Serious skin reactions have occurred following treatment with celecoxib capsules, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). These serious events may occur without warning and can be fatal.
Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of celecoxib capsules at the first appearance of skin rash or any other sign of hypersensitivity. Celecoxib capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4) ].
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as celecoxib capsules. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue celecoxib capsules and evaluate the patient immediately.
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including celecoxib capsules, in pregnant women at about 30 weeks gestation and later. NSAIDs, including celecoxib capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including celecoxib capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit celecoxib capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if celecoxib capsules treatment extends beyond 48 hours. Discontinue celecoxib capsules if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with celecoxib capsules has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
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.
NSAIDs, including celecoxib capsules, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7) ].
The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
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.
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.
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) ]
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 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.
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.
|CBX N=4146||Placebo N=1864||NAP N=1366||DCF N=387||IBU N=345|
|Body as a whole|
|Central, Peripheral Nervous system|
|Upper Respiratory Infection||8.1%||6.7%||9.9%||9.8%||9.9%|
CBX = celecoxib 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 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 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|
|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 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 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 StudyIn 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.
|All Doses Twice Daily|
|System Organ Class||Celecoxib 3 mg/kg||Celecoxib 6 mg/kg||Naproxen 7.5 mg/kg|
|Abdominal pain NOS||4||7||7|
|Abdominal pain upper||8||6||10|
|Injury and Poisoning||4||6||5|
|Dizziness (excl vertigo)||1||1||7|
|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 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.
The APC and PreSAP TrialsAdverse reactions from long-term, placebo- controlled polyp prevention studies: Exposure to celecoxib 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 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)||Placebo|
|N= 2285||N= 1303|
|Gastroesophageal reflux disease||4.7%||3.1%|
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|
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