1. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of celecoxib and other treatment options before deciding to use celecoxib capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ] Celecoxib 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 )
1.1Osteoarthritis (OA)
Celecoxib capsules are indicated for relief of the signs and symptoms of OA [ see Clinical Studies (14.1) ]
1.2Rheumatoid Arthritis (RA)
Celecoxib capsules are indicated for relief of the signs and symptoms of RA [ see Clinical Studies (14.2) ]
1.3Juvenile Rheumatoid Arthritis (JRA)
Celecoxib capsules are indicated for relief of the signs and symptoms of JRA in patients 2 years and older [ see Clinical Studies (14.3) ]
1.4Ankylosing Spondylitis (AS)
Celecoxib capsules are indicated for the relief of signs and symptoms of AS [ see Clinical Studies (14.4) ]
1.5Acute Pain (AP)
Celecoxib capsules are indicated for the management of AP in adults [ see Clinical Studies (14.5) ]
1.6Primary Dysmenorrhea (PD)
Celecoxib capsules are indicated for the treatment of PD [ see Clinical Studies (14.5) ]
4. CONTRAINDICATIONS Celecoxib capsules are contraindicated:
In patients with known hypersensitivity to celecoxib, aspirin, or other NSAIDs.
In patients who have demonstrated allergic-type reactions to sulfonamides.
In patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe anaphylactoid reactions to NSAIDs, some of them fatal, have been reported in such patients [ see Warnings and Precautions (5.7 , 5.13) ].
For the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions (5.1) ].
Known hypersensitivity to celecoxib or sulfonamides ( 4 )
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 , 5.7 , 5.8 , 5.13 )
Use during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 )
Warnings and precautions
5. WARNINGS AND PRECAUTIONS
Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke. Patients with known CV disease/risk factors may be at greater risk ( 5.1 , 14.6 , 17.2 ).
Serious gastrointestinal (GI) adverse events, which can be fatal. The risk is greater in patients with a prior history of ulcer disease or GI bleeding, and in patients at high risk for GI events, especially the elderly. Celecoxib should be used with caution in these patients ( 5.4 , 8.5 , 14.6 , 17.3 ).
Elevated liver enzymes and, rarely, severe hepatic reactions. Discontinue use of celecoxib immediately if abnormal liver enzymes persist or worsen ( 5.5 , 17.4 ).
New onset or worsening of hypertension. Blood pressure should be monitored closely during treatment with celecoxib ( 5.2 , 7.4 , 17.2 ).
Fluid retention and edema. Celecoxib should be used with caution in patients with fluid retention or heart failure ( 5.3 , 17.6 ).
Renal papillary necrosis and other renal injury with long term use. Use celecoxib with caution in the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics, ACE-inhibitors, or angiotensin II antagonists ( 5.6 , 7.4 , 8.7 , 17.6 ).
Anaphylactoid reactions. Do not use celecoxib in patients with the aspirin triad ( 5.7 , 10 , 17.7 ).
Serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal and can occur without warning even without known prior sulfa allergy. Discontinue celecoxib at first appearance of rash or skin reactions ( 5.8 , 17.5 ).
5.1Cardiovascular Thrombotic Events
Chronic use of celecoxib may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. In the APC (Adenoma Prevention with Celecoxib) trial, the hazard ratio for the composite endpoint of cardiovascular death, MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with celecoxib 200 mg twice daily compared to placebo.
Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [ see Clinical Studies (14.6) ]. All NSAIDs, both COX-2 selective and non-selective, may have a similar risk.
Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with celecoxib, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms.
Patients should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and celecoxib does increase the risk of serious GI events [ see Warnings and Precautions (5.4) ]. Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [ see Contraindications (4) ].
5.2 Hypertension As with all NSAIDs, celecoxib can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy.
The rates of hypertension from the CLASS trial in the celecoxib, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively [ see Clinical Studies (14.6) ].
5.3Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs, including celecoxib [ see Adverse Reactions (6.1) ]. In the CLASS study [ see Clinical Studies (14.6) ], the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively.
Celecoxib should be used with caution in patients with fluid retention or heart failure.
5.4Gastrointestinal (GI) Effects Risk of GI Ulceration, Bleeding, and Perforation
NSAIDs, including celecoxib, can cause serious gastrointestinal events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA.
Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [ see Clinical Studies (14.6) ]. With longer duration of use of NSAIDs, there is a trend for increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding.
Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status.
Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during celecoxib therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected.
For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
5.5Hepatic Effects
Borderline elevations of one or more liver-associated enzymes may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs, including celecoxib [ see Adverse Reactions (6.1) ].
In controlled clinical trials of celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 tim
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Interactions
7. DRUG INTERACTIONS 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.
Concomitant use of celecoxib and warfarin may result in increased risk of bleeding complications. ( 7.1 )
Concomitant use of celecoxib increases lithium plasma levels. ( 7.2 )
Concomitant use of celecoxib may reduce the antihypertensive effect of ACE Inhibitors and angiotensin II antagonists ( 7.4 )
Use caution with drugs known to inhibit P450 2C9 or metabolized by 2D6 due to the potential for increased plasma levels ( 2.6 , 8.4 , 8.8 , 12.3 )
7.1Warfarin
Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing 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 to 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 celecoxib concurrently with warfarin.
7.2 Lithium 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 celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.
7.3Aspirin
Celecoxib can be used with low-dose aspirin. However, concomitant administration of aspirin with celecoxib increases the rate of GI ulceration or other complications, compared to use of celecoxib alone [ see Warnings and Precautions (5.1 , 5.4) and Clinical Studies (14.6) ]. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis [ see Clinical Pharmacology (12.2) ].
7.4ACE-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 celecoxib capsules concomitantly with ACE-inhibitors and angiotensin II antagonists [ see Clinical Pharmacology (12.2 ].
7.5Fluconazole
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 (12.3) ]. Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole.
7.6Furosemide
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.
7.7 Methotrexate In an interaction study of rheumatoid arthritis patients taking methotrexate, celecoxib did not have an effect on the pharmacokinetics of methotrexate [ see Clinical Pharmacology (12.3) ].
7.8Concomitant NSAID Use
The concomitant use of celecoxib with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Category C.
Pregnancy category D from 30 weeks of gestation onward. Teratogenic effects : Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC 0–24 ), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC 0–24 at 200 mg twice daily) throughout organogenesis.
There are no studies in pregnant women. Celecoxib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic effects: Celecoxib produced pre implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥50 mg/kg/day (approximately 6-fold human exposure based on the AUC 0–24 at 200 mg twice daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures.
No studies have been conducted to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of celecoxib during the third trimester of pregnancy should be avoided.
Adverse reactions
6. ADVERSE REACTIONS 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. 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. Most common adverse reactions in arthritis trials (>2% and >placebo): 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 Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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.
Table 1: Adverse Events Occurring in ≥2% of Celecoxib Patients from Pre-marketing Controlled Arthritis Trials CXB N=4146 Placebo N=1864 NAP N=1366 DCF N=387 IBU N=345 CXB = celecoxib 100 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. 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% 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 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 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 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 : Allergy aggravated, 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 : BUN increased, 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 (cases reported only in 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 : Cholelithiasis, hepatitis, jaundice, liver failure Hemic and lymphatic : Thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, leucopenia Metabolic: Hypoglycemia, hyponatremia Nervous : Ataxia, suicide, aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage [see Drug Interactions (7.1) ] Renal : Acute renal failure, interstitial nephritis Skin: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis General : Sepsis, sudden death, anaphylactoid reaction, angioedema
6.2The Celecoxib Long-Term Arthritis Safety
Study [see Special Studies (14.6) ] 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 ASA 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).
6.3 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, d
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Composition
Active ingredients
CELECOXIB 200MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
