Total Cost
Free shipping on all orders

Powered by GeniusRx

celecoxib 100 mg capsule generic celebrex

Out of Stock Manufacturer MACLEODS PHARMA 33342015611
Out of Stock

Uses

Celecoxib is used in the management of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, pain, ankylosing spondylitis, and dysmenorrhea. There currently is no evidence establishing superiority of selective COX-2 inhibitors relative to prototypical NSAIAs in the management of these conditions, and the principal benefit of selective COX-2 inhibitors is a potential reduction in the incidence of certain adverse effects (e.g., GI toxicity). Both COX-2 inhibitors and prototypical NSAIAs have been associated with an increased risk of cardiovascular events. A decision to use a selective COX-2 inhibitor rather than a prototypical NSAIA usually is based on an individual assessment of the risk of ulcer complications from NSAIA therapy. There is some evidence that therapy with a COX-2 inhibitor may be no more effective in reducing the risk of NSAIA-induced GI complications than a combined regimen of a prototypical NSAIA and a proton-pump inhibitor.(See Uses: Osteoarthritis.) Additional study is planned or under way to establish more definitively the role of COX-2 inhibitors relative to prototypical NSAIAs.

Celecoxib also is used to reduce the number of adenomatous colorectal polyps in adults with familial adenomatous polyposis (FAP).

The potential benefits and risks of celecoxib therapy as well as alternative therapies should be considered prior to initiating therapy with the drug. The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.

Osteoarthritis

Celecoxib is used for the management of the signs and symptoms of osteoarthritis in adults. Medical management of osteoarthritis of the hip or knee includes both pharmacologic therapy to reduce pain and nonpharmacologic therapy to maintain and/or improve joint mobility and limit functional impairment (e.g., patient education, weight loss when necessary, aerobic and muscle-strengthening exercise programs, physical therapy and range-of-motion exercises, assistive devices for ambulation and activities of daily living, patellar taping, appropriate footwear or bracing). Pain management is considered an adjunct to nonpharmacologic measures, and is most effective when combined with nonpharmacologic strategies.

A variety of drugs have been used for management of pain in patients with osteoarthritis, including oral agents (e.g., acetaminophen, NSAIAs, tramadol), intraarticular agents (e.g., glucocorticoids, sodium hyaluronate), and topical agents (e.g., capsaicin, methylsalicylate). Factors to consider when making treatment decisions for the management of pain in patients with osteoarthritis include the presence of risk factors for serious adverse GI effects or renal toxicity (which may affect decisions regarding use of NSAIAs), existing comorbidities and concomitant therapy, and the adverse effects profiles and costs of specific therapies.

Because there is evidence that acetaminophen can be effective and because of its relative safety and low cost, the American College of Rheumatology (ACR) and other clinicians recommended use of the drug as the initial analgesic for many osteoarthritis patients. Acetaminophen appears to be as effective as NSAIAs for relief of mild to moderate joint pain in many patients with osteoarthritis; however, the drug is not effective in all patients and may not provide adequate relief in those with moderate to severe pain or when joint inflammation is present. An NSAIA can be considered an alternative initial drug of choice for patients with osteoarthritis, especially for those who have moderate to severe pain and signs of joint inflammation, and also can be considered in patients who fail to obtain adequate symptomatic relief with acetaminophen. NSAIAs that are selective inhibitors of COX-2 (e.g., celecoxib) are associated with a lower incidence of adverse GI effects than prototypical NSAIAs. Both COX-2 inhibitors and prototypical NSAIAs have been associated with an increased risk of cardiovascular events. A decision to use a selective COX-2 inhibitor (e.g., celecoxib) rather than a prototypical NSAIA usually is based on an individual assessment of the risk for GI toxicity. If a prototypical NSAIA (e.g., diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, naproxen, piroxicam, sulindac, tolmetin) is used in osteoarthritis patients at risk for GI complications, concomitant use of misoprostol or a proton-pump inhibitor (e.g., omeprazole) can be considered for preventive therapy. However, in a study comparing the efficacy of celecoxib (200 mg twice daily) versus diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding in H. pylori-negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding while receiving long-term NSAIA therapy, the protective efficacy was unexpectedly low for both regimens (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) and it appeared that neither could completely protect patients at high risk.

In several double-blind, placebo-controlled, or comparative studies of up to 12 weeks' duration, celecoxib was at least as effective as naproxen and more effective than placebo in the symptomatic management of osteoarthritis of the knee or hip in patients who experienced exacerbation of symptoms (e.g., pain, joint stiffness) following discontinuance of standard therapy with NSAIAs or other analgesics. While celecoxib and naproxen generally are comparably effective in the management of osteoarthritis, current data suggest that adverse GI effects occur less frequently with celecoxib.(See Cautions: GI Effects.)

In controlled clinical studies in adults with osteoarthritis, therapy with celecoxib (100 mg twice daily or 200 mg once daily) resulted in improvement in the Western Ontario and McMasters Universities (WOMAC) osteoarthritis index; WOMAC is a 24-item questionnaire that measures pain, stiffness, and functioning. Following initiation of celecoxib 100 or 200 mg twice daily in patients with joint pain as a result of symptomatic exacerbation of osteoarthritis, pain relief generally occurs within 24-48 hours and therapy with the drug is associated with greater reductions in joint pain than placebo. In placebo-controlled and comparative studies in patients with symptomatic exacerbation of osteoarthritis of the hip or knee, 31-36% of patients receiving celecoxib 100 mg twice daily for 12 weeks improved as measured by patient and physician assessment of the arthritic condition; improvement occurred in 29-36% of patients receiving celecoxib 200 mg twice daily, 29-37% of patients receiving naproxen 500 mg twice daily, and 17-24% of patients receiving placebo twice daily. Celecoxib dosages of 100 mg twice daily and 200 mg once daily were comparably effective in patients with osteoarthritis as measured by joint pain, disease activity, functionality, and health-related quality of life. Celecoxib dosages of 200 mg twice daily do not appear to provide additional benefit compared with dosages of 100 mg twice daily or 200 mg once daily in these patients.

Rheumatoid Arthritis in Adults

Celecoxib is used for the management of the signs and symptoms of rheumatoid arthritis in adults. Although current data suggest that the efficacy of celecoxib is similar to that of prototypical NSAIAs but with a lower risk of adverse GI effects, both selective COX-2 inhibitors and prototypical NSAIAs have been associated with an increased risk of cardiovascular events. A decision to use a selective COX-2 inhibitor (e.g., celecoxib) rather than a prototypical NSAIA usually is based on an individual assessment of the risk for GI toxicity. There is some evidence that therapy with a COX-2 inhibitor may be no more effective in reducing the risk of NSAIA-induced GI complications than a combined regimen of a prototypical NSAIA and a proton-pump inhibitor.(See Uses: Osteoarthritis.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction. Disease modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, cyclosporine, etanercept, oral or injectable gold compounds, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, penicillamine, sulfasalazine) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy. DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs. NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.

In double-blind, placebo-controlled studies, therapy with celecoxib was associated with greater reduction in joint tenderness/pain and swelling than placebo. In addition, several double-blind, comparative studies of up to 24 weeks' duration have demonstrated that celecoxib is at least as effective as naproxen or diclofenac in the symptomatic treatment of rheumatoid arthritis but is less likely to cause adverse GI effects.(See Cautions: GI Effects.) Clinical studies of celecoxib generally have included adults receiving standard therapy for rheumatoid arthritis (i.e., NSAIAs with or without DMARDs and/or low-dose oral corticosteroids) who experienced symptomatic exacerbation (symptom ''flare'') within 2-14 days of discontinuing the NSAIA component of their regimen. Symptom flare was defined as a minimum of 6 tender joints and an increase of 20% in the number of tender or painful joints or involvement of at least 2 additional joints since discontinuing NSAIA therapy; a minimum of 3 swollen joints and an increase of 20% in the number of swollen joints or involvement of at least 2 additional joints since discontinuing NSAIA therapy; and either a minimum of 45 minutes of morning stiffnessand an increase of at least 15 minutes in the duration of morning stiffness or an increase in patient-assessed arthritis pain since discontinuing NSAIA therapy.

The American College of Rheumatology criteria for a 20% improvement (ACR 20 response) in measures of disease activity were used as the principal measure of clinical response in studies evaluating the efficacy of celecoxib. An ACR 20 response is achieved if the patient experiences a 20% improvement in the number of tender and swollen joints and a 20% or greater improvement in at least 3 of the following 5 criteria: patient pain assessment; patient global assessment; physician global assessment; patient self-assessed disability; and laboratory measures of disease activity (i.e., ESR or C-reactive protein level). In placebo-controlled and comparative studies in adults with rheumatoid arthritis who had symptom flare, an ACR 20 response was achieved in 30-40% of patients who received celecoxib 100 mg twice daily for 12 weeks, 39-44% of patients who received celecoxib 200 mg twice daily for 12 weeks, 36-42% of patients who received naproxen 500 mg twice daily for 12 weeks, and 23-29% of placebo-treated patients. While celecoxib 100 mg twice daily generally was as effective as celecoxib 200 mg twice daily, some patients experienced additional benefit from the higher dosage. Dosages of 400 mg twice daily provided no additional benefit compared with dosages of 100-200 mg twice daily.

Juvenile Arthritis

Celecoxib is used for the management of the signs and symptoms of juvenile rheumatoid arthritis in children 2 years of age or older. Efficacy of celecoxib was established in pediatric patients with pauciarticular course, polyarticular course, or systemic onset juvenile rheumatoid arthritis (active systemic disease not present at study entry) in a double-blind, active-controlled study of 12 weeks' duration; pediatric patients 2-17 years of age were randomized to receive celecoxib 3 mg/kg (up to a maximum dose of 150 mg) twice daily, celecoxib 6 mg/kg (up to a maximum dose of 300 mg) twice daily, or naproxen 7.5 mg/kg (up to a maximum dose of 500 mg) twice daily. Response was measured using the juvenile rheumatoid arthritis definition of improvement (i.e., a 30% or greater improvement in at least 3 of 6 and a 30% or greater deterioration in no more than 1 of 6 core set criteria that included physician and patient/parent global assessments, active joint count, limitation of motion, functional assessment, and erythrocyte sedimentation rate: JRA DOI 30). Results of this study indicate that celecoxib is as effective as naproxen in the management of juvenile rheumatoid arthritis. Evaluation at week 12 indicated that clinical response (JRA DOI 30) was achieved in 69, 80, or 67% of pediatric patients receiving celecoxib 3 mg/kg twice daily, celecoxib 6 mg/kg twice daily, or naproxen 7.5 mg/kg twice daily, respectively. The manufacturer states that safety and efficacy of celecoxib therapy beyond 6 months in pediatric patients with juvenile arthritis have not been established.

Clinical trials indicate that either celecoxib or a prototypical NSAIA is effective in the management of juvenile rheumatoid arthritis. Celecoxib may have a lower risk of adverse GI effects compared with prototypical NSAIAs and may be useful in children who have experienced adverse GI effects with prototypical NSAIAs. In addition, celecoxib may be useful in children who have experienced other adverse effects with prototypical NSAIAs (e.g., naproxen-induced pseudoporphyria). It remains to be determined whether long-term cardiovascular risks in children exposed to celecoxib are similar to those observed in adults receiving celecoxib or other NSAIAs.(See Cautions: Cardiovascular Effects.)

Ankylosing Spondylitis

Celecoxib is used for the management of the signs and symptoms of ankylosing spondylitis in adults. Clinical trials indicate that either selective COX-2 inhibitors or prototypical NSAIAs are effective for initial symptomatic management of ankylosing spondylitis. Although celecoxib may have a lower risk of adverse GI effects compared with prototypical NSAIAs, both selective COX-2 inhibitors and prototypical NSAIAs have been associated with an increased risk of cardiovascular events. A decision to use a selective COX-2 inhibitor (e.g., celecoxib) rather than a prototypical NSAIA usually is based on an individual assessment of the risk for GI toxicity. There is some evidence that therapy with a COX-2 inhibitor may be no more effective in reducing the risk of NSAIA-induced GI complications than a combined regimen of a prototypical NSAIA and a proton-pump inhibitor.(See Uses: Osteoarthritis.)

In placebo- and active-controlled studies of 6- and 12-weeks' duration in patients with ankylosing spondylitis, celecoxib (100 mg twice daily, 200 mg once daily, or 400 mg once daily) was more effective than placebo, as assessed by global pain intensity and global disease activity (both rated using visual analog scales) and functional impairment (measured using the Bath Ankylosing Spondylitis Functional Index [BASFI]). In the 12-week study, there was no difference in the extent of improvement in those receiving celecoxib 400 mg daily relative to those receiving celecoxib 200 mg daily, but more patients receiving the 400-mg daily dose (53%) than the 200-mg daily dose (44%) were classified as responders (defined as achieving 20% or greater improvement in the Assessment in Ankylosing Spondylitis [ASAS] response criteria). There was no change in responder rates after 6 weeks.

Colorectal Polyps

Celecoxib is used to reduce the number of adenomatous colorectal polyps in adults with familial adenomatous polyposis (FAP) as an adjunct to usual care (e.g., endoscopic surveillance, surgery). Patients with FAP have an inherited mutation in the adenomatous polyposis coli (APC) gene that results in hundreds of adenomatous polyps and an almost 100% risk of colon cancer. The clinical benefit of reducing the number of polyps in individuals with FAP remains to be determined. It is not known whether use of celecoxib in patients with FAP will reduce the risk of colorectal, duodenal, or other FAP-related cancers or whether use of the drug reduces the need for endoscopic surveillance and prophylactic colectomy or other FAP-related surgery. Therefore, FAP patients receiving celecoxib should continue to receive usual care.

Efficacy of celecoxib in reducing the extent of polyposis has been evaluated in a randomized, placebo-controlled study in adults with FAP. In this study, patients with FAP were randomized to receive a 6-month regimen of celecoxib 400 mg twice daily, celecoxib 100 mg twice daily, or placebo. Patients underwent endoscopy at the beginning and end of the study to determine the number and size of polyps in specified areas (one area of the rectum and up to 4 areas of the colon); response to treatment was expressed as the mean percent change in the number of polyps and in polyp burden (expressed as the sum of polyp diameters). The mean pretreatment number of polyps was 11.5-15.5 and the mean pretreatment polyp burden was 34.8-44.7 mm. At month 6, the mean reduction in the number of polyps was 28% in patients who received celecoxib 400 mg twice daily, 12% in those who received celecoxib 100 mg twice daily, and 5% in those who received placebo; the mean reduction in polyp burden was 30.7, 14.6, and 4.9%, respectively. While administration of celecoxib (400 mg twice daily) appears to be associated with a reduction in the number of colorectal polyps in patients with FAP, the clinical benefit of reducing the number of polyps in such individuals remains to be determined and it is unclear whether the effect of celecoxib in reducing the number of polyps persists after the drug is discontinued. The manufacturer states that safety and efficacy of celecoxib therapy for longer than 6 months in patients with FAP have not been studied.

Use of celecoxib for the prevention of adenomatous colorectal polyps (colorectal adenomas) in patients without a history of FAP has been investigated in 2 long-term, National Institute of Health (NIH)-supported, multicenter studies (Adenoma Prevention with Celecoxib [APC]; Prevention of Colorectal Sporadic Adenomatous Polyps [PreSAP]). Patients included in these studies had undergone recent removal of colorectal adenomas and were at high risk of recurrent adenomas. Results of these studies indicate that administration of celecoxib (200 mg twice daily, 400 mg twice daily, or 400 mg once daily) reduces the risk of recurrent colorectal adenomas. The cumulative rate of adenoma detection during up to 3 years of treatment was 33.6-43.2% among patients receiving celecoxib compared with 49.3-60.7% among those receiving placebo. However, some clinicians state that routine use of celecoxib for the prevention of sporadic colorectal adenomas cannot be recommended because of the potential for serious cardiovascular events in celecoxib-treated patients. The studies did not evaluate whether celecoxib alters the risk of a first occurrence of colorectal adenoma or prevents the development of colorectal cancer.

Pain

Celecoxib is used in the management of acute pain, including postoperative (dental, orthopedic) pain, in adults. In pain studies evaluating the efficacy of celecoxib, the drug was effective in the relief of postoperative dental pain and postoperative orthopedic pain that was described as moderate to severe. Following administration of single doses of celecoxib, the onset of analgesia was 60 minutes. In a single-dose study, celecoxib 100 or 400 mg reportedly was more effective than placebo and as effective as aspirin 650 mg for relief of pain following dental extraction. However, limited data indicate that celecoxib 100 or 200 mg as a single dose may be less effective than single doses of ibuprofen 400 mg or naproxen sodium 550 mg for the acute relief of postoperative dental pain.

Dysmenorrhea

Celecoxib is used for the relief of primary dysmenorrhea in adults. In pain studies evaluating the efficacy of celecoxib, the drug was effective in the relief of moderate to severe pain associated with primary dysmenorrhea.

Other Uses

Celecoxib has no effect on platelet function and is not a substitute for aspirin in the prevention of adverse cardiovascular events (e.g., primary or secondary prevention of myocardial infarction).

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease among patients who received an NSAIA for 2 years or longer. Similar findings have been reported from some other, but not all, observational studies.

Dosage and Administration

Administration

The potential benefits and risks of celecoxib therapy as well as alternative therapies should be considered prior to initiating celecoxib therapy.

Celecoxib is administered orally as a single daily dose or in 2 equally divided doses daily. Once- and twice-daily regimens were equally effective in the management of osteoarthritis. The manufacturer recommends a twice-daily dosing schedule for the management of rheumatoid arthritis and juvenile arthritis. The manufacturer states that celecoxib dosages up to 200 mg twice daily may be administered without regard to meals; higher celecoxib dosages (i.e., 400 mg twice daily) should be administered with food to improve absorption.

For patients with difficulty swallowing capsules, the celecoxib capsule may be opened, the contents carefully emptied onto a level teaspoonful of applesauce at room temperature or cooler, and the mixture swallowed immediately with water. This mixture is stable for 6 hours when refrigerated.

Dispensing and Administration Precautions

Because of similarity in spelling of Celebrex (celecoxib), Celexa (citalopram hydrobromide), and Cerebyx (fosphenytoin sodium), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.

When celecoxib is used in the management of arthritis in adults, the dosage of celecoxib should be adjusted according to individual requirements and response, using the lowest possible effective dosage.

Although peak plasma concentrations and area under the plasma concentration-time curve (AUC) were increased 40 and 50%, respectively, in geriatric individuals older than 65 years of age compared with younger adults, dosage adjustment in geriatric adults based solely on age generally is not required. However, for geriatric patients weighing less than 50 kg, celecoxib therapy should be initiated at the lowest recommended dosage.

Osteoarthritis

For the symptomatic treatment of osteoarthritis, the usual adult dosage of celecoxib is 200 mg daily given as a single dose or in 2 equally divided doses. Celecoxib dosages exceeding 200 mg daily (e.g., 200 mg twice daily) do not appear to provide additional therapeutic benefit.

Rheumatoid Arthritis in Adults

For the symptomatic treatment of rheumatoid arthritis, the usual adult dosage of celecoxib is 100-200 mg twice daily. Although the overall efficacy of celecoxib was similar in patients receiving 100 or 200 mg twice daily, additional benefit was observed in some patients receiving the higher dosage. However, celecoxib dosages of 400 mg twice daily do not appear to provide additional therapeutic benefit compared with dosages of 100-200 mg twice daily.

Juvenile Arthritis

For the symptomatic management of juvenile rheumatoid arthritis in children 2 years of age or older, the recommended dosage of celecoxib for children weighing 10-25 kg is 50 mg twice daily, and the recommended dosage for children weighing more than 25 kg is 100 mg twice daily.

Ankylosing Spondylitis

For the symptomatic treatment of ankylosing spondylitis, the usual initial adult dosage of celecoxib is 200 mg daily given as a single dose or in 2 equally divided doses. If no response is observed after 6 weeks, the dosage may be increased to 400 mg daily. If no response is observed following administration of celecoxib 400 mg daily for 6 weeks, response is unlikely and alternative treatment options should be considered.

Colorectal Polyps

To reduce the number of adenomatous colorectal polyps in adults with familial adenomatous polyposis (FAP) as an adjunct to usual care (e.g., endoscopic surveillance, surgery), celecoxib should be given in a dosage of 400 mg twice daily. The manufacturer states that safety and efficacy of celecoxib therapy for longer than 6 months in patients with FAP have not been studied.

Pain and Dysmenorrhea

For the relief of acute pain or dysmenorrhea, the usual initial adult dosage of celecoxib is 400 mg given as a single dose, followed by an additional dose of 200 mg, if necessary, on the first day. For continued relief, 200 mg may be administered twice daily as needed.

Dosage in Renal and Hepatic Impairment

Celecoxib has not been studied in patients with severe renal impairment, and is not recommended for use in such patients. However, if celecoxib therapy must be used in patients with severe renal impairment, close monitoring of renal function is recommended. The AUC of celecoxib was 40% lower in adults with chronic renal insufficiency (e.g., glomerular filtration rate [GFR] 35-60 mL/minute) than that reported in adults with normal renal function although no substantial relationship was found between GFR and clearance of the drug. The manufacturer makes no specific recommendations for dosage modification in patients with chronic renal insufficiency.

The pharmacokinetics of celecoxib have not been studied in patients with severe hepatic impairment, and the manufacturer states that the drug should not be used in such patients. In addition, the AUC of celecoxib was 40 or 180% higher in adults with mild or moderate hepatic impairment, respectively, compared with that reported in patients with normal hepatic function. In patients with moderate hepatic impairment (Child-Pugh Class B), the manufacturer recommends that celecoxib dosage be reduced approximately 50%.

Cautions

Information on the safety of celecoxib has been obtained principally from clinical studies in about 12,000 patients, including those with osteoarthritis, rheumatoid arthritis, or postoperative pain. About 50 or 30% of these patients received the drug for at least 6 months or at least 1 year, respectively; a limited number of patients have received celecoxib for 2 years or longer. Information on the safety of the drug also has been obtained from studies in pediatric patients 2-17 years of age with juvenile rheumatoid arthritis who received the drug for up to 24 weeks and from colorectal adenoma prevention and Alzheimer's disease prevention studies in adults.

At usual dosages, celecoxib generally is well tolerated. Adverse effects of celecoxib usually are mild and mainly involve the GI tract. During controlled clinical studies in adults receiving celecoxib dosages of 100-800 mg daily, the incidence of celecoxib-associated adverse effects generally was similar to that reported with prototypical nonsteroidal anti-inflammatory agents (NSAIAs) (e.g., diclofenac, ibuprofen, naproxen) or placebo; however, the incidence of endoscopically confirmed GI ulceration and clinically observed upper GI perforations, ulcers, and bleeding was higher in patients receiving a prototypical NSAIA than in those receiving placebo or celecoxib. The adverse effects profile of celecoxib reported in a clinical study in adults with familial adenomatous polyposis (FAP) and in clinical studies in patients with ankylosing spondylitis or acute pain, including postoperative (e.g., dental, orthopedic) pain and primary dysmenorrhea, was similar to that reported in clinical studies in patients with arthritis. About 7.1% of adults receiving celecoxib in clinical studies discontinued therapy because of adverse effects compared with 6.1% of those receiving placebo. The most frequent adverse effects requiring discontinuance of celecoxib include dyspepsia (in about 0.8 or 0.6% of patients receiving celecoxib or placebo, respectively) and abdominal pain (in about 0.7 or 0.6% of patients receiving celecoxib or placebo, respectively).

Cardiovascular Effects

Peripheral edema has been reported in 2.1% of adults receiving celecoxib in premarketing clinical studies. Angina pectoris, chest pain, coronary artery disorder, hot flushes, myocardial infarction, palpitation, tachycardia, or aggravated hypertension has been reported in 0.1-1.9% of adults receiving the drug. Adverse cardiovascular effects reported in less than 0.1% of adults receiving celecoxib include syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis, deep-vein thrombosis, and vasculitis.

Peripheral edema or hypertension occurred in 4.5 or 2.4%, respectively, of patients receiving celecoxib (400 mg twice daily) in the Celecoxib Long-term Arthritis Safety Study (CLASS). Peripheral edema and hypertension also have been described as evidence of adverse renal effects. (See Cautions: Renal, Electrolyte, and Genitourinary Effects.)

Thrombotic Events

NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study. Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied. Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use. Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs. However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another. Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.

Rofecoxib Experience

In September 2004, one selective COX-2 inhibitor, rofecoxib, was voluntarily withdrawn from the world market based on data from a prospective, randomized, placebo-controlled study (Adenomatous Polyp Prevention on Vioxx; APPROVe). This study was designed to evaluate the efficacy of rofecoxib in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas. The primary efficacy end point was the incidence of colorectal adenoma; safety was monitored on a regular basis by an external board. In this study, there was an increased relative risk of confirmed thrombotic events (e.g., myocardial infarction, unstable angina, sudden death from cardiac causes, ischemic stroke, transient ischemic attack, peripheral arterial thrombosis, peripheral venous thrombosis, pulmonary embolism) in patients receiving rofecoxib compared with those receiving placebo. At study end point, 27 patients had experienced confirmed thrombotic events during 3327 patient-years of placebo use, and 47 had experienced confirmed thrombotic events during 3059 patient-years of rofecoxib use. The relative risk of a confirmed thrombotic event in patients receiving rofecoxib compared with those receiving placebo was 1.89 (95% confidence interval: 1.18-3.04). The difference between the 2 groups was related mainly to an increased number of myocardial infarctions and strokes in patients receiving rofecoxib. The relative risk of an Antiplatelet Trialists' Collaboration end point (death from cardiovascular, hemorrhagic, or unknown causes; nonfatal myocardial infarction; nonfatal ischemic or hemorrhagic stroke) was 2.12 (95% confidence interval: 1.2-3.74). No difference in overall mortality was observed between treatment groups.

Extended posttreatment follow-up data regarding cardiovascular events and mortality were available for approximately 84 and 95%, respectively, of patients in the APPROVe study. The median posttreatment follow-up was 550 or 538 days for rofecoxib-treated patients or placebo recipients, respectively. Over the treatment and extended follow-up periods combined, 59 rofecoxib-treated patients and 34 placebo recipients experienced an Antiplatelet Trialists' Collaboration event (hazard ratio of 1.79; 95% confidence interval: 1.17-2.73). During the first year following discontinuance of the study drug, such events occurred more frequently in patients who had received rofecoxib compared with those who had received placebo (23 versus 12 patients; hazard ratio of 1.95; 95% confidence interval: 0.97-3.93), but no difference was evident after the first posttreatment year.

In a study in adults with rheumatoid arthritis who were randomized to receive rofecoxib (50 mg daily) or naproxen (500 mg twice daily) (Vioxx Gastrointestinal Outcomes Research; VIGOR), the risk of developing a serious cardiovascular thrombotic event was substantially higher in those receiving rofecoxib than in those receiving naproxen; mortality secondary to cardiovascular events was similar in both groups. In addition, information from pooled analyses and database reviews of large populations indicate that use of rofecoxib is associated with an increased risk of major cardiovascular events (e.g., myocardial infarction) relative to use of celecoxib, prototypical NSAIAs, or no NSAIAs; some evidence indicates that rofecoxib dosages exceeding 25 mg daily are associated with a higher risk of major cardiovascular events than rofecoxib dosages of 25 mg daily or less.

Celecoxib Experience

Data from clinical trials comparing celecoxib with prototypical NSAIAs in patients with osteoarthritis or rheumatoid arthritis and from placebo-controlled trials evaluating use of celecoxib for the prevention of adenomatous polyps or Alzheimer's disease have provided varied estimates of the cardiovascular risk associated with celecoxib. Although data from some large, randomized studies (Prevention of Spontaneous Adenomatous Polyps [PreSAP], Alzheimer's Disease Anti-inflammatory Prevention Trial [ADAPT]) and database reviews of large populations have not shown an increased risk of cardiovascular events in patients receiving celecoxib, an increased incidence of cardiovascular events was observed in patients receiving celecoxib in a colorectal adenoma prevention study (Adenoma Prevention with Celecoxib [APC]).

In a study (CLASS) in adults with osteoarthritis or rheumatoid arthritis who were randomized to receive celecoxib (400 mg twice daily), ibuprofen (800 mg 3 times daily), or diclofenac sodium (75 mg twice daily), no difference in thrombotic events (myocardial infarction, pulmonary embolism, deep-vein thrombosis, unstable angina, transient ischemic attacks, ischemic cardiovascular accidents) was observed between celecoxib and the prototypical NSAIAs used in this study. Although findings from the CLASS study suggested that the risk of cardiovascular events in patients receiving celecoxib was similar to the risk in those receiving prototypical NSAIAs, the study was not designed to establish cardiovascular safety as a primary end point. There are noteworthy differences between the VIGOR and CLASS studies (patient selection relative to cardiac-related factors [e.g., use of low-dose aspirin], indication for use of the selective COX-2 inhibitor, and the active comparator agent), and conclusions regarding differences in risk of cardiovascular events between rofecoxib and celecoxib cannot be made from these studies.

Additional information on the relationship between use of celecoxib and cardiovascular risk is available from 2 long-term National Institutes of Health (NIH)-supported colorectal adenoma prevention trials and an NIH-supported Alzheimer's disease prevention trial. In one colorectal adenoma prevention trial (APC), an interim analysis of safety data revealed an increased risk of cardiovascular events in patients receiving celecoxib compared with those receiving placebo. The cumulative rates of serious cardiovascular thrombotic events began to differ between those receiving celecoxib and those receiving placebo after about 1 year of treatment. Based on these adverse cardiovascular findings, NIH suspended the study early. Final data for this study became available in 2006, and the findings of the updated safety analysis, which included data for all patients with up to 3 years of follow-up, were similar to those reported in the interim analysis. The final analysis indicated that the risk of serious cardiovascular events (cardiovascular death, myocardial infarction, or stroke) was increased in patients receiving celecoxib 200 mg twice daily (hazard ratio of 2.8; 95% confidence interval: 1.1-7.2) or celecoxib 400 mg twice daily (hazard ratio of 3.4; 95% confidence interval: 1.4-8.5), compared with that in patients receiving placebo; the increase in risk with celecoxib compared with placebo was related mainly to an increased incidence of myocardial infarction.

Findings from another colorectal adenoma prevention trial (PreSAP) did not show an increased incidence of adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke) in patients receiving celecoxib 400 mg once daily compared with patients receiving placebo. Serious cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure) occurred in 2.5% of patients receiving celecoxib and in 1.9% of patients receiving placebo (relative risk of 1.3; 95% confidence interval: 0.65-2.62). An analysis of pooled data from the APC and PreSAP studies demonstrated an increased risk for death from cardiovascular causes, myocardial infarction, stroke, or heart failure in celecoxib-treated patients.

Analysis of results from ADAPT did not show an increased risk for cardiovascular-related death, myocardial infarction, stroke, or transient ischemic attack, either individually or as composite end points, in patients receiving celecoxib (200 mg twice daily) relative to patients receiving placebo.

Data concerning the risk of cardiovascular events in patients receiving celecoxib continue to be collected and evaluated. Current evidence suggests that cardiovascular risk associated with celecoxib use may be dose related, with dosages exceeding 200 mg daily associated with greater risk. Meta-analyses of data from published and unpublished controlled clinical trials, systematic reviews, and large observational studies have yielded varied estimates of the cardiovascular risks associated with celecoxib use. A systematic review of controlled observational studies that included 11 studies of celecoxib suggested that celecoxib is not associated with an increased risk of cardiovascular events, but because only 3 of these studies provided dose-stratified risk estimates, there were insufficient data to provide stable estimates of the effect of dosage on risk. In an update of this systematic review that included 35 studies of celecoxib, both low (200 mg or less daily) and higher (exceeding 200 mg daily) dosages of celecoxib were associated with an increased risk of cardiovascular events (low dosage: relative risk of 1.26; 95% confidence interval: 1.09-1.47) (higher dosage: 1.69; 1.11-2.57); the increase in the risk estimate at higher dosages compared with lower dosages did not reach conventional levels of significance. In observational studies in patients with prior myocardial infarction, both low and higher dosages of celecoxib were associated with increased cardiovascular risk, but risk appeared to be greater at dosages exceeding 200 mg daily. A pooled analysis of data from 6 randomized placebo-controlled studies evaluating any of 3 higher-dosage regimens of celecoxib suggested that the risk of cardiovascular events was highest for a celecoxib dosage of 400 mg twice daily (hazard ratio of 3.1; 95% confidence interval: 1.5-6.1), intermediate for a dosage of 200 mg twice daily (1.8; 1.1-3.1), and lowest for a dosage of 400 mg once daily (1.1; 0.6-2).

Experience with Other COX-2 Inhibitors

Results of pooled analyses of randomized studies of valdecoxib (no longer commercially available in the US) in patients with rheumatoid arthritis or osteoarthritis and a systematic review of controlled observational studies that included limited data on valdecoxib suggested that such use is not associated with an increased risk of cardiovascular thrombotic events. However, administration of valdecoxib with or without parecoxib (a prodrug of valdecoxib; a parenteral formulation not commercially available in the US) immediately after surgery in patients undergoing coronary artery bypass grafting (CABG) has been associated with an increase in cardiovascular events compared with CABG patients receiving standard care (e.g., opiate analgesics) for postoperative pain. Therefore, NSAIAs are contraindicated in the setting of CABG surgery.

Findings of pooled analyses and observational studies suggest that use of lumiracoxib or etoricoxib (neither drug commercially available in the US) is associated with an increased risk of major cardiovascular events. Of the 7 NSAIAs studied in one meta-analysis (including celecoxib, diclofenac, etoricoxib, ibuprofen, lumiracoxib, naproxen, and rofecoxib), etoricoxib and diclofenac were associated with the highest risk of cardiovascular death; rofecoxib was associated with the highest risk of myocardial infarction, followed by lumiracoxib; and ibuprofen was associated with the highest risk of stroke, followed by diclofenac, lumiracoxib, and etoricoxib.(See Experience with Prototypical NSAIAs under Cardiovascular Effects: Thrombotic Events, in Cautions.)

Data from long-term studies of lumiracoxib and etoricoxib also are available. In the Therapeutic COX-189 Arthritis Research and Gastrointestinal Event Trial (TARGET), the incidence of myocardial infarction, stroke, or cardiac death in patients receiving lumiracoxib was similar to that in patients receiving a prototypical NSAIA (naproxen or ibuprofen). The study was designed as 2 substudies, and substudy results suggested that lumiracoxib was associated with a slightly, but not significantly, increased risk for cardiovascular events compared with naproxen and a slightly, but not significantly, decreased risk compared with ibuprofen. In the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study, a randomized controlled study designed to evaluate relative cardiovascular thrombotic risk with etoricoxib (60 or 90 mg daily) compared with diclofenac (75 mg twice daily), the risk of a serious cardiovascular event in patients receiving etoricoxib was similar to that in patients receiving diclofenac; the most common cardiovascular event was myocardial infarction.

Experience with Prototypical NSAIAs

Data concerning the risk of cardiovascular events in patients receiving prototypical NSAIAs continue to be collected and evaluated. In some studies (CLASS, MEDAL), the risk of cardiovascular events in patients receiving selective COX-2 inhibitors has been similar to that in patients receiving prototypical NSAIAs (diclofenac, ibuprofen). The risk of cardiovascular events associated with selective COX-2 inhibitors and individual prototypical NSAIAs has been evaluated in several systematic reviews of controlled observational studies and meta-analyses of published and unpublished data from randomized studies.

In one systematic review, 23 observational studies providing data on individual prototypical NSAIAs reported mainly on diclofenac, indomethacin, ibuprofen, naproxen, and piroxicam. A meta-analysis utilizing tabular data from studies found through searches conducted for the period of 1966 to early 2005 provided estimates of cardiovascular risk for 3 of these drugs (diclofenac, ibuprofen, and naproxen, generally at relatively high dosages). In the meta-analysis, the risks associated with these 3 drugs were estimated indirectly relative to placebo (i.e., from studies of prototypical NSAIAs versus selective COX-2 inhibitors and studies of selective COX-2 inhibitors versus placebo) because of insufficient data from randomized placebo-controlled trials of prototypical NSAIAs. Findings from these 2 analyses suggested that use of certain prototypical NSAIAs is associated with an increased risk of cardiovascular events. The findings suggested that use of naproxen does not alter the risk of cardiovascular events (summary relative risk of 0.99; 95% confidence interval: 0.89-1.09; based on data from 16 observational studies) (summary relative risk of 0.92; 95% confidence interval: 0.67-1.26; meta-analysis) but that the risk of cardiovascular events is increased with use of diclofenac (summary relative risk of 1.4; 95% confidence interval: 1.19-1.65; 10 observational studies) (summary relative risk of 1.63; 95% confidence interval: 1.12-2.37; meta-analysis) or indomethacin (summary relative risk of 1.36; 95% confidence interval: 1.15-1.61; 7 observational studies). The findings also suggested that use of ibuprofen may be associated with an increased risk of cardiovascular events, although the reported risk estimates from these 2 analyses did not reach conventional levels of significance (summary relative risk of 1.09; 95% confidence interval: 0.99-1.2; 17 observational studies) (summary relative risk of 1.51; 95% confidence interval: 0.96-2.37; meta-analysis). Few data were available for meloxicam or piroxicam. The available data suggested that use of meloxicam may be associated with an increased risk of cardiovascular events (summary relative risk of 1.24; 95% confidence interval: 1.06-1.45; 4 observational studies); however, the finding of increased risk was based largely on results from one study. The risk ratio reported for piroxicam does not suggest increased risk (summary relative risk of 1.16; 95% confidence interval: 0.86-1.56; 5 observational studies).

The systematic review was subsequently updated to provide updated risk estimates and to evaluate dose-response effects for certain NSAIAs. The updated review included data from 51 controlled observational studies and 43 unique data sets, and provided estimates of cardiovascular risk for 11 NSAIAs. Of the 6 NSAIAs that were evaluated in 10 or more studies (range: 14-41 studies), pooled estimates of overall cardiovascular risk were highest for rofecoxib (pooled relative risk of 1.45; 95% confidence interval: 1.33-1.59) and diclofenac (1.4; 1.27-1.55) and lowest for naproxen (1.09; 1.02-1.16); the pooled risk estimate for indomethacin (1.3; 1.19-1.41) was close to that for diclofenac, and pooled risk estimates for ibuprofen (1.18; 1.11-1.25) and celecoxib (1.17; 1.08-1.27) were somewhat lower. Dose-response data were available from a subset of studies, and analyses utilizing these data indicated that low dosages of rofecoxib (25 mg or less daily), celecoxib (200 mg or less daily), and diclofenac (defined in most studies as 100 mg or less daily) were associated with elevated risk; higher dosages of these drugs were associated with even greater risk, although the increase in risk at higher dosages did not reach conventional levels of significance for celecoxib. With ibuprofen, elevated risk was observed only at high dosages (defined in most studies as more than 1.2 g daily). In this data subset, neither low nor high dosages of naproxen were associated with increased risk. Fewer data were available for etoricoxib, etodolac, meloxicam, piroxicam, and valdecoxib; of these drugs, etoricoxib appeared to be associated with the highest risk of cardiovascular events, followed by etodolac and meloxicam. Pair-wise comparisons suggested that cardiovascular risk was lower with naproxen compared with ibuprofen and was higher with diclofenac compared with celecoxib, ibuprofen, or naproxen; with etoricoxib compared with ibuprofen or naproxen; with indomethacin compared with naproxen; and with meloxicam compared with naproxen. No substantial differences in risk were found for diclofenac compared with rofecoxib, for naproxen compared with celecoxib, or for etodolac compared with diclofenac, ibuprofen, or naproxen.

A meta-analysis from the Coxib and Traditional NSAIDs Trialists' (CNT) Collaboration that utilized data from randomized trials with results available prior to 2011 provided estimates of cardiovascular risk for diclofenac, ibuprofen, and naproxen. Data for individual participants, rather than aggregate tabular data, were utilized when available. The risks associated with diclofenac, ibuprofen, and naproxen relative to placebo were obtained by combining estimates made directly (i.e., from a small number of placebo-controlled trials) or indirectly (i.e., from studies of prototypical NSAIAs versus selective COX-2 inhibitors and studies of selective COX-2 inhibitors versus placebo). The findings suggested that vascular risks of high-dose diclofenac, and possibly those of high-dose ibuprofen, are similar to those of selective COX-2 inhibitors, but high-dose naproxen may be associated with less vascular risk. The prototypical NSAIA regimens all involved high dosages with minimal variations in dosage (diclofenac 150 mg daily, ibuprofen 2.4 g daily, naproxen 1 g daily). The findings suggested that the risk of major vascular events was increased by about one-third by diclofenac (rate ratio of 1.41; 95% confidence interval: 1.12-1.78) or a selective COX-2 inhibitor (1.37; 1.14-1.66), mainly because of an increase in major coronary events (diclofenac: 1.7; 1.19-2.41) (selective COX-2 inhibitors: 1.76; 1.31-2.37). The findings also suggested that ibuprofen increased major coronary events (2.22; 1.1-4.48) but not major vascular events (1.44; 0.89-2.33). Naproxen did not appear to increase major vascular events (0.93: 0.69-1.27) or major coronary events (0.84; 0.52-1.35). In this analysis, the risk of vascular death was increased by diclofenac (1.65; 0.95-2.85) and selective COX-2 inhibitors (1.58; 1-2.49), increased but not to conventional levels of significance by ibuprofen (1.9; 0.56-6.41), but not increased by naproxen (1.08; 0.48-2.47). The estimated excess risks for diclofenac and selective COX-2 inhibitors compared with placebo suggested that diclofenac or a selective COX-2 inhibitor could cause approximately 3 additional major vascular events, including 1 fatal event, per 1000 patients per year.

Another meta-analysis of data from 31 large randomized controlled studies provided estimates of cardiovascular risk for diclofenac, ibuprofen, naproxen, and 4 selective COX-2 inhibitors. The results supported those of other analyses indicating that both prototypical NSAIAs and selective COX-2 inhibitors increase the risk of cardiovascular events. The cardiovascular safety profiles of the individual NSAIAs compared with placebo varied depending on the specific outcome. Of the 7 NSAIAs studied, etoricoxib (rate ratio of 4.07; 95% credibility interval of 1.23-15.7) and diclofenac (3.98; 1.48-12.7) were associated with the highest risk of cardiovascular death; rofecoxib was associated with the highest risk of myocardial infarction (2.12; 1.26-3.56), followed by lumiracoxib (2; 0.71-6.21); and ibuprofen was associated with the highest risk of stroke (3.36; 1-11.6), followed by diclofenac (2.86; 1.09-8.36), lumiracoxib (2.81; 1.05-7.48), and etoricoxib (2.67; 0.82-8.72). Naproxen appeared to have the least harmful cardiovascular effects of the 7 NSAIAs.

Patients with Elevated Cardiovascular Risk

Several observational studies utilizing data from national registries of hospitalization and drug dispensing from pharmacies in Denmark have examined the cardiovascular risk associated with use of NSAIAs in patients with prior myocardial infarction. In these studies, approximately 84,000-99,000 patients who had been hospitalized for a first-time myocardial infarction during the 10 or 13-year study period were identified; approximately 42-44% of these patients subsequently claimed at least one prescription for an NSAIA. Results from these studies indicated that patients who received NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment. Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years). Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up. Similar patterns were observed for the composite end point of coronary death or nonfatal recurrent myocardial infarction.

In these Danish registry studies, the most commonly used NSAIAs were ibuprofen and diclofenac, followed by celecoxib, rofecoxib, and naproxen. When analyzed separately, these NSAIAs were associated with increased risk of cardiovascular death and increased risk of coronary death and nonfatal myocardial infarction, but increased risk was evident for ibuprofen and naproxen only at higher dosages (exceeding 1.2 g or 500 mg daily, respectively). Estimated risks were elevated at low dosages of celecoxib (200 mg or less daily), diclofenac (100 mg or less daily), and rofecoxib (25 mg or less daily), but were increased further at higher dosages of these drugs.

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following CABG surgery, the incidence of myocardial infarction and stroke was increased.(See Experience with Other COX-2 Inhibitors under Cardiovascular Effects: Thrombotic Events, in Cautions.)

Limited data are available regarding cardiovascular risks associated with use of NSAIAs in patients with stable atherothrombotic disease. A post hoc analysis of data from the International Verapamil Trandolapril Study (INVEST), which compared antihypertensive regimens in patients with stable coronary artery disease and hypertension, indicated an increased risk for the composite end point of death, nonfatal myocardial infarction, or nonfatal stroke in patients who reported long-term NSAIA use compared with patients who did not report long-term use (4.4 versus 3.7 events per 100 patient-years; hazard ratio of 1.47; 95% confidence interval: 1.19-1.82). An ongoing randomized controlled study is evaluating the cardiovascular safety of celecoxib compared with ibuprofen or naproxen in patients with high cardiovascular risk.(See Ongoing Research under Cardiovascular Effects: Cardiovascular Risk Considerations for COX-2 Inhibitors and Prototypical NSAIAs, in Cautions.)

Heart Failure

Data from observational studies indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality. Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure. In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure. Fluid retention and edema also have been observed in some patients receiving NSAIAs.

In the retrospective study utilizing Danish national registry data, more than 100,000 patients who had survived a first hospitalization for heart failure were identified from the registry; about 34% of these patients claimed at least one prescription for an NSAIA after discharge. Risks associated with the 5 most commonly used NSAIAs were analyzed separately. Low dosages of celecoxib (200 mg or less daily), diclofenac (100 mg or less daily), and rofecoxib (25 mg or less daily) were associated with an increased risk of death; higher dosages of these drugs were associated with even higher levels of risk. With ibuprofen and naproxen, only higher dosages (exceeding 1.2 g or 500 mg daily, respectively) were associated with an increased risk of death. All 5 NSAIAs were associated with an increased risk of hospitalization for myocardial infarction or heart failure.

Cardiovascular Risk Considerations for COX-2 Inhibitors and Prototypical NSAIAs

FDA reviewed the safety of NSAIAs in early 2005 and concluded that the 3 selective COX-2 inhibitors that previously had been marketed in the US or were on the market in the US at that time (celecoxib, rofecoxib, valdecoxib) were associated with an increased risk of serious adverse cardiovascular events compared with placebo. In addition, FDA noted that data from some long-term controlled studies that included both a selective COX-2 inhibitor and a prototypical NSAIA did not clearly demonstrate that use of a selective COX-2 inhibitor was associated with a greater risk of serious adverse cardiovascular events than use of prototypical NSAIAs. Long-term data from placebo-controlled clinical trials were not available to assess the potential for prototypical NSAIAs to increase the risk of serious cardiovascular events. FDA interpreted data on cardiovascular risk available in 2005 as being applicable to all NSAIAs, including selective COX-2 inhibitors and prototypical NSAIAs.

As a result of this analysis, FDA directed manufacturers of all NSAIAs (except aspirin) to add a boxed warning to the labeling of their products to alert clinicians to the increased risk of serious cardiovascular events and GI toxicity. In addition to the boxed warning and other information in the professional labeling, FDA recommended that a patient medication guide explaining the risks and benefits of these drugs be provided to the patient each time the drugs are dispensed.

At that time, short-term use of NSAIAs to relieve acute pain, especially at low dosages, did not appear to be associated with an increased risk of serious cardiovascular events (except immediately following CABG surgery). Therefore, in early 2005, FDA concluded that preparations of NSAIAs that currently were available without a prescription (OTC) had a favorable benefit-to-risk ratio when used according to labeled instructions and determined that these preparations should remain available without a prescription despite the addition of a boxed warning to the professional labeling of prescription-only NSAIA preparations. FDA directed manufacturers of nonprescription NSAIAs to revise the labeling of these preparations to include more specific information on the potential cardiovascular and GI risks and information to assist individuals in the safe use of these agents.

Following completion of additional studies and analyses of pooled study data, FDA again reviewed the cardiovascular risks associated with NSAIAs. Findings of this FDA review of published observational studies of NSAIAs, the CNT meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied. Available data now suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use. Published observational studies also indicate that use of NSAIAs in patients who have had a myocardial infarction increases the risk of reinfarction and death. Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk. Therefore, in July 2015, FDA strengthened an existing warning in the labeling of NSAIAs regarding the increased risk of cardiovascular thrombotic events in patients receiving NSAIAs and an existing caution regarding risk in patients with heart failure. FDA directed manufacturers of prescription and nonprescription NSAIA preparations to revise the labeling of these preparations to include updated information regarding cardiovascular risk.

Concomitant Aspirin Therapy

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. In several studies (APC, TARGET APPROVe), post hoc analyses or planned subset analyses suggested that the overall risk for cardiovascular events in patients receiving a COX-2 inhibitor versus placebo or a prototypical NSAIA was not influenced by use of low-dose aspirin.

Ongoing Research

Studies designed specifically to assess the relationship between NSAIAs, including selective COX-2 inhibitors and prototypical NSAIAs, and cardiovascular events are needed to determine the precise risk of cardiovascular events in patients receiving these agents. As part of ongoing research, the manufacturer of celecoxib is conducting a large randomized, double-blind, controlled clinical study (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen [PRECISION]) to evaluate the effects of celecoxib compared with ibuprofen or naproxen on cardiovascular and GI events in patients with osteoarthritis or rheumatoid arthritis and high cardiovascular risk, including a history of coronary artery disease, other occlusive arterial disease, diabetes mellitus, or at least 2 risk factors for atherosclerosis, but no history of myocardial infarction, stroke, CABG surgery, or unstable angina within the prior 3 months. Decisions regarding use of NSAIAs should take into account risks and benefits of such therapy. These agents should be used with caution and careful monitoring of outcomes and adverse effects.

GI Effects

Dyspepsia, diarrhea, abdominal pain, nausea, or flatulence occurred in 8.8, 5.6, 4.1, 3.5, or 2.2%, respectively, of adults receiving usual dosages of celecoxib in clinical studies. Anorexia, constipation, diverticulitis, dry mouth, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, increased appetite, melena, stomatitis, taste perversion, tenesmus, tooth disorder, or vomiting has been reported in 0.1-1.9% of adults receiving celecoxib. Adverse GI effects reported in less than 0.1% of adults include intestinal obstruction, intestinal perforation,colitis with bleeding, esophageal perforation, pancreatitis, cholelithiasis, and ileus. GI bleeding also was reported, albeit rarely, in patients receiving celecoxib during postmarketing surveillance. Intestinal anastomotic ulceration was reported in a few patients with FAP who received celecoxib in a clinical study; these patients had prior intestinal surgery. Dry socket (alveolar osteitis) was reported in patients receiving celecoxib for postoperative dental pain in a clinical study. Abdominal pain, nausea, diarrhea, or vomiting has been reported in 3-8% of children receiving celecoxib in an active-controlled clinical study.

GI Risk Considerations for COX-2 Inhibitors and Prototypical NSAIAs

Numerous short-term (12-24 weeks' duration), comparative, randomized, controlled studies using endoscopy have been performed in patients with osteoarthritis or rheumatoid arthritis to evaluate the incidence of celecoxib-associated upper GI ulceration relative to that associated with prototypical NSAIAs. In these studies, the incidence of endoscopically confirmed GI ulceration generally was lower in patients receiving celecoxib than in those receiving a prototypical NSAIA (e.g., diclofenac, ibuprofen, naproxen). Results of two 3-month studies showed that gastroduodenal ulcer occurred in 2.7-5.9% of patients receiving celecoxib (50-400 mg twice daily), 16.2-17.6% of patients receiving naproxen (500 mg twice daily), and 2-2.3% of patients receiving placebo. Celecoxib was associated with a lower incidence of endoscopic ulcers than diclofenac (4% versus 15%) in one 6-month study. No consistent relationship between celecoxib dosage and the incidence of GI ulcers has been established in these studies. The correlation between endoscopic findings and the incidence of clinically important upper GI events remains to be determined.

The incidence of severe adverse upper GI effects in patients receiving celecoxib relative to the incidence in those receiving prototypical NSAIAs has been evaluated in a double-blind, randomized controlled study in patients with osteoarthritis or rheumatoid arthritis (the Celecoxib Long-term Arthritis Safety Study [CLASS]). Patients were randomized to receive celecoxib (400 mg twice daily), ibuprofen (800 mg 3 times daily), or diclofenac (75 twice daily) for up to 65 weeks; patients were allowed to continue aspirin therapy (up to 325 mg daily) for cardiovascular prophylaxis. Published results of the first 6 months of the study indicated that therapy with celecoxib was associated with a lower incidence of symptomatic ulcers and ulcer complications combined than therapy with ibuprofen or diclofenac; the decrease in upper GI toxicity in patients receiving celecoxib generally was observed only in those not receiving concomitant low-dose aspirin. However, results for celecoxib therapy were less favorable at 12 months than at 6 months, since almost all of the ulcer complications reported during the second half of the study occurred in patients receiving celecoxib; however, a greater percentage of patients receiving a prototypical NSAIA (i.e., diclofenac) than patients receiving celecoxib withdrew from the study because of GI intolerance, potentially biasing GI event rates at 12 months. Overall, the incidence of complicated ulcers in patients receiving celecoxib was similar to the incidence in those receiving the comparator agents (i.e., ibuprofen or diclofenac). Patients receiving celecoxib and low-dose aspirin experienced a fourfold higher rate of complicated ulcers compared with those receiving celecoxib alone. The rate of complicated and symptomatic ulcers at 9 months was 0.78 or 2.19% in those receiving celecoxib alone or celecoxib and low-dose aspirin, respectively; the rate of these adverse GI effects was 0.47 or 1.26% in patients younger than 65 years of age or 1.4 or 3.06% in those 65 years of age and older receiving celecoxib alone or celecoxib and low-dose aspirin, respectively. In patients with a history of peptic ulcer disease, the rate of complicated and symptomatic ulcers at 48 weeks was 2.56 or 6.85% in those receiving celecoxib or celecoxib and low-dose aspirin, respectively. Low-dose aspirin did not have a clinically important effect on the rate of upper GI complications in patients receiving prototypical NSAIAs.

Serious adverse GI effects (e.g., bleeding, ulceration, perforation of the stomach, small intestine, or large intestine) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms. Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic. Therefore, clinicians should remain alert to the possible development of serious adverse GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed on a long-term basis for the development of manifestations of such effects and advised of the importance of this follow-up. In addition, patients should be advised about the signs and/or symptoms of serious NSAIA-induced GI toxicity and what action to take if such toxicity occurs. Longer duration of therapy with an NSAIA increases the likelihood of a serious adverse GI event. However, short-term therapy is not without risk.

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors. In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status. Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis. In addition, most spontaneous reports of fatal GI effects have been in geriatric or debilitated patients.

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy. Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy. In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest. In addition, efficacy of usual dosages of H2-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established. Therefore, most clinicians do not recommend use of H2-receptor antagonists for the prevention of NSAIA-associated ulcers. Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of cyclooxygenase-2 (COX-2) (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs. However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori-negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk. Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.

Nervous System Effects

Headache has been reported in about 16% of adults receiving celecoxib in clinical studies, whereas dizziness or insomnia occurred in 2 or 2.3% of these patients, respectively. Anxiety, asthenia, depression, hypertonia, hypoesthesia, migraine, nervousness, neuralgia, neuropathy, paresthesia, somnolence, or vertigo has been reported in 0.1-1.9% of adults receiving celecoxib, and aseptic meningitis, ataxia, ageusia, anosmia, fatal intracranial hemorrhage, or suicide occurred in less than 0.1% of these patients. Headache occurred in 10-13% of children receiving celecoxib in an active-controlled clinical study.

Respiratory Effects

Upper respiratory tract infection, sinusitis, pharyngitis, or rhinitis has occurred in 8.1, 5, 2.3, or 2%, respectively, of adults receiving usual dosages of celecoxib in clinical studies. Bronchitis, bronchospasm (including aggravated bronchospasm), coughing, dyspnea, laryngitis, or pneumonia has been reported in 0.1-1.9% of adults. Cough or nasopharyngitis has been reported in 5-7% of celecoxib-treated children.

Dermatologic and Sensitivity Reactions

Rash occurred in 2.2% of adults receiving celecoxib in clinical studies. Adverse dermatologic effects occurring in 0.1-1.9% of adults receiving celecoxib include alopecia, dermatitis, dry skin, erythematous rash, maculopapular rash, nail disorder, photosensitivity reaction, pruritus, skin disorder, increased sweating, and urticaria. Cellulitis, contact dermatitis, injection site reaction, or skin nodule has occurred in 0.1-1.9% of patients following topical application of celecoxib.

Allergic reactions, aggravated allergy, bronchospasm, or generalized or facial edema has been reported in 0.1-1.9% of adults receiving celecoxib. Anaphylactoid reactions and angioedema have occurred in patients receiving celecoxib. As with other NSAIAs, anaphylactic reactions have been reported rarely in patients with no previous exposure to the drug. Erythema multiforme, exfoliative dermatitis, Sweet's syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely in patients receiving celecoxib.

Hematologic Effects

Anemia has been reported in 0.6% of celecoxib-treated adults. Ecchymosis, epistaxis, or thrombocythemia has occurred in 0.1-1.9% of adults receiving celecoxib in clinical studies, and agranulocytosis, aplastic anemia, pancytopenia, leukopenia, and thrombocytopenia has occurred in less than 0.1% of these patients.

In contrast to prototypical NSAIAs, including aspirin, usual dosages of celecoxib generally do not appear to inhibit platelet aggregation, serum thromboxane B concentrations, or bleeding time. In addition, usual dosages of the drug do not affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT).(See Pharmacology: Hematologic Effects.)

Although comparative studies are limited, therapy with celecoxib is expected to be associated with fewer and less severe episodes of bleeding than therapy with prototypical NSAIAs. However, bleeding events have been reported in postmarketing experience, predominantly in geriatric patients, in association with increased PTs in patients receiving celecoxib concomitantly with warfarin.(See Warfarin under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Modest prolongation of the activated partial thromboplastin time (aPTT) with no change in PT has been reported in celecoxib-treated pediatric patients with systemic onset juvenile rheumatoid arthritis.

Renal, Electrolyte, and Genitourinary Effects

Whether COX-2 selectivity affects renal function is unclear.(See Pharmacology: Renal Effects.) Like prototypical NSAIAs, celecoxib has been associated with adverse renal effects. In one study in arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding while receiving long-term NSAIA therapy, celecoxib therapy (200 mg twice daily) was associated with a 24.3% incidence of adverse renal effects; however, this study defined hypertension as an adverse renal effect, and this was the principal adverse renal effect reported (occurring in 13.9% of treated patients and accounting for 57% of reported renal effects). Peripheral edema also was defined as an adverse renal effect in this study, occurring in 4.9% of treated patients; when its incidence was combined with that of hypertension, these 2 effects accounted for 77% of reported renal effects. The incidence of adverse renal effects was increased in patients with preexisting renal impairment.

Albuminuria; increased BUN, nonprotein nitrogen (NPN), and serum creatinine concentration; cystitis; dysuria; hematuria; frequent micturition; renal calculus; urinary incontinence; urinary tract infection; dysmenorrhea; genital moniliasis; menstrual disorder; vaginal hemorrhage; vaginitis; or prostatic disorder has occurred in 0.1-1.9% of adults receiving celecoxib. Acute renal failure, interstitial nephritis, or hyponatremia has been reported in less than 0.1% of adults receiving the drug. In one study in arthritis (principally osteoarthritis) patients receiving celecoxib 200 mg daily, renal failure (a progressive rise in serum creatinine concentration to exceed 2.2 mg/dL) was reported in 5.6% of patients; 25.7% of all celecoxib-treated patients in this study had baseline serum creatinine concentrations exceeding 1.2 mg/dL when therapy with the drug was initiated.

Long-term administration of NSAIAs has resulted in renal papillary necrosis and other renal injury.

Musculoskeletal Effects

Back pain has been reported in 2.8% of adults receiving celecoxib. Arthralgia, arthrosis, bone disorder, leg cramps, myalgia, neck stiffness, synovitis, tendinitis, or accidental fracture has occurred in 0.1-1.9% of adults receiving the drug. Arthralgia has been reported in 3-7% of children receiving celecoxib in an active-controlled clinical study.

Ocular and Otic Effects

Adverse ocular and otic effects reported in 0.1-1.9% of adults receiving celecoxib include blurred vision, cataract, conjunctivitis, ocular pain, glaucoma, deafness, ear abnormality, earache, otitis media, and tinnitus.

Hepatic Effects

In controlled clinical studies in adults, the incidence of borderline elevations in liver function test results was similar in patients receiving celecoxib or placebo, occurring in 6 or 5% of patients, respectively. Substantial increases in serum concentrations of AST (SGOT) or ALT (SGPT) occurred in 0.2 or 0.3% of patients receiving the drug or placebo, respectively.

Borderline elevations in one or more liver function test results may occur in up to 15% of patients treated with NSAIAs; meaningful (3 times the upper limit of normal) elevations in serum ALT (SGPT) or AST (SGOT) have occurred in approximately 1% of patients receiving NSAIAs in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Hepatitis, jaundice, or liver failure has been reported in patients receiving celecoxib during postmarketing surveillance. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs, including celecoxib.

Other Adverse Effects

Accidental injury has been reported in 2.9% of adults receiving celecoxib. Other adverse effects reported in 0.1-1.9% of celecoxib-treated adults include cysts (not otherwise specified), fatigue, fever, flu-like symptoms, bacterial infections, fungal infections (including moniliasis), viral infections (including herpes simplex or herpes zoster), pain, and peripheral pain. Diabetes mellitus, increases in serum concentrations of creatine kinase (CK, creatine phosphokinase, CPK) or alkaline phosphatase, hypercholesterolemia, hyperglycemia, hypokalemia, or weight gain also has been reported in 0.1-1.9% of adults receiving celecoxib. Sepsis and hypoglycemia have been reported in less than 0.1% of celecoxib-treated adults. Fever has occurred in 8-9% of children receiving the drug.

Soon after celecoxib became commercially available, the death of 10 adults receiving the drug was reported in the lay media. Review of the data indicated that the death of these adults was not attributable to the drug; 8 of these adults had substantial concomitant medical conditions, and 3 were receiving multiple drugs concomitantly. The cause of death was not known or clearly specified for the other 2 patients.

Precautions and Contraindications

Patients should be advised that celecoxib, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur.

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.

Cardiovascular Precautions

NSAIAs, including selective COX-2 inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events.(See Cautions: Cardiovascular Effects.) Although findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of these drugs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time. Until more data are available, decisions to use an NSAIA, including a selective COX-2 inhibitor (e.g., celecoxib), depend on individual assessment of risk for GI and cardiac toxicity and availability of alternative therapies. Some clinicians have suggested that use of a selective COX-2 inhibitor remains an appropriate choice for patients at low cardiovascular risk who have had serious GI events, especially while receiving a prototypical NSAIA. Some clinicians also suggest that it is prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease. Celecoxib should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if celecoxib is used in such patients, the patient should be monitored for cardiac ischemia. Additional studies, preferably randomized controlled trials, are required to more fully assess cardiovascular risks associated with individual NSAIAs in patients with established cardiovascular disease.

To minimize the potential risk of adverse cardiovascular events in patients receiving NSAIAs, the lowest effective dosage and shortest possible duration of therapy should be employed. Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy. Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. The overall risk for cardiovascular events in patients receiving a COX-2 inhibitor versus placebo or a prototypical NSAIA was not influenced by use of low-dose aspirin. Concomitant use of aspirin and celecoxib increases the risk for serious GI events.

Use of NSAIAs, including celecoxib, can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events. Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents. NSAIAs, including celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of celecoxib therapy and throughout therapy.

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that celecoxib should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if celecoxib is used in such patients, the patient should be monitored for worsening heart failure. Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure. Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema. Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).(See Drug Interactions.)

Use of celecoxib for longer than 6 months in children has not been systematically studied. It remains to be determined whether long-term cardiovascular risks in children exposed to celecoxib are similar to those observed in adults receiving celecoxib or other NSAIAs.

GI Precautions

The risk of potentially serious adverse GI effects should be considered in patients receiving celecoxib, particularly in patients receiving chronic therapy with the drug.(See Cautions: GI Effects.) Because peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to report promptly signs or symptoms of GI ulceration or bleeding to their clinician.

NSAIAs, including celecoxib, should be used with extreme caution and under close supervision in patients with a history of ulcer disease or GI bleeding. Special care should be exercised if the drug is administered to geriatric or debilitated patients because most spontaneous reports of fatal GI effects have been in such patients. To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed. For patients who are at high risk, alternative therapy other than a NSAIA should be considered.

Renal Precautions

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion. Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II antagonist concomitantly; and geriatric patients. Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs. Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy. Celecoxib should be discontinued if abnormal renal function test results persist or worsen. The manufacturer states that celecoxib-induced renal effects are similar to those reported with prototypical NSAIAs.

Celecoxib has not been evaluated in patients with severe renal impairment, and the manufacturer states that use of celecoxib is not recommended in patients with advanced renal disease. If celecoxib therapy must be used in patients with severe renal impairment, close monitoring of renal function is recommended.

Hepatic Precautions

Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving celecoxib should be evaluated for evidence of the development of a severe hepatic reaction. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported rarely in patients receiving NSAIAs. Celecoxib should be discontinued if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations (e.g., eosinophilia, rash) occur. In addition, celecoxib should be discontinued if abnormal liver function test results persist or worsen.(See Cautions: Hepatic Effects.) Patients receiving celecoxib should be instructed to report to their clinician any early signs or symptoms of possible hepatic dysfunction (e.g., fatigue, lethargy, nausea, pruritus, jaundice, right upper quadrant pain, flu-like symptoms). In addition, patients should be advised to discontinue celecoxi

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of celecoxib is mediated by the cytochrome P-450 (CYP) isoenzyme 2C9, and the possibility exists that drugs that inhibit this enzyme (e.g., fluconazole, fluvastatin, zafirlukast) may affect the pharmacokinetics of celecoxib. Therefore, celecoxib and drugs that inhibit the CYP2C9 isoenzyme should be administered concomitantly with caution. In addition, celecoxib inhibits CYP2D6, and the possibility exists that celecoxib may alter the pharmacokinetics of drugs metabolized by this isoenzyme, including various β-adrenergic blocking agents, many tricyclic and other antidepressants, various antipsychotic agents, and some antiarrhythmics (e.g., encainide, flecainide). Results of in vitro studies indicate that celecoxib is not a substrate for CYP2D6, and the drug does not inhibit the CYP2C9, CYP2C19, or CYP3A4 isoenzymes.

Fluconazole

Results of clinical studies indicate that clinically important drug interactions may occur if celecoxib is administered with fluconazole. Concomitant administration of celecoxib with fluconazole can result in substantially increased plasma concentrations of celecoxib. This pharmacokinetic interaction appears to occur because fluconazole inhibits the CYP2C9 isoenzyme involved in celecoxib metabolism. In one study, concomitant administration of fluconazole (200 mg daily) and celecoxib (a single 200-mg dose) increased plasma concentrations of celecoxib twofold. The manufacturer of celecoxib states that celecoxib therapy should be initiated at the lowest recommended dosage in patients receiving fluconazole concomitantly.

Warfarin

In one short-term (7-day) premarketing study in healthy individuals, celecoxib (200 mg twice daily) did not appear to alter the anticoagulant effect of warfarin (2-5 mg daily) as determined by the prothrombin time (PT). However, during postmarketing surveillance, bleeding complications associated with increases in PT were reported in some (mainly geriatric) patients receiving celecoxib concomitantly with warfarin. Therefore, patients receiving such concomitant therapy should be monitored appropriately for changes in anticoagulant activity (e.g., PT), particularly during the first few days after initiating or altering therapy, since these patients may be at increased risk of bleeding complications.

Other Drugs Affecting Hepatic Microsomal Enzymes

In clinical studies, concomitant administration of celecoxib with ketoconazole, phenytoin, or tolbutamide did not alter the pharmacokinetics and/or pharmacodynamics of these drugs, and no clinically important interactions have been reported.

Antacids

Administration of an antacid containing magnesium or aluminum with celecoxib decreased peak plasma concentrations of celecoxib by 37% and the area under the plasma concentration-time curve (AUC) by 10% in clinical studies. However, the manufacturer makes no specific recommendation for administration of the drug with regard to antacids because these effects are not considered clinically important.

Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

Experience with other nonsteroidal anti-inflammatory agents (NSAIAs) suggests that clinically important changes in blood pressure response may occur when celecoxib is administered concomitantly with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist. There is some evidence that concomitant administration of NSAIAs, including celecoxib, may reduce the blood pressure response to ACE inhibitors or angiotensin II receptor antagonists. Therefore, blood pressure should be monitored carefully when a NSAIA, including celecoxib, is initiated in patients receiving one of these agents.

Diuretics

NSAIAs may interfere with the natriuretic response to diuretics with activity that depends in part on prostaglandin-mediated alterations in renal blood flow (e.g., furosemide, thiazides).(See Cautions: Renal, Electrolyte, and Genitourinary Effects and also see Pharmacology: Renal Effects.)

Glyburide

In clinical studies, concomitant administration of celecoxib with glyburide did not alter the pharmacokinetics and/or pharmacodynamics of glyburide, and no clinically important interactions have been reported.

Lithium

Results of clinical studies indicate that clinically important drug interactions may occur if celecoxib is administered with lithium. Celecoxib and other NSAIAs can decrease renal clearance of lithium, which may lead to increased serum or plasma lithium concentrations. The mechanism involved in the reduction of lithium clearance by NSAIAs is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium by increasing sodium retention and thus lithium reabsorption; alternatively, inhibition of prostaglandin synthesis may reduce renal blood flow and glomerular filtration rate. In a study in healthy individuals, concomitant administration of celecoxib (200 mg daily) with lithium carbonate (450 mg twice daily) increased the mean steady-state plasma concentrations of lithium by about 17% compared with administration of lithium alone. Patients receiving lithium and celecoxib concomitantly should be monitored closely for signs of lithium toxicity and lithium dosage adjusted accordingly when celecoxib is initiated or discontinued.

Methotrexate

In clinical studies, concomitant administration of celecoxib with methotrexate did not alter the pharmacokinetics and/or pharmacodynamics of methotrexate, and no clinically important interactions have been reported.

Nonsteroidal Anti-inflammatory Agents

Although celecoxib may be used with low doses of aspirin, concomitant use of the 2 NSAIAs may increase the incidence of GI ulceration or other complications compared with that associated with celecoxib alone.(See Cautions: GI Effects.) Because celecoxib does not exhibit antiplatelet activity, the drug is not a substitute for aspirin for cardiovascular prophylaxis. However, there is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with COX-2 inhibitors.

Pharmacokinetics

The pharmacokinetics of celecoxib have been studied principally in healthy adults and in adults with acute pain, rheumatoid arthritis, or osteoarthritis. Certain pharmacokinetic parameters of celecoxib (i.e., peak plasma concentration, area under the plasma concentration-time curve [AUC]) are approximately dose proportional when the drug is administered to fasting adults in dosages up to 200 mg twice daily. However, there is a less-than-proportional increase in peak plasma concentration and AUC when the drug is administered to fasting adults in dosages exceeding 200 mg twice daily; this effect has been attributed to the low aqueous solubility of celecoxib. Limited data indicate that the pharmacokinetics of celecoxib are affected by advanced age, renal and/or hepatic function, and race.(See Pharmacokinetics: Absorption.)

Absorption

Celecoxib is well absorbed from the GI tract, and peak plasma concentrations of the drug generally are attained within 3 hours after dosing in fasting individuals. Absolute bioavailability of celecoxib has not been determined. Following oral administration of a single 200-mg dose of celecoxib in healthy, fasting adults 19-52 years of age, peak plasma concentrations of the drug averaged 705 ng/mL. Bioavailability (AUC) was increased 10-20% and time to reach peak plasma concentrations of celecoxib was delayed by 1-2 hours when the commercially available 200-mg capsules were administered with a high-fat meal (24 g fat) compared with administration with a medium-fat meal (8 g fat) or under fasting conditions. In addition, AUC and plasma concentration 12 hours after the dose were slightly (about 10%) higher when the drug was given in the evening versus the morning. When a celecoxib capsule is opened and the contents sprinkled over applesauce prior to administration, the pharmacokinetic profile of the drug (i.e., AUC, peak plasma concentration, time to peak plasma concentration, plasma elimination half-life) is similar to that following oral administration of the intact capsule. Following oral administration of celecoxib at recommended dosages (200-400 mg daily), steady-state plasma concentrations are achieved within 5 days. Drug accumulation has not been observed in individuals receiving celecoxib 400 mg twice daily.

Following oral administration of celecoxib at recommended dosages in geriatric individuals older than 65 years of age, peak plasma concentration and AUC were increased 40 and 50%, respectively, compared with younger adults. Peak plasma celecoxib concentration and AUC values were higher in geriatric women than geriatric men, predominantly because of the lower body weight of these women. Analysis of pooled pharmacokinetic data indicates that the AUC of celecoxib is about 40% higher in blacks compared with whites; the cause and clinical importance of this finding are not known.

Limited information is available on the pharmacokinetics of celecoxib in patients with mild to moderate hepatic and/or renal impairment. AUC of celecoxib at steady state reportedly was increased 40 or 180% in individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, respectively, compared with that in healthy adults with normal hepatic function. In adults with chronic renal insufficiency (glomerular filtration rates of 35-60 mL/minute), AUC of celecoxib reportedly was 40% lower than that in adults with normal renal function.

Distribution

Distribution of celecoxib into body tissues and fluids has not been fully characterized. The apparent volume of distribution of celecoxib at steady state is about 400 L (about 7.14 L/kg), suggesting extensive tissue distribution.

At therapeutic plasma concentrations, celecoxib is about 97% bound to plasma proteins, principally albumin and to a lesser extent, α1-acid glycoprotein. Celecoxib is not preferentially bound to erythrocytes in blood.

It is not known whether celecoxib crosses the placenta in humans. Although it also is not known whether celecoxib is distributed into human milk, the drug is distributed into milk in rats in concentrations similar to those in plasma.

Elimination

The plasma elimination half-life of celecoxib following oral administration of a single 200-mg dose under fasting conditions is about 11 hours, and the apparent plasma clearance of the drug is about 500 mL/minute; these parameters exhibit wide intraindividual variability, presumably because the low aqueous solubility of celecoxib prolongs absorption. The half-life of celecoxib is prolonged in patients with renal or hepatic impairment and has been reported to be 13.1 hours in patients with chronic renal insufficiency and 11 or 13.1 hours in patients with mild or moderate hepatic impairment, respectively.

The metabolic fate of celecoxib has not been fully determined, but the drug is metabolized in the liver to inactive metabolites principally by the cytochrome P-450 (CYP) isoenzyme 2C9. Metabolism of celecoxib involves hydroxylation of the 4-methyl group to form a primary alcohol (SC-60613), followed by oxidation of the primary alcohol to the corresponding carboxylic acid (SC-62807), the major metabolite. The carboxylic acid metabolite is conjugated with glucuronic acid to some extent, forming the 1-O-glucuronide. Metabolites of celecoxib do not have pharmacologic activity as cyclooxygenase-1 (COX-1) or COX-2 inhibitors. In patients with poor metabolizer phenotypes of the CYP2C9 isoenzyme, the metabolic clearance of celecoxib may be decreased and plasma concentrations may be increased.(See Cautions: Precautions and Contraindications.)

Oral clearance of celecoxib appears to increase in a less-than-proportional manner with increasing weight; pediatric patients with juvenile rheumatoid arthritis weighing 10 or 25 kg are predicted to have a 40 or 24% lower clearance, respectively, than a 70-kg adult with rheumatoid arthritis.

Celecoxib is excreted in urine and feces principally as metabolites; less than 3% of the dose is excreted unchanged. Following oral administration of a single 300-mg dose of radiolabeled celecoxib as an oral suspension (not commercially available in the US), approximately 27 and 57% of the dose was excreted in urine and feces, respectively. The principal metabolite in both urine and feces was the carboxylic acid metabolite (73% of the dose); small amounts of the glucuronide metabolite were present in urine.

Write Your Own Review

Your meds on autopilot. Forever.