CELECOXIB (Page 4 of 11)

5.13 Masking of Inflammation and Fever

The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.14 Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions ( 5.2, 5.3, 5.6) ].

In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib capsules 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 Disseminated Intravascular Coagulation (DIC)

Because of the risk of disseminated intravascular coagulation with use of celecoxib capsules in pediatric patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, and inform patients and their caregivers to report symptoms as soon as possible.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labelling:

• 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) ]

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-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 Patients from Pre-marketing Controlled Arthritis Trials

Celecoxib = 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.
	Celecoxib (N=4146)	Placebo (N=1864)	NAP (N=1366)	DCF (N=387)	IBU (N=345)
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%
Psychatric
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 capsules and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the celecoxib capsules 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 Allergy
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 function abnormal, 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, 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:

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 Special 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 was 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, 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)

* 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
		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

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 mg 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 Capsules (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