FDA label 59af839a-c08a-44aa-a1dc-9dc43c019459

Serious Skin Reactions Serious skin reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) have been reported in patients receiving BEXTRA. Some of these reactions have resulted in death. Patients appear to be at higher risk for these events within the first 2 weeks of treatment, but these may occur at any time during treatment. The reported rate of these serious skin events appears to be greater for BEXTRA as compared to other COX-2 agents. BEXTRA should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. (See WARNINGS – Serious Skin Reactions)

WARNINGS 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 6 months 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 corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status. (See CLINICAL STUDIES — Safety Studies .) Serious Skin Reactions Valdecoxib contains a sulfonamide moiety and patients with a known history of a sulfonamide allergy may be at a greater risk of skin reactions. Patients without a history of sulfonamide allergy may also be at risk for serious skin reactions. Serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving BEXTRA (see ADVERSE REACTIONS — Postmarketing Experience ). Fatalities due to Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Patients appear to be at higher risk for these events early in the course of therapy, with the onset of the event occurring in the majority of cases within the first two weeks of treatment. BEXTRA should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Serious skin reactions have been reported with other COX-2 inhibitors during postmarketing experience. The reported rate of these events appears to be greater for BEXTRA as compared to other COX-2 agents (see Boxed Warning — Serious Skin Reactions) . 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 ). 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. Coronary Artery Bypass Graft Surgery Patients treated with BEXTRA for pain following coronary artery bypass graft surgery have a higher risk for cardiovascular/thromboembolic events, deep surgical infections or sternal wound complications. BEXTRA is therefore contraindicated for the treatment of postoperative pain following CABG surgery. (See CONTRAINDICATIONS and CLINICAL STUDIES-Safety Studies ) . Advanced Renal Disease No information is available regarding the safe use of BEXTRA Tablets in patients with advanced kidney disease. Therefore, treatment 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.

ADVERSE REACTIONS Of the patients treated with BEXTRA Tablets in controlled arthritis trials, 2665 were patients with OA, and 2684 were patients with RA. More than 4000 patients have received a chronic total daily dose of BEXTRA 10 mg or more. More than 2800 patients have received BEXTRA 10 mg/day, or more, for at least 6 months and 988 of these have received BEXTRA for at least 1 year. Osteoarthritis and Rheumatoid Arthritis Table 4 lists all adverse events, regardless of causality, that occurred in > 2.0% of patients receiving BEXTRA 10 and 20 mg/day in studies of three months or longer from 7 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Table 4 Adverse Events with Incidence ≥2.0% in Valdecoxib Treatment Groups: Controlled Arthritis Trials of Three Months or Longer (Total Daily Dose) Valdecoxib Diclofenac Ibuprofen Naproxen Adverse Event Number Treated Placebo 973 10 mg 1214 20 mg 1358 150 mg 711 2400 mg 207 1000 mg 766 Autonomic Nervous System Disorders Hypertension 0.6 1.6 2.1 2.5 2.4 1.7 Body as a Whole Back pain 1.6 1.6 2.7 2.8 1.4 1.0 Edema peripheral 0.7 2.4 3.0 3.2 2.9 2.1 Influenza-like symptoms 2.2 2.0 2.2 3.1 2.9 2.0 Injury accidental 2.8 4.0 3.7 3.9 3.9 3.0 Central and Peripheral Nervous System Disorders Dizziness 2.1 2.6 2.7 4.2 3.4 2.7 Headache 7.1 4.8 8.5 6.6 4.3 5.5 Gastrointestinal System Disorders Abdominal fullness 2.0 2.1 1.9 3.0 2.9 2.5 Abdominal pain 6.3 7.0 8.2 17.0 8.2 10.1 Diarrhea 4.2 5.4 6.0 10.8 3.9 4.7 Dyspepsia 6.3 7.9 8.7 13.4 15.0 12.9 Flatulence 4.1 2.9 3.5 3.1 7.7 5.4 Nausea 5.9 7.0 6.3 8.4 7.7 8.7 Musculoskeletal System Disorders Myalgia 1.6 2.0 1.9 2.4 2.4 1.4 Respiratory System Disorders Sinusitis 2.2 2.6 1.8 1.1 3.4 3.4 Upper respiratory tract infection 6.0 6.7 5.7 6.3 4.3 6.4 Skin and Appendages Disorders Rash 1.0 1.4 2.1 1.5 0.5 1.4 In these placebo- and active-controlled clinical trials, the discontinuation rate due to adverse events was 7.5% for arthritis patients receiving valdecoxib 10 mg daily, 7.9% for arthritis patients receiving valdecoxib 20 mg daily and 6.0%for patients receiving placebo. In the seven controlled OA and RA studies, the following adverse events occurred in 0.1–1.9% of patients treated with BEXTRA 10–20 mg daily, regardless of causality. Application site disorders: Cellulitis, dermatitis contact Cardiovascular: Aggravated hypertension, aneurysm, angina pectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disorder, heart murmur, hypotension Central, peripheral nervous system: Cerebrovascular disorder, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, tremor, twitching, vertigo Endocrine: Goiter Female reproductive : Amenorrhea, dysmenorrhea, leukorrhea, mastitis, menstrual disorder, menorrhagia, menstrual bloating, vaginal hemorrhage Gastrointestinal : Abnormal stools, constipation, diverticulosis, dry mouth, duodenal ulcer, duodenitis, eructation, esophagitis, fecal incontinence, gastric ulcer, gastritis, gastroenteritis, gastroesophageal reflux, hematemesis, hematochezia, hemorrhoids, hemorrhoids bleeding, hiatal hernia, melena, stomatitis, stool frequency increased, tenesmus, tooth disorder, vomiting General : Allergy aggravated, allergic reaction, asthenia, chest pain, chills, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, halitosis, malaise, pain, periorbital swelling, peripheral pain Hearing and vestibular: Ear abnormality, earache, tinnitus Heart rate and rhythm: Bradycardia, palpitation, tachycardia Hemic: Anemia Liver and biliary system: Hepatic function abnormal, hepatitis, ALT increased, AST increased Male reproductive: Impotence, prostatic disorder Metabolic and nutritional: Alkaline phosphatase increased, BUN increased, CPK increased, creatinine increased, diabetes mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypocalcemia, hypokalemia, LDH increased, thirst increased, weight decrease, weight increase, xerophthalmia Musculoskeletal: Arthralgia, fracture accidental, neck stiffness, osteoporosis, synovitis, tendonitis Neoplasm: Breast neoplasm, lipoma, malignant ovarian cyst Platelets (bleeding or clotting): Ecchymosis, epistaxis, hematoma NOS, thrombocytopenia Psychiatric: Anorexia, anxiety, appetite increased, confusion, depression, depression aggravated, insomnia, nervousness, morbid dreaming, somnolence Resistance mechanism disorders: Herpes simplex, herpes zoster, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media Respiratory: Abnormal breath sounds, bronchitis, bronchospasm, coughing, dyspnea, emphysema, laryngitis, pneumonia, pharyngitis, pleurisy, rhinitis Skin and appendages: Acne, alopecia, dermatitis, dermatitis fungal, eczema, photosensitivity allergic reaction, pruritus, rash erythematous, rash maculopapular, rash psoriaform, skin dry, skin hypertrophy, skin ulceration, sweating increased, urticaria Special senses: Taste perversion Urinary system: Albuminuria, cystitis, dysuria, hematuria, micturition frequency increased, pyuria, urinary incontinence, urinary tract infection Vascular: Claudication intermittent, hemangioma acquired, varicose vein Vision: Blurred vision, cataract, conjunctival hemorrhage, conjunctivitis, eye pain, keratitis, vision abnormal White cell and RES disorders: Eosinophilia, leukopenia, leukocytosis, lymphadenopathy, lymphangitis, lymphopenia Other serious adverse events that were reported rarely (estimated <0.1%) in clinical trials, regardless of causality, in patients taking BEXTRA: Autonomic nervous system disorders: Hypertensive encephalopathy, vasospasm Cardiovascular: Abnormal ECG, aortic stenosis, atrial fibrillation, carotid stenosis, coronary thrombosis, heart block, heart valve disorders, mitral insufficiency, myocardial infarction, myocardial ischemia, pericarditis, syncope, thrombophlebitis, unstable angina, ventricular fibrillation Central, peripheral nervous system: Convulsions Endocrine: Hyperparathyroidism Female reproductive: Cervical dysplasia Gastrointestinal: Appendicitis, colitis with bleeding, dysphagia, esophageal perforation, gastrointestinal bleeding, ileus, intestinal obstruction, peritonitis Hemic: Lymphoma-like disorder, pancytopenia Liver and biliary system: Cholelithiasis Metabolic: Dehydration Musculoskeletal: Pathological fracture, osteomyelitis Neoplasm: Benign brain neoplasm, bladder carcinoma, carcinoma, gastric carcinoma, prostate carcinoma, pulmonary carcinoma Platelets (bleeding or clotting): Embolism, pulmonary embolism, thrombosis Psychiatric: Manic reaction, psychosis Renal: Acute renal failure Resistance mechanism disorders: Sepsis Respiratory: Apnea, pleural effusion, pulmonary edema, pulmonary fibrosis, pulmonary infarction, pulmonary hemorrhage, respiratory insufficiency Skin: Basal cell carcinoma, malignant melanoma Urinary system: Pyelonephritis, renal calculus Vision: Retinal detachment Postmarketing Experience The following reactions have been identified during postmarketing use of BEXTRA. These reactions have been chosen for inclusion either due to their seriousness, reporting frequency, possible causal relationship to BEXTRA, or a combination of these factors. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General: Hypersensitivity reactions (including anaphylactic reactions and angioedema) Gastrointestinal: Pancreatitis Skin and appendages: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

<table width="75%" ID="ia0cd1ce0-812a-4908-86d3-4d2f3092c15c"> <caption>Table 4 Adverse Events with Incidence &#x2265;2.0% in Valdecoxib Treatment Groups: Controlled Arthritis Trials of Three Months or Longer</caption> <col align="left"/> <col align="center"/> <col align="center"/> <col align="center"/> <col align="center"/> <col align="center"/> <col align="center"/> <thead> <tr> <th colspan="2"> </th> <th colspan="5">(Total Daily Dose)</th> </tr> <tr> <th colspan="2"> </th> <th colspan="2">Valdecoxib </th> <th>Diclofenac</th> <th>Ibuprofen</th> <th>Naproxen</th> </tr> <tr> <th>Adverse Event Number Treated</th> <th>Placebo 973</th> <th>10 mg 1214</th> <th>20 mg 1358</th> <th>150 mg 711</th> <th>2400 mg 207</th> <th>1000 mg 766</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Autonomic Nervous System Disorders</content> </td> </tr> <tr> <td>Hypertension</td> <td>0.6</td> <td>1.6</td> <td>2.1</td> <td>2.5</td> <td>2.4</td> <td>1.7</td> </tr> <tr> <td> <content styleCode="bold">Body as a Whole</content> </td> </tr> <tr> <td>Back pain</td> <td>1.6</td> <td>1.6</td> <td>2.7</td> <td>2.8</td> <td>1.4</td> <td>1.0</td> </tr> <tr> <td>Edema peripheral</td> <td>0.7</td> <td>2.4</td> <td>3.0</td> <td>3.2</td> <td>2.9</td> <td>2.1</td> </tr> <tr> <td>Influenza-like symptoms</td> <td>2.2</td> <td>2.0</td> <td>2.2</td> <td>3.1</td> <td>2.9</td> <td>2.0</td> </tr> <tr> <td>Injury accidental</td> <td>2.8</td> <td>4.0</td> <td>3.7</td> <td>3.9</td> <td>3.9</td> <td>3.0</td> </tr> <tr> <td> <content styleCode="bold">Central and Peripheral Nervous System Disorders</content> </td> </tr> <tr> <td>Dizziness</td> <td>2.1</td> <td>2.6</td> <td>2.7</td> <td>4.2</td> <td>3.4</td> <td>2.7</td> </tr> <tr> <td>Headache</td> <td>7.1</td> <td>4.8</td> <td>8.5</td> <td>6.6</td> <td>4.3</td> <td>5.5</td> </tr> <tr> <td> <content styleCode="bold">Gastrointestinal System Disorders</content> </td> </tr> <tr> <td>Abdominal fullness</td> <td>2.0</td> <td>2.1</td> <td>1.9</td> <td>3.0</td> <td>2.9</td> <td>2.5</td> </tr> <tr> <td>Abdominal pain</td> <td>6.3</td> <td>7.0</td> <td>8.2</td> <td>17.0</td> <td>8.2</td> <td>10.1</td> </tr> <tr> <td>Diarrhea</td> <td>4.2</td> <td>5.4</td> <td>6.0</td> <td>10.8</td> <td>3.9</td> <td>4.7</td> </tr> <tr> <td>Dyspepsia</td> <td>6.3</td> <td>7.9</td> <td>8.7</td> <td>13.4</td> <td>15.0</td> <td>12.9</td> </tr> <tr> <td>Flatulence</td> <td>4.1</td> <td>2.9</td> <td>3.5</td> <td>3.1</td> <td>7.7</td> <td>5.4</td> </tr> <tr> <td>Nausea</td> <td>5.9</td> <td>7.0</td> <td>6.3</td> <td>8.4</td> <td>7.7</td> <td>8.7</td> </tr> <tr> <td> <content styleCode="bold">Musculoskeletal System Disorders</content> </td> </tr> <tr> <td>Myalgia</td> <td>1.6</td> <td>2.0</td> <td>1.9</td> <td>2.4</td> <td>2.4</td> <td>1.4</td> </tr> <tr> <td> <content styleCode="bold">Respiratory System Disorders</content> </td> </tr> <tr> <td>Sinusitis</td> <td>2.2</td> <td>2.6</td> <td>1.8</td> <td>1.1</td> <td>3.4</td> <td>3.4</td> </tr> <tr> <td>Upper respiratory tract infection</td> <td>6.0</td> <td>6.7</td> <td>5.7</td> <td>6.3</td> <td>4.3</td> <td>6.4</td> </tr> <tr> <td> <content styleCode="bold">Skin and Appendages Disorders</content> </td> </tr> <tr> <td>Rash</td> <td>1.0</td> <td>1.4</td> <td>2.1</td> <td>1.5</td> <td>0.5</td> <td>1.4</td> </tr> </tbody> </table>