Ansaid

ANSAID (flurbiprofen) Tablets are available as follows:

50 mg: white, oval, film-coated, imprinted ANSAID (flurbiprofen) 50 mg

Bottles of 2000 NDC 0009-0170-24

100 mg: blue, oval, film-coated, imprinted ANSAID (flurbiprofen) 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) .

Distributed by: Pharmacia & Upjohn Company, Division of Pfizer Inc, NY, NY 10017. Revised July 2010

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

ANSAID (flurbiprofen) 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 (flurbiprofen) and other treatment options before deciding to use ANSAID (flurbiprofen). 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 (flurbiprofen) , 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 (flurbiprofen) 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 (flurbiprofen) Tablets are contraindicated in patients with known hypersensitivity to flurbiprofen. ANSAID (flurbiprofen) 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 (flurbiprofen) is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

WARNINGS

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 (flurbiprofen) , 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 (flurbiprofen) , 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 (flurbiprofen) should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including ANSAID (flurbiprofen) , 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 gastrointestinal 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 antiinflammatory 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 (flurbiprofen) is not recommended in these patients with advanced renal disease. If ANSAID (flurbiprofen) 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 (flurbiprofen). ANSAID (flurbiprofen) 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 (flurbiprofen) , can cause serious skin adverse events such as exfoliative dermatitis, Steven-Johnson Syndrom (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 (flurbiprofen) should be avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS

General

ANSAID (flurbiprofen) 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 (flurbiprofen) 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 (flurbiprofen). 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 (flurbiprofen). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), ANSAID (flurbiprofen) should be discontinued.

Hematological effects

Anemia is sometimes seen in patients receiving nonsteroidal anti-inflammatory drugs, including ANSAID (flurbiprofen). 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 (flurbiprofen) , 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 (flurbiprofen) does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving ANSAID (flurbiprofen) 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 (flurbiprofen) 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 (flurbiprofen) and other nonsteroidal anti-inflammatory drugs. Patients experiencing eye complaints should have ophthalmologic examinations.

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 (flurbiprofen) 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 (flurbiprofen) 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 (flurbiprofen) 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 (flurbiprofen) 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 (flurbiprofen) 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 (flurbiprofen) was reduced in elderly patients who also received antacids, although the extent of absorption was not affected (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

SIDE EFFECTS

TABLE 2: Reported adverse events in patients receiving ANSAID (flurbiprofen) or other nonsteroidal anti-inflammatory drugs

DRUG INTERACTIONS

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 antiinflammatory drugs concomitantly with ACE-inhibitors.

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 (flurbiprofen) 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 (flurbiprofen) 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 anti-inflammatory drugs are administered concomitantly with methotrexate.

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

PRECAUTIONS

TABLE 2: Reported adverse events in patients receiving ANSAID (flurbiprofen) or other nonsteroidal anti-inflammatory drugs

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

Absorption

The mean oral bioavailability of flurbiprofen from ANSAID (flurbiprofen) Tablets 100 mg is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from ANSAID (flurbiprofen) , with peak plasma concentrations occurring at about 2 hours (see Table 1). Administration of ANSAID (flurbiprofen) 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 (flurbiprofen).

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'-methoxyflurbiprofen, 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 P4502C9 (CYP2C9) plays an important role in the metabolism of flurbiprofen to its major metabolite 4'-hydroxy-flurbiprofen (see Special Populations). The 4'hydroxy-flurbiprofen metabolite showed little anti-inflammatory activity in animal models of inflammation. In vitro studies also demonstrated glucuronidation of both enantiomers of flurbiprofen and 4'-hydroxy-flurbiprofen. UGT2B7 is the predominant UGT isozyme responsible for the glucuronidation. 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 flurbiprofen, 4'-hydroxy-flurbiprofen, and their acyl-glucuronide conjugates. 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 (t½) 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 (flurbiprofen).

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