methotrexate: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant NSAID therapy. Avoid use during moderate or high-dose methotrexate (increased and prolonged methotrexate levels). NSAID use during low-dose treatment of rheumatoid arthritis has not been fully evaluated; extreme caution is warranted.

Thiazides antihypertensive effects are decreased; avoid concurrent use.

Warfarin's INRs may be increased by piroxicam. Other NSAIDs may have the same effect depending on dose and duration. Monitor INR closely. Use the lowest dose of NSAIDs possible and for the briefest duration.

Verapamil plasma concentration is decreased by some NSAIDs; avoid concurrent use.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may enhance gastric mucosal irritation).

Food: Food may decrease the rate but not the extent of absorption.

Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng (all have additional antiplatelet activity).


Mechanism of Action

 Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors


Pharmacodynamics/Kinetics

Onset of action: ~1-2 hours

Distribution: Vd: 0.12 L/kg

Protein binding: 99%, primarily albumin

Metabolism: Hepatic via CYP2C9; forms metabolites

Half-life elimination: 5.7 hours

Time to peak: 1.5 hours

Excretion: Urine


Dosage

Oral:

Rheumatoid arthritis and osteoarthritis: 200-300 mg/day in 2-, 3-, or 4 divided doses; do not administer more than 100 mg for any single dose; maximum: 300 mg/day

Dental: Management of postoperative pain: 100 mg every 12 hours

Ophthalmic: Instill 1 drop every 30 minutes, beginning 2 hours prior to surgery (total of 4 drops in each affected eye)


Administration

 Tablet: Take with a full glass of water.


Dietary Considerations

 Tablet may be taken with food, milk, or antacid to decrease GI effects.


Patient Education

 Oral: Take this medication exactly as directed; do not increase dose without consulting prescriber. Do not crush tablets. Take with food or milk to reduce GI distress. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Do not use alcohol, aspirin or aspirin-containing medication, or any other anti-inflammatory medications without consulting prescriber. You may experience drowsiness, dizziness, nervousness, or headache (use caution when driving or engaging in tasks requiring alertness until response to drug is known); anorexia, nausea, vomiting, or heartburn (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); fluid retention (weigh yourself weekly and report unusual (3-5 lb/week) weight gain). GI bleeding, ulceration, or perforation can occur with or without pain; discontinue medication and contact prescriber if persistent abdominal pain or cramping, or blood in stool occurs. Report breathlessness, respiratory difficulty, or unusual cough; chest pain, rapid heartbeat, palpitations; unusual bruising/bleeding; blood in urine, stool, mouth, or vomitus; swollen extremities; skin rash or itching; acute fatigue; or hearing changes (ringing in ears). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 3rd trimester of pregnancy. Breast-feeding is not recommended.

Ophthalmic: Wash hands before instilling. Sit or lie down to instill. Open eye, look at ceiling, and instill prescribed amount of medication. Close eye and roll eye in all directions, and apply gentle pressure to inner corner of eye. Do not let tip of applicator touch eye; do not contaminate tip of applicator (may cause eye infection, eye damage, or vision loss). Use protective dark eyewear until healed; avoid direct sunlight. Temporary stinging or burning may occur. Report persistent pain, burning, redness, vision changes, swelling, itching, or worsening of condition.


Nursing Implications

 Care should be taken to avoid contamination of the solution container tip


Anesthesia and Critical Care Concerns/Other Considerations

 The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) suggest that NSAIDs may be used in combination with opioids in select patients for pain management. Concern about adverse events (increased risk of renal dysfunction, altered platelet function and gastrointestinal irritation) limits its use in patients who have other underlying risks for these events.

In short-term use, NSAIDs vary considerably in their effect on blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema; may precipitate renal failure in dehydrated patients.


Cardiovascular Considerations

 In short-term use, NSAIDs vary considerably in their effect on blood pressure. A recent meta-analysis (see References) showed that indomethacin and naproxen had the largest effect on blood pressure. Other NSAIDs, including piroxicam, ibuprofen, and sulindac had less of an effect. Ibuprofen combined with captopril or losartan may attenuate the antihypertensive effects of ACE inhibition or receptor blockade on sitting or 24-hour ambulatory diastolic blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema. One study showed that NSAID use in elderly patients had an increased risk of hospitalization for heart failure. This study gives compelling reasons to avoid or limit the use of NSAIDs in patients with congestive heart failure, particularly in the elderly population.


Dental Health: Effects on Dental Treatment

 NSAID formulations are known to reversibly decrease platelet aggregation via mechanisms different than observed with aspirin. The dentist should be aware of the potential of abnormal coagulation. Caution should also be exercised in the use of NSAIDs in patients already on anticoagulant therapy with drugs such as warfarin (Coumadin®).


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 Dizziness is common; may cause nervousness; may rarely cause drowsiness, confusion, depression, or hallucinations


Mental Health: Effects on Psychiatric Treatment

 May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; may decrease the clearance of lithium resulting in elevated serum levels and potential toxicity; monitor serum lithium levels


Dosage Forms

Solution, ophthalmic, as sodium (Ocufen®): 0.03% (2.5 mL) [contains thimerosal]

Tablet (Ansaid®): 50 mg, 100 mg


References

Albert KS, Gillespie WR, Raabe A, et al, "Determination of Flurbiprofen in Human Serum by Reverse-Phase High-Performance Liquid Chromatography With Fluorescence Detection," J Pharm Sci , 1984, 73(12):1823-5.

Bragger U, Muhle T, Fourmousis I, et al, "Effect of the NSAID Flurbiprofen on Remodeling After Periodontal Surgery," J Periodontal Res , 1997, 32(7):575-82.

Brooks CD, Linet OI, Schellenberg D, et al, "Clinical Safety of Flurbiprofen," J Clin Pharmacol , 1990, 30(4):342-51.

Brooks PM and Day RO, "Nonsteroidal Anti-inflammatory Drugs - Differences and Similarities," N Engl J Med , 1991, 324(24):1716-25.

Clinch D, Banerjee AK, and Ostick G, "Absence of Abdominal Pain in Elderly Patients With Peptic Ulcer," Age Ageing , 1984, 13(2):120-3.

Clive DM and Stoff JS, "Renal Syndromes Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1984, 310(9):563-72.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients," Hypertension , 2000, 36(3):461-5.

Cooper SA and Kupperman A, "The Analgesic Efficacy of Flurbiprofen Compared to Acetaminophen With Codeine," J Clin Dent , 1991, 2(3):70-4.

Cooper SA, Mardirossian G, and Miles M, "Analgesic Relative Potency Assay Comparing Flurbiprofen 50, 100, and 150 mg, Aspirin 600 mg, and Placebo in Postsurgical Dental Pain," Clin J Pain , 1988, 4:175-81.

Court H and Volans GN, "Poisoning After Overdose With Nonsteroidal Anti-inflammatory Drugs," Adverse Drug React Acute Poisoning Rev , 1984, 3(1):1-21.

Davis NM, "Clinical Pharmacokinetics of Flurbiprofen and its Enantiomers," Clin Pharmacokinet , 1995, 28(2):100-14.

Dionne RA, "Suppression of Dental Pain by the Preoperative Administration of Flurbiprofen," Am J Med , 1986, 80(3A):41-9.

Dionne RA, Snyder J, and Hargreaves KM, "Analgesic Efficacy of Flurbiprofen in Comparison With Acetaminophen, Acetaminophen Plus Codeine, and Placebo After Impacted Third Molar Removal," J Oral Maxillofac Surg , 1994, 52(9):919-24.

Forbes JA, Yorio CC, Selinger LR, et al, "An Evaluation of Flurbiprofen, Aspirin, and Placebo in Postoperative Oral Surgery Pain," Pharmacotherapy , 1989, 9(2):66-73.

Gallardo F and Rossi E, "Analgesic Efficacy of Flurbiprofen as Compared to Acetaminophen and Placebo After Periodontal Surgery," J Periodontol , 1990, 61(4):224-7.

Graham DY, "Prevention of Gastroduodenal Injury Induced by Chronic Nonsteroidal Anti-inflammatory Drug Therapy," Gastroenterology , 1989, 96(2 Pt 2 Suppl):675-81.

Hawkey CJ, Karrasch JA, Szczepa&ntilde;ski L, et al, "Omeprazole Compared With Misoprostrol for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):727-34.

Heerdink ER, Leufkens HG, Herings RM, et al, "NSAIDs Associated With Increased Risk of Congestive Heart Failure in Elderly Patients Taking Diuretics," Arch Intern Med , 1998, 158(10):1108-12.

Hoppmann RA, Peden JG, and Ober SK, "Central Nervous System Side Effects of Nonsteroidal Anti-inflammatory Drugs. Aseptic Meningitis, Psychosis, and Cognitive Dysfunction," Arch Intern Med , 1991, 151(7):1309-13.

Jacobi J, Fraser GL, Coursin DB, et al, "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult," Crit Care Med , 2002, 30(1):119-41. Available at: http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003.

Jeffcoat MK, Reddy MS, Haigh S, et al, "A Comparison of Topical Ketorolac, Systemic Flurbiprofen, and Placebo for the Inhibition of Bone Loss in Adult Periodontitis," J Periodontol , 1995, 66(5):329-38.

Jeffcoat MK, Reddy MS, Wang IC, et al, "The Effect of Systemic Flurbiprofen on Bone Supporting Dental Implants," J Am Dent Assoc , 1995, 126(3):305-11.

Knodel LC, "Preventing NSAID-Induced Ulcers: The Role of Misoprostol," Consult Pharm , 1989, 4:37-41.

Lesko SM and Mitchell AA, "An Assessment of the Safety of Pediatric Ibuprofen; A Practitioner-Based Randomized Clinical Trial," JAMA , 1995, 273(12):929-33.

Malmberg AB and Yaksh TL, "Antinociception Produced by Spinal Delivery of the S and R Enantiomers of Flurbiprofen in the Formalin Test," Eur J Pharmacol , 1994, 256(2):205-9.

Morgan TO, Anderson A, and Bertram D, "Effect of Indomethacin on Blood Pressure in Elderly People With Essential Hypertension Well Controlled on Amlodipine or Enalapril," Am J Hypertens , 2000, 13(11):1161-7.

Page J and Henry D, "Consumption of NSAIDs and the Development of Congestive Heart Failure in Elderly Patients: An Underrecognized Public Health Problem," Arch Intern Med , 2000, 160(6):777-84.

Pope JE, Anderson JJ, and Felson DT, "A Meta-analysis of the Effects of Nonsteroidal Anti-inflammatory Drugs on Blood Pressure," Arch Intern Med , 1993, 153(4):477-84.

Pounder R, "Silent Peptic Ulceration: Deadly Silence or Golden Silence?" Gastroenterology , 1989, 96(2 Pt 2 Suppl):626-31.

Smolinske SC, Hall AH, Vandenberg SA, et al, "Toxic Effects of Nonsteroid Anti-inflammatory Drugs in Overdose. An Overview of Recent Evidence on Clinical Effects and Dose-Response Relationships," Drug Saf , 1990, 5(4):252-74.

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Verbeeck RK, "Pharmacokinetic Drug Interactions With Nonsteroidal Anti-inflammatory Drugs," Clin Pharmacokinet , 1990, 19(1):44-66.

Yeomans ND, Tulassay Z, Juhasz L, et al, "A Comparison of Omeprazole With Ranitidine for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):719-26.


International Brand Names

 Acustop Cataplasma® (SG); Alti-Flurbiprofen (CA); Ansaid® (CA, CL, CR, GT, HN, MX, PA, PL, SV); Antadys® (MC); Apo-Flurbiprofen® (CA, ZA); Bedice® (GR); Benactiv® (IT); Bonatol-R® (GR); Cebutid® (FR); Clinadol® (AR); Distex® (CL); Dobendan Direkt Fluribiprofen® (DE); Dobrofen® (DE); Fievrinol® (GR); Fladolef® (GR); Flugalin® (CZ, HU, PL, RU, YU); Flurbiprofen® (YU); Flurofen® (DK); Flurozin® (CY, TH); Frini® (GR); Froben® (AT, BE, CA, CH, ES, GB, HK, IE, IN, IT, LU, NL, NZ, PT, ZA); Froben-SR® (CA); Iovic® (GR); Kirik® (GR); Luarprofeno® (AR); Majezik® (TR); Mirafen® (CO); Neliacan® (GR); Neo Artrol® (ES); Novo-Flurprofen (CA); Nu-Flurprofen (CA); Ocufen® (AU, BR); Ocufen™ (CA); Ocufen® (CL, CO, FR, GB, HK, IE, IT, SG, TR); Ocuflur® (AT, BE, CH, CZ, DE, ES, HR, HU, LU, PL); Ocuflur Liquifilm® (HR); Pizar® (GR); Rograpon® (GR); Ropion® (JP); Strefen® (GB); Streflam® (GB); Strepfen® (NZ); Strepsils Dolointensive® (PL); Strepten® (RO); Tantum Activ Gola® (IT); Targus® (BR); Tolerane® (AR); Transact Lat® (IT); Transact® (PT, ZA)


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