WARNINGS

Serious Skin Reactions :Serious skin reactions,including exfoliative dermatitis,Stevens-Johnson syndrome,and toxic epidermal necrolysis,have been reported through postmarketing surveillance in patients receiving BEXTRA (see ADVERSE REACTIONS-Postmarketing Experience).As these reactions can be life threatening,BEXTRA should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Gastrointestinal (GI) Effects—Risk of GI Ulceration, Bleeding, and Perforation

Serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine can occur at any time with or without warning symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs).Minor gastrointestinal problems such as dyspepsia are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding even in the absence of previous GI tract symptoms. Patients should be informed about the signs and symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation caused by NSAIDs appear to occur in approximately 1% of patients treated for 3 to 6months and 2-4% of patients treated for one year. These trends continue, thus 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 patients with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corti-costeroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status.(See CLINICAL STUDIES—Safety Studies.)

Anaphylactoid Reactions

Anaphylactoid reactions were not reported in patients receiving BEXTRA in clinical trials. However, as with NSAIDs in general, ana-phylactoid reactions may occur in patients without known prior exposure to BEXTRA.BEXTRA 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.

Anaphylactoid Reactions :In postmarketing experience,cases of hypersensitivity reactions (anaphylactic reactions and angioedema)have been reported in patients receiving BEXTRA (see ADVERSE REACTIONS- Postmarketing Experience).These cases have occurred in patients with and without a history of allergic-type reactions to sulfonamides (see CONTRAINDICATIONS).

Advanced Renal Disease

No information is available regarding the safe use of BEXTRA Tablets in patients with advanced kidney disease. Therefore, treat-ment with BEXTRA is not recommended in these patients. If therapy with BEXTRA must be initiated, close monitoring of the patient’s kidney function is advisable (see

PRECAUTIONS

—Renal Effects).

Pregnancy

In late pregnancy, BEXTRA should be avoided because it may cause premature closure of the ductus arteriosus.


PRECAUTIONS

General

BEXTRA Tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of cor-ticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corti-costeroids.

The pharmacological activity of valdecoxib 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 NSAIDs. 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 NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may remain transient with continuing ther-apy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs. In controlled clinical trials of valdecoxib, the incidence of borderline (defined as 1.2-to 3.0-fold) elevations of liver tests was 8.0% for valdecoxib and 8.4% for placebo, while approximately 0.3% of patients taking valdecoxib, and 0.2% of patients taking placebo, had notable (defined as greater than 3-fold) elevations of ALT or AST.

A patient with symptoms and/or signs suggesting liver dysfunc-tion, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with BEXTRA. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g.,eosinophilia, rash),BEXTRA should be discontinued.

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, adminis-tration 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 decompen-sation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and Angiotensin Converting Enzyme (ACE) inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Caution should be used when initiating treatment with BEXTRA in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with BEXTRA. Caution is also recommended in patients with preexisting kidney disease.(See

WARNINGS

—Advanced Renal Disease.)

Hematological Effects

Anemia is sometimes seen in patients receiving BEXTRA. Patients on long-term treatment with BEXTRA should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

BEXTRA does not generally affect platelet counts, prothrombin time (PT),or activated partial thromboplastin time (APTT),and does not appear to inhibit platelet aggregation at indicated dosages (see CLINICAL STUDIES—Safety Studies—Platelets).

Fluid Retention and Edema

Fluid retention and edema have been observed in some patients taking BEXTRA (see ADVERSE REACTIONS).Therefore, BEXTRA should be used with caution in patients with fluid retention, hypertension, or heart failure.

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 reac-tivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, BEXTRA should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients

BEXTRA can cause GI discomfort and, rarely, more serious GI side effects, which may result in hospitalization and even fatal out-comes. 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. Patients should be apprised of the importance of this follow-up (see

WARNINGS

—Gastrointestinal (GI) Effects—Risk of GI Ulceration, Bleeding, and Perforation).

Patients should report to their physicians, signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, weight gain, or edema.

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 attention.

Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see

WARNINGS

—Anaphylactoid Reactions).

In late pregnancy, BEXTRA 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 and symptoms of GI bleeding.