"The U.S. Food and Drug Administration today approved the first generic versions of Celebrex (celecoxib) capsules, a treatment for rheumatoid arthritis, osteoarthritis, short-term (acute) pain, and other conditions.
Teva Pharmaceutical Indus"...
Of the CELEBREX (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 CELEBREX (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 CELEBREX (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.
Pre-marketing Controlled Arthritis Trials
Table 1 lists all adverse events, regardless of causality, occurring in ≥ 2% of patients receiving CELEBREX (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.
Table 1: Adverse Events Occurring in > 2% of CELEBREX (celecoxib) Patients
from Pre-marketing Controlled Arthritis Trials
|Body as a whole|
|Central, Peripheral Nervous system|
|CBX = CELEBREX (celecoxib) 100 – 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 CELEBREX (celecoxib) and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the CELEBREX (celecoxib) treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of CELEBREX (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 - 1.9% of patients treated with CELEBREX (celecoxib) (100 - 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
General: Allergy aggravated, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain
Heart rate and rhythm: Palpitation, tachycardia
Application site disorders: Cellulitis, dermatitis contact
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):
The Celecoxib Long-Term Arthritis Safety Study
[see Special Studies]
The incidence of clinically significant decreases in hemoglobin ( > 2 g/dL) was lower in patients on CELEBREX (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 CELEBREX (celecoxib) was maintained with or without ASA use [see CLINICAL PHARMACOLOGY].
Withdrawals/Serious Adverse Events
Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for CELEBREX (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 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
|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 CELEBREX (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/RAstudies.
Adverse Events from Analgesia and Dysmenorrhea Studies
Approximately 1,700 patients were treated with CELEBREX (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 CELEBREX (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 Trials
Adverse reactions from long-term, placebo-controlled polyp prevention studies
Exposure to CELEBREX (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].
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 (celecoxib) pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with CELEBREX (celecoxib) were greater as compared to the arthritis pre-marketing trials were as follows:
|CELEBREX (400 to 800 mg daily)
N = 2285
|Gastroesophageal reflux disease||4.7%||3.1%|
The following additional adverse reactions occurred in ≥ 0.1% and < 1% of patients taking CELEBREX (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
Vascular disorders: Deep vein thrombosis
Reproductive system and breast disorders: Ovarian cyst
Investigations: Blood potassium increased, blood sodium increased, blood testosterone decreased
Read the Celebrex (celecoxib) Side Effects Center for a complete guide to possible side effects
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.
Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing CELEBREX (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 2-5 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 CELEBREX (celecoxib) concurrently with warfarin.
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 CELEBREX (celecoxib) 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when CELEBREX (celecoxib) is introduced or withdrawn.
CELEBREX (celecoxib) can be used with low-dose aspirin. However, concomitant administration of aspirin with CELEBREX (celecoxib) increases the rate of GI ulceration or other complications, compared to use of CELEBREX alone [see WARNINGS AND PRECAUTIONS and Clinical Studies].
Because of its lack of platelet effects, CELEBREX (celecoxib) is not a substitute for aspirin for cardiovascular prophylaxis [see CLINICAL PHARMACOLOGY].
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 CELEBREX (celecoxib) concomitantly with ACE-inhibitors and angiotensin II antagonists [see CLINICAL PHARMACOLOGY].
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]. CELEBREX (celecoxib) should be introduced at the lowest recommended dose in patients receiving fluconazole.
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.
Concomitant NSAID Use
The concomitant use of CELEBREX (celecoxib) with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.
Last reviewed on RxList: 4/4/2011
This monograph has been modified to include the generic and brand name in many instances.
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