1 INDICATIONS AND USAGE Celecoxib capsules are indicated Celecoxib Capsules is a nonsteroidal 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) For the management of the signs and symptoms of OA [ see Clinical Studies (14.1) ].

1.2 Rheumatoid Arthritis (RA) For the management of the signs and symptoms of RA [ see Clinical Studies (14.2) ].

1.3 Juvenile Rheumatoid Arthritis (JRA) For the management of the signs and symptoms of JRA in patients 2 years and older [ see Clinical Studies (14.3) ].

1.4 Ankylosing Spondylitis (AS) For the management of the signs and symptoms of AS [ see Clinical Studies (14.4) ].

1.5 Acute Pain For the management of acute pain in adults [ see Clinical Studies (14.5) ].

1.6 Primary Dysmenorrhea For the management of primary dysmenorrhea [ see Clinical Studies (14.5) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1) ] GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Hypertension [see Warnings and Precautions (5.4) ] Heart Failure and Edema [see Warnings and Precautions (5.5) ] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6) ] Anaphylactic Reactions [see Warnings and Precautions (5.7) ] Serious Skin Reactions [see Warnings and Precautions (5.9) ] Hematologic Toxicity [see Warnings and Precautions (5.12) ] Most common adverse reactions in arthritis trials (>2% and >placebo) are: 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 Umedica Laboratories USA Inc.

at 1-855-288-5777 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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.

Of the celecoxib capsules-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 capsules 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 capsules 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.

Pre-marketing Controlled Arthritis Trials Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving celecoxib capsules 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 Capsules Patients from Pre-marketing Controlled Arthritis Trials CBX N=4146 Placebo N=1864 NAP N=1366 DCF N=387 IBU N=345 Gastrointestinal Abdominal Pain Diarrhea Dyspepsia Flatulence Nausea 4.1% 5.6% 8.8% 2.2% 3.5% 2.8% 3.8% 6.2% 1.0% 4.2% 7.7% 5.3% 12.2% 3.6% 6.0% 9.0% 9.3% 10.9% 4.1% 3.4% 9.0% 5.8% 12.8% 3.5% 6.7% Body as a whole Back Pain Peripheral Edema Injury-Accidental 2.8% 2.1% 2.9% 3.6% 1.1% 2.3% 2.2% 2.1% 3.0% 2.6% 1.0% 2.6% 0.9% 3.5% 3.2% Central, Peripheral Nervous system Dizziness Headache 2.0% 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 Upper Respiratory Infection 2.3% 2.0% 5.0% 8.1% 1.1% 1.3% 4.3% 6.7% 1.7% 2.4% 4.0% 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 capsules 100 mg 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 capsules 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 capsules (100 mg 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: Hypersensitivity, 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 enzyme increased (including SGOT increased, SGPT increased) Metabolic and nutritional: blood urea nitrogen (BUN) increased, creatine phosphokinase (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, cough, 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.

Cardiovascular: Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis Gastrointestinal: Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus General: Sepsis, sudden death Liver and biliary: Cholelithiasis Hemic and lymphatic: Thrombocytopenia Nervous: Ataxia, suicide [ see Drug Interactions (7) ] Renal: Acute renal failure The Celecoxib Long-Term Arthritis Safety Study [ see Clinical Studies (14.7) ] Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on celecoxib capsules 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 capsules were maintained with or without aspirin 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 capsules, 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).

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 twice daily, 82 patients were treated with celecoxib 6 mg/kg twice daily, and 83 patients were treated with naproxen 7.5 mg/kg twice daily.

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 twice daily 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 twice daily.

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* 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 * 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 Other Pre-Approval Studies Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with celecoxib capsules 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 capsules 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 capsules 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.

The APC and PreSAP Trials Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to celecoxib capsules in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [ see clinical Studies (14.7) ].

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 capsules pre-marketing controlled arthritis trials , above).

The adverse reactions for which these differences in patients treated with celecoxib capsules 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% Nephrolithiasis 2.1% 0.8% The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking celecoxib capsules, 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.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of celecoxib capsules.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Cardiovascular: Vasculitis, deep venous thrombosis General: Anaphylactoid reaction, angioedema Liver and biliary: Liver necrosis, hepatitis, jaundice, hepatic failure Hemic and lymphatic: Agranulocytosis, aplastic anemia, pancytopenia, leucopenia Metabolic: Hypoglycemia, hyponatremia Nervous: Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage Renal: Interstitial nephritis Skin and Appendages: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and fixed drug eruption (FDE)