ADVERSE REACTIONS
Of the CELEBREX treated patients in the premarketing 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 have received a total daily dose of CELEBREX of 200 mg (100 mg BID or 200 mg QD) or more, including more than 400 treated at 800 mg (400 mg BID). Approximately 3,900 patients have received CELEBREX 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.
Adverse events from CELEBREX premarketing controlled arthritis trials
Table 3 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving CELEBREX 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 3 | Adverse Events Occurring in ≥2% of CELEBREX Patients From CELEBREX Premarketing Controlled Arthritis Trials |
|---|
| Celebrex
(100–200 mg BID or 200 mg QD) | Placebo | Naproxen
500 mg BID | Diclofenac
75 mg BID | Ibuprofen
800 mg TID |
|---|
| (n=4146) | (n=1864) | (n=1366) | (n=387) | (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 and 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 tract 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 CELEBREX and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the CELEBREX treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of CELEBREX patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.
The following adverse events occurred in 0.1 – 1.9% of patients regardless of causality.
| CELEBREX | |
|---|
| (100 – 200 mg BID or 200 mg QD) | |
|---|
| Gastrointestinal: | Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, tooth disorder, vomiting |
| Cardiovascular: | Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction |
| General: | Allergy aggravated, allergic reaction, asthenia, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain |
| Resistance mechanism disorders: | Herpes simplex, herpes zoster, infection bacterial, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media |
| Central, peripheral nervous system: | Leg cramps, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, vertigo |
| Female reproductive: | Breast fibroadenosis, breast neoplasm, breast pain, dysmenorrhea, menstrual disorder, vaginal hemorrhage, vaginitis |
| Male reproductive: | Prostatic disorder |
| Hearing and vestibular: | Deafness, ear abnormality, earache, tinnitus |
| Heart rate and rhythm: | Palpitation, tachycardia |
| Liver and biliary system: | Hepatic function abnormal, SGOT increased, SGPT increased |
| Metabolic and nutritional: | BUN increased, CPK increased, diabetes mellitus, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increase, creatinine increased, alkaline phosphatase increased, weight increase |
| Musculoskeletal: | Arthralgia, arthrosis, bone disorder, fracture accidental, myalgia, neck stiffness, 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, nail disorder, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria |
| Application site disorders: | Cellulitis, dermatitis contact, injection site reaction, skin nodule |
| Special senses: | Taste perversion |
| Urinary system: | Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus, urinary incontinence, urinary tract infection |
| Vision: | Blurred vision, cataract, conjunctivitis, eye pain, glaucoma |
Other serious adverse reactions which occur rarely (estimated <0.1%), regardless of causality
The following serious adverse events have occurred rarely in patients taking CELEBREX. Cases reported only in the 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 system: | Cholelithiasis, hepatitis, jaundice, liver failure |
| Hemic and lymphatic: | Thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, leukopenia |
| Metabolic: | Hypoglycemia, hyponatremia |
| Nervous system: | Ataxia, suicide, aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage (see PRECAUTIONS – Drug Interactions – Warfarin) |
| Renal: | Acute renal failure, interstitial nephritis |
| Skin: | Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis |
| General: | Sepsis, sudden death, anaphylactoid reaction, angioedema |
Adverse reactions from long-term, placebo-controlled polyp prevention studies
Exposure to CELEBREX in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years; see Special Studies - Adenomatous Polyp Prevention Studies.
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 CELEBREX premarketing controlled arthritis trials). The adverse reactions for which these differences in patients treated with CELEBREX were greater as compared to the arthritis pre-marketing trials were as follows:
| CELEBREX
(400 – 800 mg daily dose) | Placebo |
|---|
| (n=2285) | (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 CELEBREX, 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 disorders: Labyrinthitis
Cardiac disorders: Angina unstable, aortic valve incompetence, 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
Safety Data from CLASS Study
Hematological Events
During this study (see Special Studies – CLASS), the incidence of clinically significant decreases in hemoglobin (>2 g/dL) confirmed by repeat testing was lower in patients on CELEBREX 400 mg BID (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP) compared to patients on either diclofenac 75 mg BID or ibuprofen 800 mg TID: 0.5%, 1.3% and 1.9%, respectively. The lower incidence of events with CELEBREX was maintained with or without ASA use (see CLINICAL PHARMACOLOGY - Platelets).
Withdrawals/Serious Adverse Events
Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for CELEBREX, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e. those causing hospitalization or felt to be life threatening or otherwise medically significant) regardless of causality were not different across treatment groups, respectively, 8%, 7%, and 8%.
Adverse events from 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 4). 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 4: Incidence of Adverse Events Occurring in ≥5% of JRA Patients in the Clinical Trial in Any Treatment Group by System Organ Class System Organ Class/
Adverse Event Preferred Term | Celecoxib
3 mg/kg BID
N=77 | Celecoxib
6 mg/kg BID
N=82 | Naproxen
7.5 mg/kg BID
N=83 |
|---|
| Any Event, % | 64 | 70 | 72 |
| Eye Disorders | 5 | 5 | 5 |
| Gastrointestinal Disorders | 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 Disorders and Administration Site Conditions | 13 | 11 | 18 |
| Pyrexia | 8 | 9 | 11 |
| Infections and Infestations | 25 | 20 | 27 |
| Nasopharyngitis | 5 | 6 | 5 |
| Injury and Poisoning | 4 | 6 | 5 |
| InvestigationsAbnormal 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, Connective Tissue and Bone Disorders | 8 | 10 | 17 |
| Arthralgia | 3 | 7 | 4 |
| Nervous System Disorders | 17 | 11 | 21 |
| Headache NOS | 13 | 10 | 16 |
| Dizziness (excluding vertigo) | 1 | 1 | 7 |
| Respiratory, Thoracic and Mediastinal Disorders | 8 | 15 | 15 |
| Cough | 7 | 7 | 8 |
| Skin & Subcutaneous Tissue Disorders | 10 | 7 | 18 |
Adverse events from ankylosing spondylitis studies
A total of 378 patients were treated with CELEBREX in placebo- and active- controlled ankylosing spondylitis studies. Doses up to 400 mg QD were studied. The types of adverse events reported in the ankylosing spondylitis studies were similar to those reported in the arthritis studies.
Adverse events from analgesia and dysmenorrhea studies
Approximately 1,700 patients were treated with CELEBREX 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 CELEBREX 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.
Adverse events from the controlled trial in familial adenomatous polyposis
The adverse event profile reported for the 83 patients with familial adenomatous polyposis enrolled in the randomized, controlled clinical trial was similar to that reported for patients in the arthritis controlled trials. Intestinal anastomotic ulceration was the only new adverse event reported in the FAP trial, regardless of causality, and was observed in 3 of 58 patients (one at 100 mg BID, and two at 400 mg BID) who had prior intestinal surgery.
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