FLURBIPROFEN TABLETS, USP 100 mg
0711, Rx only

Flurbiprofen is a nonsteroidal anti-inflammatory agent. Flurbiprofen is a phenylalkanoic acid derivative designated chemically as (±)-2-(2-fluoro-4-biphenylyl)propionic acid. Flurbiprofen is a white or slightly yellow crystalline powder. It is slightly soluble in water at pH 7.0 and readily soluble in most polar solvents. Its structural formula is:

C₁₅H₁₃FO_2, M.W. 244.26

Each tablet, for oral administration, contains 100 mg flurbiprofen. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, titanium dioxide and FD&C Blue #1 aluminum lake.

Flurbiprofen is a nonsteroidal anti-inflammatory agent which has shown anti-inflammatory, analgesic, and antipyretic properties in pharmacologic studies. As with other such drugs, its mode of action is not known. However, it is a potent prostaglandin synthesis inhibitor, and this property may be involved in its anti-inflammatory effect.

Flurbiprofen is well absorbed after oral administration, reaching peak blood levels in approximately 1.5 hours (range 0.5 to 4 hours). Administration with food alters the rate of absorption but does not affect the extent of drug availability. The elimination half-life is approximately 6 hours with 90% of the half-life values from 3 to 9 hours. Individual half-life values ranged from 2.8 to 12 hours. There is no evidence of drug accumulation and flurbiprofen does not induce enzymes that alter its metabolism. Excretion of flurbiprofen is 88% to 98% complete 24 hours after the last dose.

Flurbiprofen is extensively metabolized and excreted primarily in the urine, about 20% as free and conjugated drug and about 50% as hydroxylated metabolites. About 90% of the flurbiprofen in urine is present as conjugates. The major metabolite, 4’-hydroxy-flurbiprofen, has been detected in human plasma, but in animal models of inflammation this metabolite showed little anti-inflammatory activity. Flurbiprofen is more than 99% bound to human serum proteins.

In a reported study the average maximum serum concentration of flurbiprofen, following a 100 mg oral dose of flurbiprofen tablets in normal volunteers (n=184), was 15.2 µg/mL, with 90% of the values between 10 and 22 µg/mL. In geriatric subjects (n=7) between the ages of 58 and 77 years, 100 mg flurbiprofen resulted in an average peak drug level of 18.0 µg/mL and an average elimination half-life of 6.5 hours (range 3-10 hours). In geriatric rheumatoid arthritis patients (n=13) between the ages of 65 and 83 years receiving 100 mg flurbiprofen, the average maximum blood level was 12.7 µg/mL and the average elimination half-life was 5.6 hours (range 4-10 hours).

In a study assessing flurbiprofen pharmacokinetics in end stage renal disease (ESRD), mean urinary recovery of a 100 mg dose was 73% in 48 hours for 9 normal subjects and 17% in 96 hours for 8 ESRD patients undergoing continuous ambulatory peritoneal dialysis. Plasma concentrations of flurbiprofen were about 40% lower in the ESRD patients; the elimination half-life of flurbiprofen was unchanged. Elimination of the 4’-hydroxy-flurbiprofen metabolite was markedly reduced in the ESRD patients. The pharmacokinetics of flurbiprofen in patients with decreased renal function but not ESRD have not been determined.

The pharmacokinetics of flurbiprofen in patients with hepatic disease have not been determined.

The efficacy of flurbiprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis. Using standard assessments of therapeutic response, flurbiprofen (200-300 mg/day) demonstrated effectiveness comparable to aspirin (2000-4000 mg/day), ibuprofen (2400-3200 mg/day), and indomethacin (75-150 mg/day).

In patients with rheumatoid arthritis, flurbiprofen may be used in combination with gold salts or corticosteroids.

Flurbiprofen tablets are indicated for the acute or long-term treatment of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Flurbiprofen tablets are contraindicated in patients who have previously demonstrated hypersensitivity to the product. Flurbiprofen should not be given to patients in whom flurbiprofen, aspirin, or other nonsteroidal anti-inflammatory drugs induce asthma, urticaria, or other allergic-type reactions. Fatal asthmatic reactions have been reported in such patients receiving this type of drug.

Serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with nonsteroidal anti-inflammatory drugs. Although minor upper GI problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with nonsteroidal anti-inflammatory drugs, even in the absence of previous GI tract symptoms. In patients observed in clinical trials of such agents for several months to two years, symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.

Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various nonsteroidal anti-inflammatory agents in causing such reactions. High doses of any such agent probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.

Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.

Flurbiprofen, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Nonsteroidal anti-inflammatory drugs are often essential agents in the management of arthritis, but they also may be commonly employed for conditions which are less serious. Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections) and likely benefits of nonsteroidal anti-inflammatory drug treatment, particularly when the drugs are used for less serious conditions where treatment without such agents may represent an acceptable alternative to both the patient and the physician.

An 80-week study in mice at doses of 2, 5, and 12 mg/kg/day and a 2-year study in rats at doses of 0.5, 2, and 4 mg/kg/day did not show evidence of carcinogenicity at maximum tolerated doses of flurbiprofen.

Flurbiprofen did not impair the fertility of male or female rats treated orally at 2.25 mg/kg/day for 65 days and 16 days, respectively, before mating.

Flurbiprofen’s effects on labor and delivery in women are not known. As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and delayed parturition occurred in rats treated throughout pregnancy. Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use of flurbiprofen during late pregnancy is not recommended.

Concentrations of flurbiprofen in breast milk and plasma of nursing mothers suggested that a nursing infant could receive approximately 0.10 mg flurbiprofen per day in the established milk of a woman taking 200 mg/day. Because of possible adverse effects of prostaglandin-inhibiting drugs on neonates, flurbiprofen is not recommended for use in nursing mothers.

Safety and effectiveness in pediatric patients have not been established.

Adverse reaction information was derived from patients who received flurbiprofen in blinded-controlled and open-label clinical trials, and from worldwide marketing experience and from publications. In the description below, rates of the more common events (greater than 1%) and many of the less common events (less than 1%) represent clinical study results. For rarer events that were derived principally from worldwide marketing experience and the literature (printed in italics), accurate rate estimates are generally impossible.

Of the 4123 patients in premarketing studies, 2954 were treated for at least 1 month, 1448 for at least 3 months, 948 for at least 6 months, 356 for at least 1 year, and 100 for at least 2 years. Of the 4123 patients, 9.4% dropped out of the studies because of an adverse drug reaction, principally involving the gastrointestinal tract (5.8%), central nervous system and special senses (1.4%), skin (0.6%) and genitourinary tract (0.5%).

An asterisk after a reaction identifies reactions which occurred in 3-9% of patients treated with flurbiprofen. Reactions occurring in 1-3% of the patients are unmarked.

Gastrointestinal: Dyspepsia*, diarrhea*, abdominal pain*, nausea*, constipation, GI bleeding, flatulence, elevated liver enzymes, and vomiting.

Central Nervous System: Headache*, nervousness, and other manifestations of CNS “stimulation” (e.g., anxiety, insomnia, reflexes increased, and tremor), and symptoms associated with CNS “inhibition” (e.g., amnesia, asthenia, somnolence, malaise, and depression).

Respiratory: Rhinitis.

Dermatological: Rash.

Special Senses: Dizziness, tinnitus, and changes in vision.

Genitourinary: Signs and symptoms suggesting urinary tract infection*.

Body as a Whole: Edema*.

Metabolic/Nutritional: Body weight changes.

The reactions uled in this category occurred in <1% of patients in the clinical trials or were reported during postmarketing experience from other countries. Adverse reactions reported only in worldwide postmarketing experience or the literature (which presumably indicates that they are rarer) are italicized.

Gastrointestinal: Peptic ulcer disease (see also WARNINGS, Risk of Gastrointestinal (GI) Ulcerations, Bleeding and Perforation with Nonsteroidal Anti-inflammatory Therapy), gastritis, bloody diarrhea, stomatitis, esophageal disease, hematemesis, and hepatitis; cholestatic and non-cholestatic jaundice.

Central Nervous System: Ataxia, cerebrovascular ischemia, confusion, paresthesia, and twitching.

Hematologic: Decrease in hemoglobin and hematocrit, iron deficiency anemia, hemolytic anemia and aplastic anemia; leukopenia; eosinophilia; ecchymosis and thrombocytopenia. (See also PRECAUTIONS, Effect on Platelets and Coagulation.)

Respiratory: Asthma and epistaxis.

Dermatological: Angioedema, urticaria, eczema, and pruritus; photosensitivity, toxic epidermal necrolysis, and exfoliative dermatitis.

Special Senses: Conjunctivitis and parosmia.

Genitourinary: Hematuria and renal failure; interstitial nephritis.

Body as a Whole: Chills and fever; anaphylactic reaction.

Metabolic/Nutritional: Hyperuricemia.

Cardiovascular: Heart failure, hypertension, vascular diseases and vasodilation.

The following reactions have been reported in patients taking flurbiprofen under circumstances that do not permit a clear attribution of the reaction to flurbiprofen. These reactions are being included as alerting information for physicians. Adverse reactions reported only in worldwide postmarketing experience or the literature (which presumably indicates that they are rarer) are italicized.

Gastrointestinal: Periodontal abscess, appetite changes, cholecystitis, and dry mouth.

Central Nervous System: Convulsion, meningitis, hypertonia, cerebrovascular accident, emotional lability, and subarachnoid hemorrhage.

Hematologic: Lymphadenopathy.

Respiratory: Bronchitis, laryngitis, dyspnea, pulmonary embolism, pulmonary infarct, and hyperventilation.

Dermatological: Alopecia, nail disorder, herpes simplex, zoster, dry skin, and sweating.

Special Senses: Ear disease, corneal opacity, glaucoma, retrobulbar neuritis, changes in taste, and transient hearing loss; retinal hemorrhage.

Genitourinary: Menstrual disturbances, vaginal and uterine hemorrhage, vulvovaginitis, and

prostate disease.

Metabolic/Nutritional: Hyperkalemia.

Cardiovascular: Arrhythmias, angina pectoris, and myocardial infarction.

Musculoskeletal: Myasthenia.

No drug abuse or drug dependence has been observed with flurbiprofen.

Information on overdosage is available for 13 children and 12 adults. Nine of the 13 children were less than 6 years old. Drowsiness occurred after doses of 150 to 800 mg in 3 of these young children (with dilated pupils in 1), and in a 2-year-old who also had semiconsciousness, pinpoint pupils, diminished tone, and elevated liver enzymes. Other children who ingested doses of 200 mg to 2.5 g showed no symptoms.

Among the adults, a 70-year-old man with a history of chronic obstructive airway disease died. Toxicological analysis showed acute flurbiprofen overdose and a blood ethanol concentration of 100 mg/dL. In the other cases, symptoms were as follows: coma and respiratory depression after 3-6 g; drowsiness, nausea and epigastric pain after 2.5-5 g; epigastric pain and dizziness after 3 g; headache and nausea after ≤ 2 g; agitation after 1.5 g; and drowsiness after 1.0 g. One patient, who took 200-400 mg flurbiprofen and 2.4 g fenoprofen, had disorientation and diplopia. Three adults had no symptoms after 3-5 g flurbiprofen.

Treatment of an overdose: the stomach should be emptied by vomiting or lavage, though little drug will likely be recovered if more than an hour has elapsed since ingestion. Supportive treatment should be instituted as necessary. Some patients have been given supplemental oral or intravenous fluids and required no other treatment.

In mice, the flurbiprofen LD₅₀ was 750 mg/kg when administered orally and 200 mg/kg when administered intraperitoneally. The primary signs of toxicity were prostration, ataxia, loss of righting reflex, labored respiration, twitches, convulsions, CNS depression, and splayed hind limbs. In rats, the flurbiprofen LD₅₀ was 160 mg/kg when administered orally and 400 mg/kg when administered intraperitoneally. The primary signs of toxicity were tremors, convulsions, labored respiration, and prostration. These were observed mostly in the intraperitoneal studies.

Flurbiprofen is administered orally.

Rheumatoid arthritis and osteoarthritis: Recommended starting dose is 200 to 300 mg total daily dose administered BID, TID, or QID. (Most experience in rheumatoid arthritis has been with TID or QID dosage.) The largest recommended single dose in a multiple-dose daily regimen is 100 mg. The dose should be tailored to each patient according to the severity of the symptoms and the response to therapy.

Although a few patients have received higher doses, doses above 300 mg per day are not recommended until more clinical experience with flurbiprofen is obtained.

Flurbiprofen Tablets USP, 100 mg are round, blue, film-coated tablets debossed “93”-“711” available in bottles of 100 and 500.

Store at controlled room temperature, between 20° and 25°C (68° and 77°F) (see USP).

Dispense spans in a well-closed container as defined in the USP/NF, with a child-resistant closure (as required).

Manufactured By:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. E 6/2003