Cardiovascular Risk: NSAIDS may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Elderly patients and patients with CV disease or risk factors for CV disease may be at greater risk (see Pharmacology: Clinical Trials under Actions).
CELEBREX is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
Asthma and Skin Reaction: CELEBREX is contraindicated to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs (see PRECAUTIONS).
Congestive Heart Failure and Edema: CELEBREX should be used with caution in patients with fluid retention or heart failure.
Hepatic Effects: A patients with symptoms and/or signs suggesting liver dysfunction, or in whom abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with CELEBREX (see PRECAUTIONS).
Renal Effects: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.
Cardiovascular Thrombotic Events: Chronic use of CELEBREX may cause an increased risk of serious adverse CV thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. In the APC trial, the relative risk for the composite endpoint of CV death, MI, or stroke was 3.4 (95% CI 1.4 - 8.5) for CELEBREX 400 mg twice daily and 2.8 (95% CI 1.1 - 7.2) for the CELEBREX 200 mg twice daily compared to placebo (see Pharmacology: Clinical Studies: Special Studies: Adenomatous Polyp Studies under Actions).
All NSAIDs, both COX-2 selective and non-selective, may have a similar risk. This risk may increase with dose and duration of use. The relative increase of this risk appears to be similar in those with or without known CV disease or CV risk factors. However, patients with CV disease or CV risk factors may be at greater risk in terms of absolute incidence, due to their increased rate at baseline. To minimize the potential risk for an adverse CV event in patients treated with CELEBREX, the lowest effective dose should be used for the shortest duration possible. 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 symptoms of serious CV toxicity and the steps to take if they occur (see Pharmacology: Clinical Studies under Actions).
There is no consistent evidence that concurrent use of acetyl salicylic acid mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of acetyl salicylic acid and CELEBREX does increase the risk of serious GI events (see Gastrointestinal (GI) Effect - Risk of GI Ulceration, Bleeding and perforation under WARNINGS).
Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension: As with all NSAIDS, CELEBREX can lead to the onset of new hypertension or worsening of pre-existing 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 CELEBREX, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with CELEBREX and throughout the course of therapy. The rates of hypertension from the CLASS trial in the CELEBREX, ibuprofen and diclofenac treated patients were 2.4%, 4.2% and 2.5%, respectively (see Pharmacology: Clinical Studies: Special Studies: Celecoxib Long-term Arthritis Safety Study under Actions).
Congestive Heart Failure and Edema: Fluid retention and edema have been observed in some patients taking NSAIDs, including CELEBREX (see ADVERSE REACTIONS). In the CLASS study (see Pharmacology: Clinical Studies: Special Studies: Celecoxib Long-term Arthritis Safety Study under Actions), the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on CELEBREX 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. CELEBREX should be used with caution in patients with fluid retention or heart failure. Celecoxib should be used with caution in patients with compromised cardiac function, pre-existing edema, or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolemia.
Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation: NSAIDs, including CELEBREX, can cause serious GI events including bleeding, inflammation, ulceration, and upper and lower GI perforation, 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. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA (see Pharmacology: Clinical Studies: Special Studies: Celecoxib Long-term Arthritis Safety Study under Actions). 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 and who use NSAIDs, have a greater than 10-fold higher 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 CV disease, concomitant use of oral corticosteroids, glucocorticoids 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 in patients treated with NSAIDs, the lowest effective dose should be used for the shortest possible duration. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during CELEBREX therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
Use with Other NSAIDs: The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
Renal Effects: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Such patients should be carefully monitored while receiving treatment with celecoxib. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state. Clinical trials with CELEBREX have shown renal effects similar to those observed with comparator NSAIDs.
Caution should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate patients first and then start therapy with celecoxib.
Advanced Renal Disease: No information is available regarding the use of CELEBREX in patients with advanced renal disease. Therefore, treatment with CELEBREX is not recommended in these patients with advanced renal disease. If CELEBREX therapy must be initiated, close monitoring of the patient's renal function is advisable (see DOSAGE & ADMINISTRATION).
Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to CELEBREX. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving CELEBREX. CELEBREX should not be given to patients with the acetyl salicylic acid triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking acetyl salicylic acid or other NSAIDs (see CONTRAINDICATIONS and Pre-existing Asthma under PRECAUTIONS). Emergency help shouldbe sought in cases where an anaphylactoid reaction occurs.
Skin Reactions: CELEBREX is a sulfonamide and can cause serious skin adverse events, such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TENS), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy: In late pregnancy CELEBREX should be avoided because it may cause premature closure of the ductus arteriosus (see Use in Pregnancy under PRECAUTIONS).