FDA label 2ebb850f-d998-06ea-e054-00144ff8d46c

WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS See full prescribing information for complete boxed warning Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDS) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal . This risk may occur early in treatment and may increase with duration of use. (see Warnings and Precautions ) ( 5.1 ) Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see Contraindications , Warnings and Precautions ). ( 4 , 5.1 ) Gastrointestinal Risk NSAIDs, including celecoxib, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events. ( 5.4 ) Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDS) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see Warnings and Precautions ( 5.1 ). Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see Contraindications , Warnings and Precautions ( 4 , 5.1 ) Gastrointestinal Risk NSAIDs, including celecoxib, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. ( 5.4 )

5. WARNINGS AND PRECAUTIONS Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke. Patients with known CV disease/risk factors may be at greater risk ( 5.1 , 14.6 , 17.2 ). Serious gastrointestinal (GI) adverse events, which can be fatal. The risk is greater in patients with a prior history of ulcer disease or GI bleeding, and in patients at high risk for GI events, especially the elderly. Celecoxib should be used with caution in these patients ( 5.4 , 8.5 , 14.6 , 17.3 ). Elevated liver enzymes and, rarely, severe hepatic reactions. Discontinue use of celecoxib immediately if abnormal liver enzymes persist or worsen ( 5.5 , 17.4 ). New onset or worsening of hypertension. Blood pressure should be monitored closely during treatment with celecoxib ( 5.2 , 7.4 , 17.2 ). Fluid retention and edema. Celecoxib should be used with caution in patients with fluid retention or heart failure ( 5.3 , 17.6 ). Renal papillary necrosis and other renal injury with long term use. Use celecoxib with caution in the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics, ACE-inhibitors, or angiotensin II antagonists ( 5.6 , 7.4 , 8.7 , 17.6 ). Anaphylactoid reactions. Do not use celecoxib in patients with the aspirin triad ( 5.7 , 10 , 17.7 ). Serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal and can occur without warning even without known prior sulfa allergy. Discontinue celecoxib at first appearance of rash or skin reactions ( 5.8 , 17.5 ). 5.1 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, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses [ see Clinical Studies (14.6) ]. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as celecoxib increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions ( 5.4 ) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications ( 4 ) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of celecoxib in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If celecoxib is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Hypertension As with all NSAIDs, celecoxib can lead to the onset of new hypertension or worsening of preexisting 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 celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy. The rates of hypertension from the CLASS trial in the celecoxib, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively [ see Clinical Studies (14.6) ]. 5.3 Congestive Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated NSAIDs. Use of [active moiety] may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor clockers (ARBs)] (see Drug Interactions ). Avoid the use of celecoxib in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If celecoxib is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.4 Gastrointestinal (GI) Effects Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including celecoxib, can cause serious gastrointestinal events including 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. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [ see Clinical Studies (14.6) ]. With longer duration of use of NSAIDs, there is a trend for 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. 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 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, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during celecoxib therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. 5.5 Hepatic Effects Borderline elevations of one or more liver-associated enzymes may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately 3 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 be transient with continuing therapy. 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, including celecoxib [ see Adverse Reactions (6.1) ]. In controlled clinical trials of celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST. A patient with symptoms and/or signs suggesting liver dysfunction, 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 celecoxib. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), celecoxib should be discontinued. 5.6 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 an NSAID 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, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. No information is available from controlled clinical studies regarding the use of celecoxib in patients with advanced renal disease. Therefore, treatment with celecoxib is not recommended in these patients with advanced renal disease. If celecoxib therapy must be initiated, close monitoring of the patient's renal function is advisable. 5.7 Anaphylactoid Reactions As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to celecoxib. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving celecoxib. Celecoxib 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 (4) , Warnings and Precautions (5.7) ]. Emergency help should be sought in cases where an anaphylactoid reaction occurs. 5.8 Skin Reactions Celecoxib is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy. 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. 5.9 Pregnancy In late pregnancy, starting at 30 weeks gestation, celecoxib should be avoided because it may cause premature closure of the ductus arteriosus [ see Use in Specific Populations (8.1) ]. 5.10 Corticosteroid Treatment Celecoxib cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids 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 corticosteroids. 5.11 Hematological Effects Anemia is sometimes seen in patients receiving celecoxib. In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. Celecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages [ see Clinical Pharmacology (12.2) ]. 5.12 Disseminated Intravascular Coagulation (DIC) Celecoxib should be used only with caution in pediatric patients with systemic onset JRA due to the risk of disseminated intravascular coagulation. 5.13 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, celecoxib should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. 5.14 Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, celecoxib should be discontinued. In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established. 5.15 Inflammation The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions. 5.16 Concomitant NSAID Use The concomitant use of celecoxib with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.

6. ADVERSE REACTIONS Of the celecoxib-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Most common adverse reactions in arthritis trials (>2% and >placebo): abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, rash ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Pre-marketing Controlled Arthritis Trials Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence. Table 1: Adverse Events Occurring in ≥2% of Celecoxib Patients from Pre-marketing Controlled Arthritis Trials CXB N=4146 Placebo N=1864 NAP N=1366 DCF N=387 IBU N=345 CXB = celecoxib 100 to 200 mg twice daily or 200 mg once daily; NAP = Naproxen 500 mg twice daily; DCF = Diclofenac 75 mg twice daily; IBU = Ibuprofen 800 mg three times daily. Gastrointestinal Abdominal Pain 4.1% 2.8% 7.7% 9.0% 9.0% Diarrhea 5.6% 3.8% 5.3% 9.3% 5.8% Dyspepsia 8.8% 6.2% 12.2% 10.9% 12.8% Flatulence 2.2% 1.0% 3.6% 4.1% 3.5% Nausea 3.5% 4.2% 6.0% 3.4% 6.7% Body as a whole Back Pain 2.8% 3.6% 2.2% 2.6% 0.9% Peripheral Edema 2.1% 1.1% 2.1% 1.0% 3.5% Injury-Accidental 2.9% 2.3% 3.0% 2.6% 3.2% Central, Peripheral Nervous system Dizziness 2.0% 1.7% 2.6% 1.3% 2.3% Headache 15.8% 20.2% 14.5% 15.5% 15.4% Psychiatric Insomnia 2.3% 2.3% 2.9% 1.3% 1.4% Respiratory Pharyngitis 2.3% 1.1% 1.7% 1.6% 2.6% Rhinitis 2.0% 1.3% 2.4% 2.3% 0.6% Sinusitis 5.0% 4.3% 4.0% 5.4% 5.8% Upper Respiratory Infection 8.1% 6.7% 9.9% 9.8% 9.9% Skin Rash 2.2% 2.1% 2.1% 1.3% 1.2% In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain. The following adverse reactions occurred in 0.1 to 1.9% of patients treated with celecoxib (100 to 200 mg twice daily or 200 mg once daily): Gastrointestinal : Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting Cardiovascular: Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction General : Allergy aggravated, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain Central, peripheral nervous system: Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia, vertigo Hearing and vestibular : Deafness, tinnitus Heart rate and rhythm : Palpitation, tachycardia Liver and biliary : Hepatic function abnormal, SGOT increased, SGPT increased Metabolic and nutritional : BUN increased, CPK increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased Musculoskeletal : Arthralgia, arthrosis, myalgia, synovitis, tendinitis Platelets (bleeding or clotting) : Ecchymosis, epistaxis, thrombocythemia Psychiatric : Anorexia, anxiety, appetite increased, depression, nervousness, somnolence Hemic : Anemia Respiratory : Bronchitis, bronchospasm, bronchospasm aggravated, coughing, dyspnea, laryngitis, pneumonia Skin and appendages : Alopecia, dermatitis, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria Application site disorders : Cellulitis, dermatitis contact Urinary : Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus The following serious adverse events (causality not evaluated) occurred in <0.1% of patients (cases reported only in post-marketing experience are indicated in italics ): Cardiovascular : Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis, vasculitis, deep venous thrombosis Gastrointestinal : Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus Liver and biliary : Cholelithiasis, hepatitis, jaundice, liver failure Hemic and lymphatic : Thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, leucopenia Metabolic: Hypoglycemia, hyponatremia Nervous : Ataxia, suicide, aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage [see Drug Interactions (7.1) ] Renal : Acute renal failure, interstitial nephritis Skin: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis General : Sepsis, sudden death, anaphylactoid reaction, angioedema 6.2 The Celecoxib Long-Term Arthritis Safety Study [see Special Studies (14.6) ] Hematological Events : The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on celecoxib 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with celecoxib was maintained with or without ASA use [ see Clinical Pharmacology (12.2) ]. Withdrawals/Serious Adverse Events : Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively). 6.3 Juvenile Rheumatoid Arthritis Study In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg BID, 82 patients were treated with celecoxib 6 mg/kg BID, and 83 patients were treated with naproxen 7.5 mg/kg BID. The most commonly occurring (≥5%) adverse events in celecoxib treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring (≥5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg BID had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups. In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg BID. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged. Table 2: Adverse Events Occurring in ≥5% of JRA Patients in Any Treatment Group, by System Organ Class (% of patients with events) All Doses Twice Daily System Organ Class Preferred Term Celecoxib 3 mg/kg N=77 Celecoxib 6 mg/kg N=82 Naproxen 7.5 mg/kg N=83 Any Event 64 70 72 Eye Disorders 5 5 5 Gastrointestinal 26 24 36 Abdominal pain NOS 4 7 7 Abdominal pain upper 8 6 10 Vomiting NOS 3 6 11 Diarrhea NOS 5 4 8 Nausea 7 4 11 General 13 11 18 Pyrexia 8 9 11 Infections 25 20 27 Nasopharyngitis 5 6 5 Injury and Poisoning 4 6 5 Investigations Abnormal laboratory tests, which include: Prolonged activated partial thromboplastin time, Bacteriuria NOS present, Blood creatine phosphokinase increased, Blood culture positive, Blood glucose increased, Blood pressure increased, Blood uric acid increased, Hematocrit decreased, Hematuria present, Hemoglobin decreased, Liver function tests NOS abnormal, Proteinuria present, Transaminase NOS increased, Urine analysis abnormal NOS 3 11 7 Musculoskeletal 8 10 17 Arthralgia 3 7 4 Nervous System 17 11 21 Headache NOS 13 10 16 Dizziness (excl vertigo) 1 1 7 Respiratory 8 15 15 Cough 7 7 8 Skin & Subcutaneous 10 7 18 6.4 Other Pre-Approval Studies Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with celecoxib in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RAstudies. Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with celecoxib in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of celecoxib were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies. 6.5 The APC and PreSAP Trials Adverse reactions from long-term, placebo-controlled polyp prevention studies : Exposure to celecoxib in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [ see Special Studies Adenomatous Polyp Prevention Studies (14.6) ]. Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from celecoxib pre-marketing controlled arthritis trials , above). The adverse reactions for which these differences in patients treated with celecoxib were greater as compared to the arthritis pre-marketing trials were as follows: Celecoxib (400 to 800 mg daily) N = 2285 Placebo N=1303 Diarrhea 10.5% 7.0% Gastroesophageal reflux disease 4.7% 3.1% Nausea 6.8% 5.3% Vomiting 3.2% 2.1% Dyspnea 2.8% 1.6% Hypertension 12.5% 9.8% The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking celecoxib, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies: Nervous system disorders: Cerebral infarction Eye disorders : Vitreous floaters, conjunctival hemorrhage Ear and labyrinth : Labyrinthitis Cardiac disorders : Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy Vascular disorders : Deep vein thrombosis Reproductive system and breast disorders : Ovarian cyst Investigations : Blood potassium increased, blood sodium increased, blood testosterone decreased Injury, poisoning and procedural complications: Epicondylitis, tendon rupture

<table ID="table1" width="100%"> <caption>Table 1: Adverse Events Occurring in &#x2265;2% of Celecoxib Patients from Pre-marketing Controlled Arthritis Trials</caption> <col align="left" valign="top" width="25%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule">CXB N=4146 </th> <th styleCode="Rrule">Placebo N=1864 </th> <th styleCode="Rrule">NAP N=1366 </th> <th styleCode="Rrule">DCF N=387 </th> <th styleCode="Rrule">IBU N=345 </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6">CXB = celecoxib 100 to 200 mg twice daily or 200 mg once daily; NAP = Naproxen 500 mg twice daily; DCF = Diclofenac 75 mg twice daily; IBU = Ibuprofen 800 mg three times daily. </td> </tr> </tfoot> <tbody> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Abdominal Pain</td> <td styleCode="Rrule">4.1%</td> <td styleCode="Rrule">2.8%</td> <td styleCode="Rrule">7.7%</td> <td styleCode="Rrule">9.0%</td> <td styleCode="Rrule">9.0%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">5.6%</td> <td styleCode="Rrule">3.8%</td> <td styleCode="Rrule">5.3%</td> <td styleCode="Rrule">9.3%</td> <td styleCode="Rrule">5.8%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Dyspepsia</td> <td styleCode="Rrule">8.8%</td> <td styleCode="Rrule">6.2%</td> <td styleCode="Rrule">12.2%</td> <td styleCode="Rrule">10.9%</td> <td styleCode="Rrule">12.8%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Flatulence</td> <td styleCode="Rrule">2.2%</td> <td styleCode="Rrule">1.0%</td> <td styleCode="Rrule">3.6%</td> <td styleCode="Rrule">4.1%</td> <td styleCode="Rrule">3.5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">3.5%</td> <td styleCode="Rrule">4.2%</td> <td styleCode="Rrule">6.0%</td> <td styleCode="Rrule">3.4%</td> <td styleCode="Rrule">6.7%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Body as a whole</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Back Pain</td> <td styleCode="Rrule">2.8%</td> <td styleCode="Rrule">3.6%</td> <td styleCode="Rrule">2.2%</td> <td styleCode="Rrule">2.6%</td> <td styleCode="Rrule">0.9%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Peripheral Edema</td> <td styleCode="Rrule">2.1%</td> <td styleCode="Rrule">1.1%</td> <td styleCode="Rrule">2.1%</td> <td styleCode="Rrule">1.0%</td> <td styleCode="Rrule">3.5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Injury-Accidental</td> <td styleCode="Rrule">2.9%</td> <td styleCode="Rrule">2.3%</td> <td styleCode="Rrule">3.0%</td> <td styleCode="Rrule">2.6%</td> <td styleCode="Rrule">3.2%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Central, Peripheral Nervous system</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Dizziness</td> <td styleCode="Rrule">2.0%</td> <td styleCode="Rrule">1.7%</td> <td styleCode="Rrule">2.6%</td> <td styleCode="Rrule">1.3%</td> <td styleCode="Rrule">2.3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">15.8%</td> <td styleCode="Rrule">20.2%</td> <td styleCode="Rrule">14.5%</td> <td styleCode="Rrule">15.5%</td> <td styleCode="Rrule">15.4%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Psychiatric</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Insomnia</td> <td styleCode="Rrule">2.3%</td> <td styleCode="Rrule">2.3%</td> <td styleCode="Rrule">2.9%</td> <td styleCode="Rrule">1.3%</td> <td styleCode="Rrule">1.4%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Pharyngitis</td> <td styleCode="Rrule">2.3%</td> <td styleCode="Rrule">1.1%</td> <td styleCode="Rrule">1.7%</td> <td styleCode="Rrule">1.6%</td> <td styleCode="Rrule">2.6%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Rhinitis</td> <td styleCode="Rrule">2.0%</td> <td styleCode="Rrule">1.3%</td> <td styleCode="Rrule">2.4%</td> <td styleCode="Rrule">2.3%</td> <td styleCode="Rrule">0.6%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Sinusitis</td> <td styleCode="Rrule">5.0%</td> <td styleCode="Rrule">4.3%</td> <td styleCode="Rrule">4.0%</td> <td styleCode="Rrule">5.4%</td> <td styleCode="Rrule">5.8%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Upper Respiratory Infection</td> <td styleCode="Rrule">8.1%</td> <td styleCode="Rrule">6.7%</td> <td styleCode="Rrule">9.9%</td> <td styleCode="Rrule">9.8%</td> <td styleCode="Rrule">9.9%</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold">Skin</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Rash</td> <td styleCode="Rrule">2.2%</td> <td styleCode="Rrule">2.1%</td> <td styleCode="Rrule">2.1%</td> <td styleCode="Rrule">1.3%</td> <td styleCode="Rrule">1.2%</td> </tr> </tbody> </table>

<table width="80%"> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="75%"/> <tbody> <tr styleCode="toprule"> <td> <content styleCode="bold"> <content styleCode="italics">Gastrointestinal</content> </content> <content styleCode="italics">:</content> </td> <td>Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Cardiovascular:</content> </content> </td> <td>Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">General</content> </content> <content styleCode="italics">:</content> </td> <td>Allergy aggravated, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Central, peripheral nervous system:</content> </content> </td> <td>Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia, vertigo</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Hearing and vestibular</content> </content> <content styleCode="italics">:</content> </td> <td>Deafness, tinnitus</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Heart rate and rhythm</content> </content> <content styleCode="italics">:</content> </td> <td>Palpitation, tachycardia</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Liver and biliary</content> </content> <content styleCode="italics">:</content> </td> <td>Hepatic function abnormal, SGOT increased, SGPT increased</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Metabolic and nutritional</content> </content> <content styleCode="italics">:</content> </td> <td>BUN increased, CPK increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Musculoskeletal</content> </content> <content styleCode="italics">:</content> </td> <td>Arthralgia, arthrosis, myalgia, synovitis, tendinitis</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Platelets (bleeding or clotting)</content> </content> <content styleCode="italics">:</content> </td> <td>Ecchymosis, epistaxis, thrombocythemia</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Psychiatric</content> </content> <content styleCode="italics">:</content> </td> <td>Anorexia, anxiety, appetite increased, depression, nervousness, somnolence</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Hemic</content> </content> <content styleCode="italics">: </content> </td> <td>Anemia</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Respiratory</content> </content> <content styleCode="italics">:</content> </td> <td>Bronchitis, bronchospasm, bronchospasm aggravated, coughing, dyspnea, laryngitis, pneumonia</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Skin and appendages</content> </content> <content styleCode="italics">:</content> </td> <td>Alopecia, dermatitis, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Application site disorders</content> </content> <content styleCode="italics">:</content> </td> <td>Cellulitis, dermatitis contact</td> </tr> <tr styleCode="Botrule"> <td> <content styleCode="bold"> <content styleCode="italics">Urinary</content> </content> <content styleCode="italics">:</content> </td> <td>Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus</td> </tr> </tbody> </table>

<table width="80%"> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="75%"/> <tbody> <tr styleCode="toprule"> <td> <content styleCode="bold"> <content styleCode="italics">Cardiovascular</content> </content> <content styleCode="italics">:</content> </td> <td>Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis, <content styleCode="italics">vasculitis, deep venous thrombosis</content> </td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Gastrointestinal</content> </content> <content styleCode="italics">:</content> </td> <td>Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus</td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Liver and biliary</content> </content> <content styleCode="italics">:</content> </td> <td>Cholelithiasis, <content styleCode="italics">hepatitis, jaundice, liver failure</content> </td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Hemic and lymphatic</content> </content> <content styleCode="italics">:</content> </td> <td>Thrombocytopenia, <content styleCode="italics">agranulocytosis, aplastic anemia, pancytopenia, leucopenia</content> </td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Metabolic:</content> </content> </td> <td> <content styleCode="italics">Hypoglycemia, hyponatremia</content> </td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Nervous</content> </content> <content styleCode="italics">:</content> </td> <td>Ataxia, suicide, <content styleCode="italics"> aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage [see <linkHtml href="#S7.1">Drug Interactions (7.1)</linkHtml>] </content> </td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Renal</content> </content> <content styleCode="italics">:</content> </td> <td>Acute renal failure, <content styleCode="italics"> interstitial nephritis</content> </td> </tr> <tr> <td> <content styleCode="bold"> <content styleCode="italics">Skin:</content> </content> </td> <td> <content styleCode="italics">Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis</content> </td> </tr> <tr styleCode="botrule"> <td> <content styleCode="bold"> <content styleCode="italics">General</content> </content> <content styleCode="italics">:</content> </td> <td>Sepsis, sudden death, <content styleCode="italics">anaphylactoid reaction, angioedema</content> </td> </tr> </tbody> </table>