CELECOXIB

Celecoxib USP is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical formula is C17H14F3N3O2S, and the molecular weight is 381.38; the chemical structure is as follows: Celecoxib oral capsules contain either50 mg, 100 mg, 200 mg or 400 mg of celecoxib, together with inactive ingredients including: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, sodium lauryl sulfate, titanium dioxide and gelatin. Details of non-volatile components of the imprinting ink are given below. 50 mg capsule contains shellac, propylene glycol and red iron oxide. 100 mg capsule contains shellac, propylene glycol and FD & C Blue No. # 2 aluminum lake. 200 mg capsule contains shellac, propylene glycol and yellow iron oxide. 400 mg capsule contains shellac, propylene glycol, titanium dioxide, yellow iron oxide and FD & C Blue No. # 2 aluminum lake. Structure

Carefully consider the potential benefits and risks of celecoxib and other treatment options before deciding to use celecoxib. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ] Celecoxib is a non steroidal anti-inflammatory drug indicated for: Osteoarthritis (OA) (1.1) Rheumatoid Arthritis (RA) (1.2) Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older(1.3) Ankylosing Spondylitis (AS) (1.4) Acute Pain (AP) (1.5) Primary Dysmenorrhea (PD) (1.6) 1.1 Osteoarthritis (OA) Celecoxib is indicated for relief of the signs and symptoms of OA [ see Clinical Studies (14.1) ] 1.2 Rheumatoid Arthritis (RA) Celecoxib is indicated for relief of the signs and symptoms of RA [ see Clinical Studies (14.2) ] 1.3 Juvenile Rheumatoid Arthritis (JRA) Celecoxib is indicated for relief of the signs and symptoms of JRA in patients 2 years and older [ see Clinical Studies (14.3) ] 1.4 Ankylosing Spondylitis (AS) Celecoxib is indicated for the relief of signs and symptoms of AS [ see Clinical Studies (14.4) ] 1.5 Acute Pain (AP) Celecoxib is indicated for the management of AP in adults [ see Clinical Studies (14.5) ] 1.6 Primary Dysmenorrhea (PD) Celecoxib is indicated for the treatment of PD [ see Clinical Studies (14.5) ]

Use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient. These doses can be given without regard to timing of meals. Use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient. (1,5.1,5.4) OA : 200 mg once daily or 100 mg twice daily (2.1,14.1) RA : 100 to 200 mg twice daily (2.2,14.2) JRA : 50 mg twice daily in patients 10 to 25 kg. 100 mg twice daily in patients more than 25 kg (2.3,14.3) AS : 200 mg once daily single dose or 100mg twice daily. If no effect is observed after 6 weeks, a trial of 400 mg (single or divided doses) may be of benefit (2.4,14.4) AP and PD : 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg twice daily as needed (2.5,14.5) Reduce daily dose by 50% inpatients with moderate hepatic impairment (Child-PughClassB). Consider a dose reduction by 50% (oral ternative management for JRA) in patients who are know nor suspected to be CYP2C9 poor metabolizers, (2.6,8.4,8.8,12.3). 2.1 Osteoarthritis For relief of the signs and symptoms of OA the recommended oral dose is 200 mg per day administered as a single dose or as 100 mg twice daily. 2.2 Rheumatoid Arthritis For relief of the signs and symptoms of RA the recommended oral dose is 100 to 200 mg twice daily. 2.3 Juvenile Rheumatoid Arthritis For the relief of the signs and symptoms of JRA the recommended oral dose for pediatric patients (age 2 years and older) is based on weight. For patients ≥10 kg to ≤25 kg the recommended dose is 50 mg twice daily. For patients >25 kg the recommended dose is 100 mg twice daily. For patients who have difficulty swallowing capsules, the contents of a celecoxib capsule can be added to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce are stable for up to 6 hours under refrigerated conditions (2 to 8°C/ 35 to 45°F). 2.4 Ankylosing Spondylitis For the management of the signs and symptoms of AS, the recommended dose of celecoxibis 200 mg daily in single (once per day) or divided (twice per day) doses. If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options. 2.5 Management of Acute Pain and Treatment of Primary Dysmenorrhea The recommended dose of celecoxib is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed. 2.6 Special Populations Hepatic insufficiency: The daily recommended dose of celecoxib in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of celecoxib in patients with severe hepatic impairment is not recommended [ see Warnings and Precautions (5.5),Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e. CYP2C9*3/*3). Consider using alternative management in JRA patients who are poor metabolizes [ see Use in Specific populations (8.8) and Clinical Pharmacology (12.5) ].

Celecoxib is contraindicated: In patients with known hypersensitivity to celecoxib, aspirin, or other NSAIDs. In patients who have demonstrated allergic-type reactions to sulfonamides. In patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe anaphylactoid reactions to NSAIDs, some of them fatal, have been reported in such patients [ see Warnings and Precautions (5.7,5.13) ]. For the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG)surgery [ see Warnings and Precautions(5.1) ]. Known hypersensitivity to celecoxib or sulfonamides (4) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4, 5.7, 5.8, 5.13) Use during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1)

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 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 celecoxibfrom 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 CBX N=4,146 Placeb o N=1,864 NAP N=1,366 DCF N=387 IBU N=345 Gastrointestinal AbdominalPain Diarrhea Dyspepsia Flatulence Nausea 4.1% 5.6% 8.8% 2.2% 3.5% 2.8% 3.8% 6.2% 1% 4.2% 7.7% 5.3% 12.2%3.6% 6% 9% 9.3% 10.9%4.1% 3.4% 9% 5.8% 12.8% 3.5% 6.7% Bodyasawhole BackPain PeripheralEdema Injury-Accidental 2.8% 2.1% 2.9% 3.6% 1.1% 2.3% 2.2% 2.1% 3% 2.6% 1% 2.6% 0.9% 3.5% 3.2% Central, Peripheral Nervoussystem Dizziness Headache 2%15.8% 1.7% 20.2% 2.6% 14.5% 1.3% 15.5% 2.3% 15.4% Psychiatric Insomnia 2.3% 2.3% 2.9% 1.3% 1.4% Respiratory Pharyngitis Rhinitis Sinusitis UpperRespiratory Infection 2.3% 2% 5% 8.1% 1.1% 1.3% 4.3% 6.7% 1.7% 2.4% 4% 9.9% 1.6% 2.3% 5.4% 9.8% 2.6% 0.6% 5.8% 9.9% Skin Rash 2.2% 2.1% 2.1% 1.3% 1.2% CBX = 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. 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) System Organ Class Preferred Term All Doses Twice Daily 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 AbdominalpainNOS Abdominalpainupper Vomiting NOS DiarrheaNOS Nausea 4 8 3 5 7 7 6 6 4 4 7 10 11 8 11 General 13 11 18 Pyrexia 8 9 11 Infections 25 20 27 Nasopharyngitis 5 6 5 Injury and Poisoning 4 6 5 Investigations* 3 11 7 Musculoskeletal 8 10 17 Arthralgia 3 7 4 Nervous System 17 11 21 Headache NOS Dizziness (excl vertigo) 13 1 10 1 16 7 Respiratory 8 15 15 Cough 7 7 8 Skin & Subcutaneous 10 7 18 * 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 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/RA studies. 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 celecoxibwere greater as compared to the arthritis pre-marketing trials were as follows: Celecoxib (400 to 800 mg daily) N=2,285 Placebo N = 1,303 Diarrhea 10.5% 7% 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 Eyedisorders : 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, tendonrupture

General: Celecoxib metabolism is predominantly mediated via cytochrome P450(CYP)2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 should be done with caution. Significant interactions may occur when celecoxib is administered together with drugs that inhibit CYP2C9. In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6. • Concomitant use of celecoxib and warfarin may result in increased risk of bleeding complications. (7.1) • Concomitant use of celecoxib increases lithium plasma levels. (7.2) • Concomitant use of celecoxib may reduce the antihypertensive effect of ACE Inhibitors and angiotensin II antagonists (7.4) • Use caution with drugs known to inhibit P450 2C9 or metabolized by 2D6 due to the potential for increased plasma levels (2.6, 8.4, 8.8, 12.3) 7.1 Warfarin Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing celecoxib therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily 2 to 5 mg doses of warfarin. In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, serious bleeding events, some of which were fatal, have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving celecoxib concurrently with warfarin. 7.2 Lithium In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn. 7.3 Aspirin Celecoxib can be used with low-dose aspirin. However, concomitant administration of aspirin with celecoxib increases the rate of GI ulceration or other complications, compared to use of celecoxib alone [ see Warnings and Precautions (5.1, 5.4) and Clinical Studies (14.6) ]. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis [ see Clinical Pharmacology (12.2) ]. 7.4 ACE-inhibitors and Angiotensin II Antagonists Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin II antagonists. This interaction should be given consideration in patients taking celecoxibconcomitantly with ACE-inhibitors and angiotensin II antagonists [ see Clinical Pharmacology (12.2) ]. 7.5 Fluconazole Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole [ see Clinical Pharmacology (12.3) ]. Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole. 7.6 Furosemide Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. 7.7 Methotrexate In an interaction study of rheumatoid arthritis patients taking methotrexate, celecoxib did not have an effect on the pharmacokinetics of methotrexate [ see Clinical Pharmacology (12.3) ]. 7.8 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.