ANSAID Tablets contain flurbiprofen, which is a member of the phenylalkanoic acid derivative group of nonsteroidal antiinflammatory drugs. ANSAID Tablets are white, oval, filmcoated tablets for oral administration. Flurbiprofen is a racemic mixture of (+)S- and (-)R- enantiomers. 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. The chemical name is [1,1'-biphenyl]-4-acetic acid, 2-fluoro-alpha-methyl-, (±)-. The molecular weight is 244.26. Its molecular formula is C₁₅H₁₃FO₂ and it has the following structural formula:

The inactive ingredients in ANSAID (both strengths) include carnauba wax, colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, and titanium dioxide. In addition, the 100 mg tablet contains FD&C Blue No. 2.

Carefully consider the potential benefits and risks of ANSAID and other treatment options before deciding to use ANSAID. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). ANSAID is indicated:

• For relief of the signs and symptoms of rheumatoid arthritis.
• For relief of the signs and symptoms of osteoarthritis.

Carefully consider the potential benefits and risks of ANSAID and other treatment options before deciding to use ANSAID. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with ANSAID, the dose and frequency should be adjusted to suit an individual patient's needs.

For relief of the signs and symptoms of rheumatoid arthritis or osteoarthritis, the recommended starting dose of ANSAID is 200 to 300 mg per day, divided for administration two, three, or four times a day. The largest recommended single dose in a multiple-dose daily regimen is 100 mg.

ANSAID Tablets are available as follows:

50 mg: white, oval, film-coated, imprinted ANSAID 50 mg

Bottles of 2000............................NDC 0009-0170-24

100 mg: blue, oval, film-coated, imprinted ANSAID 100 mg

Bottles of 100............................NDC 0009-0305-03
Bottles of 2000..........................NDC 0009-0305-30

Store at controlled room temperature 20° to 25°C (68° to 77°F)

[see USP].

Pharmacia & Upjohn Company Division of Pfizer Inc, NY, NY 10017. Revised January 2007. FDA Rev date: 6/21/2007

TABLE 2. Reported adverse events in patients receiving ANSAID or other nonsteroidal anti-inflammatory drugs

ACE-inhibitors

Reports suggest that nonsteroidal anti-inflammatory drugs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking nonsteroidal anti-inflammatory drugs concomitantly with ACEinhibitors.

Anticoagulants

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. The physician should be cautious when administering ANSAID to patients taking warfarin or other anticoagulants.

Aspirin

Concurrent administration of aspirin lowers serum flurbiprofen concentrations (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of flurbiprofen and aspirin is not generally recommended because of the potential for increased adverse effects.

Beta-adrenergic blocking agents

Flurbiprofen attenuated the hypotensive effect of propranolol but not atenolol (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). The mechanism underlying this interference is unknown. Patients taking both flurbiprofen and a beta-blocker should be monitored to ensure that a satisfactory hypotensive effect is achieved.

Diuretics

Clinical studies, as well as post marketing observations, have shown that ANSAID can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.

These effects have been attributed to inhibition of renal prostaglandin synthesis by the nonsteroidal anti-inflammatory drug. Thus, when nonsteroidal anti-inflammatory drugs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate:

Nonsteroidal anti-inflammatory drugs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when nonsteroidal antiinflammatory drugs are administered concomitantly with methotrexate.

Cardiovascular Effects

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs including ANSAID, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ANSAID, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. ANSAID should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including ANSAID, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gas- trointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

In clinical studies, the elimination half-life of flurbiprofen was unchanged in patients with renal impairment. Flurbiprofen metabolites are eliminated primarily by the kidneys. Elimination of 4'-hydroxy-flurbiprofen was reduced in patients with moderate to severe renal impairment. Therefore, treatment with ANSAID is not recommended in these patients with advanced renal disease. If ANSAID therapy must be initiated, close monitoring of the patients renal function is advisable (see CLINICAL PHARMACOLOGY).

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ANSAID. ANSAID should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including ANSAID, can cause serious skin adverse events such as exfoliative dermatitis, Steven-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, ANSAID should be avoided because it may cause premature closure of the ductus arteriosus.

General

ANSAID cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of ANSAID in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking nonsteroidal anti-inflammatory drugs, including ANSAID. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with nonsteroidal anti-inflammatory drugs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ANSAID. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), ANSAID should be discontinued.

Hematological effects

Anemia is sometimes seen in patients receiving nonsteroidal anti-inflammatory drugs, including ANSAID. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with nonsteroidal anti-inflammatory drugs, including ANSAID, should have their hemoglobin or hematocrit checked periodically even if they do not exhibit any signs or symptoms of anemia.

Nonsteroidal anti-inflammatory drugs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. ANSAID does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving ANSAID who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, ANSAID should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Vision changes

Blurred and/or diminished vision has been reported with the use of ANSAID and other nonsteroidal anti-inflammatory drugs. Patients experiencing eye complaints should have ophthalmologic examinations.

Information For Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

• ANSAID, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, CARDIOVASCULAR EFFECTS).
• ANSAID, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation).
• ANSAID, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
• Patients should promptly report, signs or symptoms of unexplained weight gain, or edema to their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactoid Reactions).
• In late pregnancy, as with other NSAIDs, ANSAID should be avoided because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs of symptoms of GI bleeding. Patients on long-term treatment with nonsteroidal anti-inflammatory drugs should have their CBC and chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash etc.), or abnormal liver tests persist or worsen, ANSAID should be discontinued.

Pregnancy

Teratogenic effects: Pregnancy Category C

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. ANSAID should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic effects

Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

Labor and Delivery

In rat studies with nonsteroidal anti-inflammatory drugs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of ANSAID on labor and delivery in pregnant women are unknown.

Nursing Mothers

Concentrations of flurbiprofen in breast milk and plasma of nursing mothers suggest that a nursing infant could receive approximately 0.10 mg flurbiprofen per day in the established milk of a woman taking ANSAID 200 mg/day. Because of possible adverse effects of prostaglandin-inhibiting drugs on neonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

As with any NSAID, caution should be exercised in treating the elderly (65 years and older).

Clinical experience with ANSAID suggests that elderly patients may have a higher incidence of gastrointestinal complaints than younger patients, including ulceration, bleeding, flatulence, bloating, and abdominal pain. To minimize the potential risk for gastrointestinal events, the lowest effective dose should be used for the shortest possible duration (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation). Likewise, elderly patients are at greater risk of developing renal decompensation (see WARNINGS, Renal Effects).

The pharmacokinetics of flurbiprofen do not seem to differ in elderly patients from those in younger individuals (see CLINICAL PHARMACOLOGY, Special Populations). The rate of absorption of ANSAID was reduced in elderly patients who also received antacids, although the extent of absorption was not affected (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

Symptoms following acute overdoses with nonsteroidal antiinflammatory drugs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of nonsteroidal antiinflammatory drugs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following overdose with a nonsteroidal anti-inflammatory drug. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms, or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

ANSAID Tablets are contraindicated in patients with known hypersensitivity to flurbiprofen.

ANSAID should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nonsteroidal anti-inflammatory drugs. Severe, rarely fatal, anaphylactic-like reactions to nonsteroidal anti-inflammatory drugs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma).

ANSAID is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Pharmacodynamics

ANSAID Tablets contain flurbiprofen, a nonsteroidal antiinflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of ANSAID, like that of other nonsteroidal antiinflammatory drugs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Absorption: The mean oral bioavailability of flurbiprofen from ANSAID Tablets 100 mg is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from ANSAID, with peak plasma concentrations occurring at about 2 hours (see Table 1). Administration of ANSAID with either food or antacids may alter the rate but not the extent of flurbiprofen absorption. Ranitidine has been shown to have no effect on either the rate or extent of flurbiprofen absorption from ANSAID.

Distribution:The apparent volume of distribution (Vz/F) of both R- and S-flurbiprofen is approximately 0.12 L/Kg. Both flurbiprofen enantiomers are more than 99% bound to plasma proteins, primarily albumin. Plasma protein binding is relatively constant for the typical average steady-state concentrations ( ≤ 10 µg/mL) achieved with recommended doses. Flurbiprofen is poorly excreted into human milk. The nursing infant dose is predicted to be approximately 0.1 mg/day in the established milk of a woman taking ANSAID 200 mg/day (see PRECAUTIONS, Nursing Mothers).

Metabolism: Several flurbiprofen metabolites have been identified in human plasma and urine. These metabolites include 4'-hydroxy-flurbiprofen, 3', 4'-dihydroxy-flurbiprofen, 3'-hydroxy- 4'-methoxy-flurbiprofen, their conjugates, and conjugated flurbiprofen. Unlike other arylpropionic acid derivatives (eg, ibuprofen), metabolism of R-flurbiprofen to S-flurbiprofen is minimal. In vitro studies have demonstrated that cytochrome P450 2C9 plays an important role in the metabolism of flurbiprofen to its major metabolite, 4'-hydroxy-flurbiprofen. The 4'-hydroxy-flurbiprofen metabolite showed little antiinflammatory activity in animal models of inflammation. Flurbiprofen does not induce enzymes that alter its metabolism.

The total plasma clearance of unbound flurbiprofen is not stereoselective, and clearance of flurbiprofen is independent of dose when used within the therapeutic range.

Excretion: Following dosing with ANSAID, less than 3% of flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as parent drug and metabolites. Because renal elimination is a significant pathway of elimination of flurbiprofen metabolites, dosing adjustment in patients with moderate or severe renal dysfunction may be necessary to avoid accumulation of flurbiprofen metabolites. The mean terminal disposition half-lives (t 1/2) of R- and S-flurbiprofen are similar, about 4.7 and 5.7 hours, respectively. There is little accumulation of flurbiprofen following multiple doses of ANSAID.

Table 1. Mean (SD) R,S-Flurbiprofen Pharmacokinetic Parameters Normalized to a 100 mg Dose of ANSAID

Special Populations

Pediatric: The pharmacokinetics of flurbiprofen have not been investigated in pediatric patients.

Race: No pharmacokinetic differences due to race have been identified.

Geriatric: Flurbiprofen pharmacokinetics were similar in geriatric arthritis patients, younger arthritis patients, and young healthy volunteers receiving ANSAID Tablets 100 mg as either single or multiple doses.

Hepatic insufficiency: Hepatic metabolism may account for > 90% of flurbiprofen elimination, so patients with hepatic disease may require reduced doses of ANSAID Tablets compared to patients with normal hepatic function. The pharmacokinetics of R- and S-flurbiprofen were similar, however, in alcoholic cirrhosis patients (N=8) and young healthy volunteers (N=8) following administration of a single 200 mg dose of ANSAID tablets.

Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1 g/dL (see PRECAUTIONS, Hepatic Effects).

Renal insufficiency: Renal clearance is an important route of elimination for flurbiprofen metabolites, but a minor route of elimination for unchanged flurbiprofen ( ≤ 3% of total clearance). The unbound clearances of R- and S-flurbiprofen did not differ significantly between normal healthy volunteers (N=6, 50 mg single dose) and patients with renal impairment (N=8, inulin clearances ranging from 11 to 43 mL/min, 50 mg multiple doses). Flurbiprofen plasma protein binding may be decreased in patients with renal impairment and serum albumin concentrations below 3.9 g/dL. Elimination of flurbiprofen metabolites may be reduced in patients with renal impairment (see WARNINGS, Renal Effects).

Flurbiprofen is not significantly removed from the blood into dialysate in patients undergoing continuous ambulatory peritoneal dialysis.

Drug-Drug Interactions

(see also PRECAUTIONS: DRUG INTERACTIONS)

Antacids: Administration of ANSAID to volunteers under fasting conditions or with antacid suspension yielded similar serum flurbiprofen-time profiles in young adult subjects (n=12). In geriatric subjects (n=7), there was a reduction in the rate but not the extent of flurbiprofen absorption.

Aspirin: Concurrent administration of ANSAID and aspirin resulted in 50% lower serum flurbiprofen concentrations. This effect of aspirin (which is also seen with other nonsteroidal anti- inflammatory drugs) has been demonstrated in patients with rheumatoid arthritis (n=15) and in healthy volunteers (n=16) (see PRECAUTIONS: DRUG INTERACTIONS).

Beta-adrenergic blocking agents: The effect of flurbiprofen on blood pressure response to propranolol and atenolol was evaluated in men with mild uncomplicated hypertension (n=10). Flurbiprofen pretreatment attenuated the hypotensive effect of a single dose of propranolol but not atenolol. Flurbiprofen did not appear to affect the beta-blocker-mediated reduction in heart rate. Flurbiprofen did not affect the pharmacokinetic profile of either drug (see PRECAUTIONS: DRUG INTERACTIONS).

Cimetidine, Ranitidine: I n normal volunteers (n=9), pretreatment with cimetidine or ranitidine did not affect flurbiprofen pharmacokinetics, except for a small (13%) but statistically significant increase in the area under the serum concentration curve of flurbiprofen in subjects who received cimetidine.

Digoxin: In studies of healthy males (n=14), concomitant administration of flurbiprofen and digoxin did not change the steady state serum levels of either drug.

Diuretics: Studies in healthy volunteers have shown that, like other nonsteroidal anti-inflammatory drugs, flurbiprofen can interfere with the effects of furosemide. Although results have varied from study to study, effects have been shown on furosemide-stimulated diuresis, natriuresis, and kaliuresis. Other nonsteroidal anti-inflammatory drugs that inhibit prostaglandin synthesis have been shown to interfere with thiazide and potassium-sparing diuretics (see PRECAUTIONS: DRUG INTERACTIONS).

Lithium: In a study of 11 women with bipolar disorder receiving lithium carbonate at a dosage of 600 to 1200 mg/day, administration of 100 mg ANSAID every 12 hours increased plasma lithium concentrations by 19%. Four of 11 patients experienced a clinically important increase ( > 25% or > 0.2 mmol/L). Nonsteroidal antiinflammatory drugs have also been reported to decrease the renal clearance of lithium by about 20% (see PRECAUTIONS: DRUG INTERACTIONS).

Methotrexate: In a study of six adult arthritis patients, coadministration of methotrexate (10 to 25 mg/dose) and ANSAID (300 mg/day) resulted in no observable interaction between these two drugs.

Oral Hypoglycemic Agents: In a clinical study, flurbiprofen was administered to adult diabetics who were already receiving glyburide (n=4), metformin (n=2), chlorpropamide with phenformin (n=3), or glyburide with phenformin (n=6). Although there was a slight reduction in blood sugar concentrations during concomitant administration of flurbiprofen and hypoglycemic agents, there were no signs or symptoms of hypoglycemia.

Ansaid
(flurbiprofen tablets, USP)

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-Steroidal AntiInflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called "corticosteroids" and "anticoagulants"
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include:

• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma

Other side effects include:

• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• skin rash or blisters with fever
• unusual weight gain
• swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over -the -counter). Talk to your healthcare provider before using over -the -counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

This Medication Guide has been approved by the U.S. Food and Drug Administration.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

FLURBIPROFEN - ORAL

(flure-BEE-proe-fen)

COMMON BRAND NAME(S): Ansaid

WARNING: This drug may infrequently cause serious (rarely fatal) bleeding from the stomach or intestines. Also, related drugs rarely have caused blood clots to form, resulting in heart attacks and strokes. This medication might also rarely cause similar problems. Talk to your doctor or pharmacist about the benefits and risks of treatment, as well as other possible medication choices.

If you notice any of the following rare but very serious side effects, stop taking flurbiprofen and seek immediate medical attention: black stools, persistent stomach/abdominal pain, vomit that looks like coffee grounds, chest pain, weakness on one side of the body, sudden vision changes, slurred speech.

USES: Flurbiprofen is used to reduce pain, swelling, and joint stiffness from arthritis. This medication is known as a nonsteroidal anti-inflammatory drug (NSAID).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat arthritis of the spine.

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using flurbiprofen and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth with a full glass of water (8 ounces or 240 milliliters), unless your doctor directs you otherwise. Do not lie down for at least 30 minutes after taking this drug. If stomach upset occurs while taking this medication, take it with food, milk, or an antacid.

Dosage is based on your medical condition and response to therapy. Do not increase your dose or take it more frequently than recommended because this may increase your risk of stomach bleeding. Do not take more than 100 milligrams as a single dose.

It may take up to 2 weeks before the full benefits take effect when this drug is taken regularly.

Inform your doctor if your condition worsens.

SIDE EFFECTS: See also Warning section.

Upset stomach, constipation, diarrhea, gas, heartburn, nausea, vomiting, dizziness, drowsiness, fatigue, or headache may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: stomach pain, swelling of the hands or feet, sudden or unexplained weight gain, vision changes, hearing changes (e.g., ringing in the ears), mental/mood changes, fast/pounding heartbeat, persistent/severe headache, fainting, difficult/painful swallowing.

Tell your doctor immediately if any of these rare but very serious side effects occur: change in the amount of urine, easy bruising or bleeding, signs of infection (e.g., fever, persistent sore throat), unexplained stiff neck, slurred speech.

This drug may rarely cause serious (possibly fatal) liver disease. If you notice any of the following highly unlikely but very serious side effects, stop taking flurbiprofen and consult your doctor or pharmacist immediately: yellowing eyes or skin, dark urine, unusual/extreme tiredness, severe stomach/abdominal pain, persistent nausea/vomiting.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking flurbiprofen, tell your doctor or pharmacist if you are allergic to it; or to aspirin or other NSAIDs (e.g., ibuprofen, naproxen, celecoxib); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: aspirin-sensitive asthma (a history of worsening breathing with runny/stuffy nose after taking aspirin or other NSAIDs), recent heart bypass surgery (CABG).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, poorly controlled diabetes, stomach/intestine/esophagus problems (e.g., bleeding, ulcers, recurring heartburn), heart disease (e.g., congestive heart failure, history of heart attack), stroke, high blood pressure, swelling (edema, fluid retention), dehydration, blood disorders (e.g., anemia), bleeding or clotting problems, asthma, growths in the nose (nasal polyps).

Before having surgery, tell your doctor or dentist that you are taking this medication.

This drug may make you dizzy or drowsy; use caution engaging in activities requiring alertness such as driving or using machinery.

This medicine may cause stomach bleeding. Daily use of alcohol and tobacco, especially when combined with this medicine, may increase your risk for stomach bleeding. Limit alcohol and stop smoking. Consult your doctor or pharmacist for more information.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths or sunlamps. Use a sunscreen and wear protective clothing when outdoors.

Caution is advised when using this drug in the elderly because they may be more sensitive to its side effects, especially stomach bleeding and kidney effects.

This medication should be used only when clearly needed during the first 6 months of pregnancy. It is not recommended for use during the last 3 months of pregnancy due to possible harm to an unborn baby and interference with normal labor/delivery. Discuss the risks and benefits with your doctor.

This medication passes into breast milk and may have undesirable effects on a nursing infant. Therefore, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: cidofovir, ketorolac.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting flurbiprofen.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anti-platelet drugs (e.g., cilostazol, clopidogrel), oral bisphosphonates (e.g., alendronate), "blood thinners" (e.g., enoxaparin, heparin, warfarin), corticosteroids (e.g., prednisone), cyclosporine, desmopressin, high blood pressure drugs (including ACE inhibitors such as captopril, angiotensin II receptor antagonists such as losartan, and beta-blockers such as metoprolol), lithium, methotrexate, pemetrexed, probenecid, SSRI antidepressants (e.g., fluoxetine, sertraline), "water pills" (diuretics such as furosemide, hydrochlorothiazide, triamterene).

Check all prescription and nonprescription medicine labels carefully for other pain/fever drugs (NSAIDs such as aspirin, celecoxib, ibuprofen). These drugs are similar to this medication, so taking one of these drugs while also taking this medication may increase your risk of side effects. However, if your doctor has prescribed low doses of aspirin to prevent heart attack or stroke (usually at dosages of 81-325 milligrams a day), you should continue to take the aspirin. Daily use of NSAIDs (e.g., ibuprofen) may decrease aspirin's ability to prevent heart attack/stroke. Consult your doctor or pharmacist for more details and to discuss other possible treatments (e.g., acetaminophen) for your pain/fever.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: severe stomach pain, vomit that looks like coffee grounds, extreme drowsiness, loss of consciousness, slowed or shallow breathing.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood counts, liver and kidney function tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Non-drug treatment for arthritis as approved by your doctor (e.g., weight loss if needed, strengthening and conditioning exercises) may help improve your flexibility, range of motion, and joint function. Consult your doctor for specific instructions.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.