REMS: FDA approved a REMS for the fixed combination of celecoxib and tramadol hydrochloride under a shared REMS system (Opioid Analgesic REMS) to ensure that the benefits outweigh the risks. The REMS consists of the following: medication guide and elements to assure safe use. See the FDA REMS page [Web] |
Celecoxib is a nonsteroidal anti-inflammatory agent (NSAIA)1,2,3,4,5,8,11,41 that is a selective inhibitor of cyclooxygenase-2 (COX-2).1,2,8,52
Celecoxib is used in the management of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, pain, ankylosing spondylitis, and dysmenorrhea.1 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).51,52,53,145 Both COX-2 inhibitors and prototypical NSAIAs have been associated with an increased risk of cardiovascular events.103,104,108,113,122,129,130,131,134,137,138,139,140,141,146,147,148,500,502,508 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.41,51,52,53,112,121,128,130 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.100,101 (See Uses: Osteoarthritis.) Additional study is planned or under way to establish more definitively the role of COX-2 inhibitors relative to prototypical NSAIAs.52,106,130
Celecoxib also is used for the acute treatment of attacks of migraine with or without aura.161,165
Celecoxib also has been used to reduce the number of adenomatous colorectal polyps in adults with familial adenomatous polyposis (FAP).60,162
The potential benefits and risks of celecoxib therapy as well as alternative therapies should be considered prior to initiating therapy with the drug.1 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1
Celecoxib is used for the management of the signs and symptoms of osteoarthritis in adults.1,2,3,9,18,28,29,32,64 Medical management of osteoarthritis of the hip, knee, and/or hand includes both pharmacologic therapy and nonpharmacologic (e.g., educational, behavioral, psychosocial, physical) interventions to reduce pain, maintain and/or improve joint mobility, limit functional impairment, and enhance overall well-being.32 The American College of Rheumatology (ACR) strongly recommends exercise, weight loss when necessary in patients with osteoarthritis of the knee and/or hip, self-efficacy and self-management programs, tai chi, cane use, hand orthoses, knee bracing, topical NSAIAs for osteoarthritis of the knee, oral NSAIAs, and intra-articular glucocorticoid injections for osteoarthritis of the knee or hip.32 Other pharmacologic or nonpharmacologic interventions may be recommended conditionally.32 Interventions and the order of their selection are patient specific.32 Factors to consider when making decisions regarding therapy for osteoarthritis include patients' values and preferences, the presence of risk factors for serious adverse GI effects, existing comorbidities (e.g., hypertension, heart failure, other cardiovascular disease, chronic kidney disease), injuries, disease severity, surgical history, and access to and availability of the interventions.32 Pharmacologic therapy should be initiated with treatments resulting in the least systemic exposure or toxicity.32 For some patients with limited disease, topical NSAIAs may be an appropriate initial choice for pharmacologic therapy; for other patients, particularly those with osteoarthritis of the hip or with polyarticular involvement, oral NSAIAs may be more appropriate.32
NSAIAs that are selective inhibitors of COX-2 (e.g., celecoxib) are associated with a lower incidence of adverse GI effects than prototypical NSAIAs.1,3,9,21,22,24,28,29,33,38,63,99 Both COX-2 inhibitors and prototypical NSAIAs have been associated with an increased risk of cardiovascular events.103,104,108,113,122,129,130,131,134,137,138,139,140,141,146,147,148,500,502,508 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.41,51,52,53,112,121,128,130 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.32,62 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.100,101
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.1,2,3,28,29,64 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.1,2,28,29,99 (See GI Effects under Cautions.)
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 McMaster Universities (WOMAC) osteoarthritis index; WOMAC is a 24-item questionnaire that measures pain, stiffness, and functioning.1,2 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.1 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.2,50 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.1,2 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.1,2
Rheumatoid Arthritis in Adults
Celecoxib is used for the management of the signs and symptoms of rheumatoid arthritis in adults.1,2,3,9,10,21,23,24,28,65,66,99 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,1,2,3,9,10,21,23,24,28,65,66 both selective COX-2 inhibitors and prototypical NSAIAs have been associated with an increased risk of cardiovascular events. 103,104,113,121,122,123,129,130,131,134,137,138,139,140,141,146,147,148,500,502,508 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.41,51,52,53,112,121,128,130 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.100,101 (See Osteoarthritis under Uses.)
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.30,67,78 Disease-modifying antirheumatic drugs (DMARDs) (e.g., abatacept, hydroxychloroquine, leflunomide, methotrexate, rituximab, sulfasalazine, tocilizumab, tofacitinib, tumor necrosis factor [TNF; TNF-α] blocking agents) 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.30,67 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.30,67 NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.30,78
In double-blind, placebo-controlled studies, therapy with celecoxib was associated with greater reduction in joint tenderness/pain and swelling than placebo.1,2 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.1,2,3,9,10,21,22,23,24,28,65,66 (See GI Effects under Cautions.) 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.2,10,50 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 stiffness and 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.10
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.1,2,25,26,27 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).25,26,27 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.2 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.1,2 Dosages of 400 mg twice daily provided no additional benefit compared with dosages of 100-200 mg twice daily.1,2
Celecoxib is used for the management of the signs and symptoms of juvenile rheumatoid arthritis in children 2 years of age or older.1 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.1 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).1,159 Results of this study indicate that celecoxib is as effective as naproxen in the management of juvenile rheumatoid arthritis.1 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.1 The manufacturer states that safety and efficacy of celecoxib therapy beyond 6 months in pediatric patients with juvenile arthritis have not been established.1
Clinical trials indicate that either celecoxib or a prototypical NSAIA is effective in the management of juvenile rheumatoid arthritis.160 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.160 In addition, celecoxib may be useful in children who have experienced other adverse effects with prototypical NSAIAs (e.g., naproxen-induced pseudoporphyria).160 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.508 (See Cardiovascular Effects under Cautions.)
Celecoxib is used for the management of the signs and symptoms of ankylosing spondylitis in adults.1 Clinical trials indicate that either selective COX-2 inhibitors or prototypical NSAIAs are effective for initial symptomatic management of ankylosing spondylitis.154,155,156 Although celecoxib may have a lower risk of adverse GI effects compared with prototypical NSAIAs,1,2,3,9,10,21,23,24,28,65,66 both selective COX-2 inhibitors and prototypical NSAIAs have been associated with an increased risk of cardiovascular events.103,104,113,121,122,123,129,130,131,134,137,138,139,140,141,146,147,500,502,508 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.41,51,52,53,112,121,128,130,156 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.100,101 (See Osteoarthritis under Uses.)
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]).1,132 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).1 There was no change in responder rates after 6 weeks.1
Celecoxib has been 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).60,162 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.60 Celecoxib previously was FDA-labeled for this use; however, approval was granted under FDA's accelerated approval regulations, and a postapproval study was required to verify clinical benefit.169 Patient accrual in the study was slow and the manufacturer was unable to provide confirmatory data.169,170 Therefore, the labeled indication was withdrawn.169 Because celecoxib therapy in patients with FAP has involved high-dose, long-term use of the drug, there is concern that potential risks (e.g., GI, cardiovascular) of celecoxib might not be outweighed by the uncertain benefit.170,171
Efficacy of celecoxib in reducing the extent of polyposis has been evaluated in a randomized, placebo-controlled study in adults with FAP.60 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.60 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).60 The mean pretreatment number of polyps was 11.5-15.5 and the mean pretreatment polyp burden was 34.8-44.7 mm.60 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;60 the mean reduction in polyp burden was 30.7, 14.6, and 4.9%, respectively.60
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]).149,150 Patients included in these studies had undergone recent removal of colorectal adenomas and were at high risk of recurrent adenomas.149,150 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.149,150 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.149,150 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.149 The studies did not evaluate whether celecoxib alters the risk of a first occurrence of colorectal adenoma or prevents the development of colorectal cancer.149,150
Celecoxib is used in the management of acute pain, including postoperative (dental, orthopedic) pain, in adults.1 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.1 Following administration of single doses of celecoxib, the onset of analgesia was 60 minutes.1 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.8,42,43 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.3
Celecoxib in fixed combination with tramadol hydrochloride (celecoxib/tramadol) is used for the management of acute pain in adults that is severe enough to require an opiate analgesic and for which alternative treatments are inadequate; because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, reserve celecoxib/tramadol for use in patients for whom alternative treatment options (e.g., nonopiate analgesics) have not been, or are not expected to be, adequate or tolerated.172
Celecoxib is used for the acute treatment of attacks of migraine with or without aura;161,165 celecoxib should not be used for the prophylaxis of migraine.161
In 2 randomized, double-blind, placebo-controlled clinical trials (NCT03009019, NCT03006276), efficacy of celecoxib (120-mg dose given as an oral solution) for the acute treatment of migraine attacks was evaluated in a total of 1253 adults (86% female, 74% White, mean age of 41 years) experiencing a migraine attack causing moderate to severe pain.161,165 At 2 hours after treatment, freedom from headache pain was reported by a greater proportion of patients receiving celecoxib compared with those receiving placebo in one study (35 versus 21%) but not in the other study (32 versus 25%).161 Relief of the patient's most bothersome symptom (i.e., photophobia, nausea, or phonophobia) at 2 hours after treatment was reported by greater proportions of celecoxib recipients in both studies (57-58 versus 44%).161
Celecoxib is used for the relief of primary dysmenorrhea in adults.1 In pain studies evaluating the efficacy of celecoxib, the drug was effective in the relief of moderate to severe pain associated with primary dysmenorrhea.1
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).1,2
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.93,94 Similar findings have been reported from some other, but not all, observational studies.93,94,95,96,97,98
The potential benefits and risks of celecoxib therapy as well as alternative therapies should be considered prior to initiating celecoxib therapy.1
Celecoxib is administered orally as a single daily dose or in 2 equally divided doses daily.1 Once- and twice-daily regimens were equally effective in the management of osteoarthritis.1 The manufacturer recommends a twice-daily dosing schedule for the management of rheumatoid arthritis and juvenile arthritis.1 The manufacturer of celecoxib capsules states that 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.1 For the acute treatment of migraine attack, celecoxib oral solution may be administered without regard to food.161 The patient may drink up to 240 mL of water after administering the oral solution.161
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.1 This mixture is stable for 6 hours when refrigerated.1
Celecoxib oral solution is commercially available in single-dose bottles containing celecoxib 25 mg/mL (120 mg in 4.8 mL).161 When the intended dose is less than the entire contents of the bottle, use of a calibrated measuring device to accurately measure and deliver the dose is recommended; any remaining solution in the bottle should be discarded.161 The manufacturer's instructions for use should be consulted for additional information on administration of the drug.161
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.34
The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.1
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.1,130
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.1 However, for geriatric patients weighing less than 50 kg, celecoxib therapy should be initiated at the lowest recommended dosage.1
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.1,2,3 Celecoxib dosages exceeding 200 mg daily (e.g., 200 mg twice daily) do not appear to provide additional therapeutic benefit.1 Tablets containing celecoxib in fixed combination with amlodipine are available in only one strength of celecoxib (200 mg) and should not be used in patients requiring lower doses of the drug; the manufacturer states that the fixed combination should be administered only once daily in patients requiring celecoxib for symptomatic treatment of osteoarthritis and amlodipine for the management of hypertension.1201
Rheumatoid Arthritis in Adults
For the symptomatic treatment of rheumatoid arthritis, the usual adult dosage of celecoxib is 100-200 mg twice daily.1,78 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.1 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.1
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.1
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.1 If no response is observed after 6 weeks, the dosage may be increased to 400 mg daily.1 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.1
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.1 For continued relief, 200 mg may be administered twice daily as needed.1
When celecoxib is used in fixed combination with tramadol hydrochloride for the management of acute pain in adults, the recommended dosage is 2 tablets (containing 56 mg of celecoxib and 44 mg of tramadol hydrochloride each) every 12 hours as needed for relief of pain.172
For the acute treatment of migraine with or without aura, the usual adult dosage of celecoxib is a single 120-mg dose (as oral solution).161 The maximum recommended dosage is 120 mg per 24-hour period.161 The efficacy and safety of administering a second dose within a 24-hour period have not been established.161 Celecoxib should be used on an as-needed basis for the fewest possible number of days per month.161
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.1,161 However, if celecoxib therapy must be used in patients with severe renal impairment, close monitoring of renal function is recommended.1 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.1 When celecoxib is used for the acute treatment of migraine attacks in patients with mild or moderate renal impairment, no adjustment of the usual recommended dosage is required.161 The manufacturer makes no specific recommendations for dosage modification in patients with chronic renal insufficiency receiving celecoxib for other indications.1
The pharmacokinetics of celecoxib have not been studied in patients with severe hepatic impairment, and the manufacturers state that the drug should not be used in such patients.1,161 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.1 In patients with moderate hepatic impairment (Child-Pugh class B), the manufacturer recommends that celecoxib dosage be reduced by approximately 50%.1 For acute treatment of migraine attacks in patients with moderate hepatic impairment, the recommended and maximum dosage of celecoxib is 60 mg.161
Pharmacogenomic Dosage Considerations
The manufacturer states that, based on experience with other drugs that are substrates of cytochrome P-450 isoenzyme 2C9 (CYP2C9), initial celecoxib dosage should be reduced by 50% in patients who are known or suspected CYP2C9 poor metabolizers with the CYP2C9*3/*3 diplotype.1 For the acute treatment of migraine attacks in adults who are known or suspected CYP2C9 poor metabolizers, the recommended and maximum dosage of celecoxib is 60 mg.161 Use of alternatives to celecoxib should be considered in pediatric patients with juvenile rheumatoid arthritis who are known or suspected CYP2C9 poor metabolizers.1 (See Elimination under Pharmacokinetics.)
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that, in patients who are CYP2C9 poor metabolizers (i.e., diplotype functional activity score of 0.5 or 0 [e.g., CYP2C9*2/*3, CYP2C9*3/*3]), celecoxib should be initiated at a dosage that is 25-50% of the lowest recommended initial dosage (i.e., 50-75% dosage reduction) and cautiously titrated to a clinically effective dosage, up to a dosage that is 25-50% of the maximum recommended dosage.520 Dosage should not be increased until steady-state concentrations are attained (at least 8 days following the initial dose in poor metabolizers).520 Alternatively, a drug that is not metabolized by CYP2C9 or is not substantially affected by CYP2C9 genetic variants in vivo should be considered.520 In addition, CPIC guidelines state that, in patients who are CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1, celecoxib may be initiated at the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to the maximum recommended dosage.520 Intermediate metabolizers with an AS of 1.5 may receive dosages recommended for normal metabolizers.520 (See Pharmacogenomic Precautions under 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.1,2,3,9,21,24,28,29,33 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.1 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 weeks1 and from acute migraine treatment, colorectal adenoma prevention, and Alzheimer's disease prevention studies in adults.129,130,131,135,136,161,165
At usual dosages, celecoxib generally is well tolerated.1,2,3,9,21,24,28,29 Adverse effects of celecoxib usually are mild and mainly involve the GI tract.1,2,3 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.1,3,9,21,22,24,28,29,33,38 63,99 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.1 About 7.1% of adults receiving celecoxib in clinical studies discontinued therapy because of adverse effects compared with 6.1% of those receiving placebo.1,2 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).1
Peripheral edema has been reported in 2.1% of adults receiving celecoxib in premarketing clinical studies.1,2 Angina pectoris,1 chest pain,1 coronary artery disorder,1 hot flushes,1 myocardial infarction,1 palpitation,1 tachycardia,1 or aggravated hypertension1 has been reported in 0.1-1.9% of adults receiving the drug.1 Adverse cardiovascular effects reported in less than 0.1% of adults receiving celecoxib include syncope,1 congestive heart failure,1 ventricular fibrillation,1 pulmonary embolism,1 cerebrovascular accident,1 peripheral gangrene,1 thrombophlebitis,1 deep-vein thrombosis,1 and vasculitis.1 In long-term colorectal polyp prevention studies, deep-vein thrombosis, unstable angina, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, or ventricular hypertrophy occurred in less than 1% of patients receiving celecoxib.1
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).1,33 In a substudy of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial, ambulatory blood pressure monitoring performed 4 months after initiation of therapy indicated a difference between celecoxib and ibuprofen, but not between celecoxib and naproxen, in the effect of the drug on systolic blood pressure.1,167 In this study, the mean 24-hour systolic blood pressure decreased by 0.3 mm Hg in patients receiving celecoxib 100 mg twice daily but increased by 3.7 or 1.6 mm Hg in those receiving ibuprofen 600-800 mg 3 times daily or naproxen 375-500 mg twice daily, respectively.1 Peripheral edema and hypertension also have been described as evidence of adverse renal effects. (See Renal, Electrolyte, and Genitourinary Effects under Cautions.)
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.500,502,508 Because findings from clinical trials of celecoxib, other selective COX-2 inhibitors, or prototypical NSAIAs of up to 3 years' duration have shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, all NSAIAs are considered to be potentially associated with this risk.1
The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study.102,103,104,105,117,128,129,130,133,146,147,148,151,500 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 information500,501,502 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.500 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.500,502,505,506,508 An increase in risk has been observed most consistently at higher NSAIA dosages.1 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.500,502,506,508
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.146,147,148,151,500,501,502,503,506 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.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500
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).103,104 This study was designed to evaluate the efficacy of rofecoxib in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas.103,104 The primary efficacy end point was the incidence of colorectal adenoma; safety was monitored on a regular basis by an external board.103 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.103,104 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.103,514 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).103,514 The difference between the 2 groups was related mainly to an increased number of myocardial infarctions and strokes in patients receiving rofecoxib.103 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).103,514 No difference in overall mortality was observed between treatment groups.103
Extended posttreatment follow-up data regarding cardiovascular events and mortality were available for approximately 84 and 95%, respectively, of patients in the APPROVe study.514 The median posttreatment follow-up was 550 or 538 days for rofecoxib-treated patients or placebo recipients, respectively.514 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).514 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.514
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.102,109,116 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;107,108,111,118,122,123,127,134,147,151,501,503,506,510 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.107,108,111,122,123,157,158,506
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.33,102,110,125,130,131,133,135,136,149,150,168,508,515 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,1,33,102,107,110,119,130,131,133,136,146,150,515 an increased incidence of cardiovascular events was observed in patients receiving celecoxib in a colorectal adenoma prevention study (Adenoma Prevention with Celecoxib [APC]).129,130,131,135,149,508
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.1,33,102,110,125 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,102,110,125 the study was not designed to establish cardiovascular safety as a primary end point.126,128,133 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.102
The PRECISION trial also did not show an increased risk for cardiovascular events in patients receiving celecoxib compared with those receiving ibuprofen or naproxen.1,168 The PRECISION trial was a randomized, double-blind, controlled, noninferiority trial in 24,081 patients with osteoarthritis or rheumatoid arthritis who had or were at high risk for cardiovascular disease.1,168 Randomization was stratified by baseline use of low-dose aspirin.1,168 In the intention-to-treat (ITT) population, in which all patients were followed for a maximum of 30 months, the incidence of adverse cardiovascular events (cardiovascular death [including hemorrhagic death], myocardial infarction, stroke) was 2.3, 2.7, or 2.5% in patients receiving celecoxib 100 mg twice daily, ibuprofen 600-800 mg 3 times daily, or naproxen 375-500 mg twice daily, respectively.1,168 In the modified ITT (on-treatment) population, in which patients were followed until 30 days following drug discontinuance or for 43 months, whichever occurred first, the incidence of adverse cardiovascular events was 1.7, 1.9, or 1.8% in patients receiving these respective treatments.1,168 Because only about 6% of celecoxib-treated patients received a dosage of 200 mg twice daily, the safety of this higher dosage relative to the comparator NSAIAs could not be determined.1 The mean durations of treatment and follow-up were 20.3 and 34.1 months, respectively.168
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.129,130,131,135,136,149,150 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.135 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.1,135 Based on these adverse cardiovascular findings, NIH suspended the study early.129 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.149 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;1,508 serious cardiovascular events occurred in 2.5 or 3% of patients receiving celecoxib 200 or 400 mg twice daily, respectively, compared with 0.9% of those receiving placebo.1 The increase in risk with celecoxib compared with placebo was related mainly to an increased incidence of myocardial infarction.1,508
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.1,130,131,150 Serious cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke) occurred in 2.3% of patients receiving celecoxib and in 1.9% of patients receiving placebo (hazard ratio of 1.2; 95% confidence interval: 0.6-2.4).1 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.152
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.133,136,515
Data concerning the risk of cardiovascular events in patients receiving celecoxib continue to be collected and evaluated.148,500 Current evidence suggests that cardiovascular risk associated with celecoxib use may be dose related, with dosages exceeding 200 mg daily associated with greater risk.147,157,158,512 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.146,147,148,151,501,503,506,510 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.146 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.506 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.157,158,512 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).518
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.114,115,147,151,506 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.113,114,120,137 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.508
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.503,506,510 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.503 (See Experience with Prototypical NSAIAs under Cautions.)
Data from long-term studies of lumiracoxib and etoricoxib also are available.133 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).133,141 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.133,141 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.513
Experience with Prototypical NSAIAs
Data concerning the risk of cardiovascular events in patients receiving prototypical NSAIAs continue to be collected and evaluated.133,146,147,148,151,501,502,503,506 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).133,513 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.146,147,501,503,506
In one systematic review, 23 observational studies providing data on individual prototypical NSAIAs reported mainly on diclofenac, indomethacin, ibuprofen, naproxen, and piroxicam.146 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).147,151 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.151 Findings from these 2 analyses suggested that use of certain prototypical NSAIAs is associated with an increased risk of cardiovascular events.146,147,148 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)146,147,148 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)146 (summary relative risk of 1.63; 95% confidence interval: 1.12-2.37; meta-analysis)147 or indomethacin (summary relative risk of 1.36; 95% confidence interval: 1.15-1.61; 7 observational studies).146 The findings also suggested that use of ibuprofen may be associated with an increased risk of cardiovascular events,148,157 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).146,147,148 Few data were available for meloxicam or piroxicam.146 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.146 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).146
The systematic review was subsequently updated to provide updated risk estimates and to evaluate dose-response effects for certain NSAIAs.506 The updated review included data from 51 controlled observational studies and 43 unique data sets, and provided estimates of cardiovascular risk for 11 NSAIAs.506 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.506 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.506 With ibuprofen, elevated risk was observed only at high dosages (defined in most studies as more than 1.2 g daily).506 In this data subset, neither low nor high dosages of naproxen were associated with increased risk.506 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.506 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.506 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.506
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.501 Data for individual participants, rather than aggregate tabular data, were utilized when available.501 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).501 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.501 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).501 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).501 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).501 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).501 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).501 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.501
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.503 The results supported those of other analyses indicating that both prototypical NSAIAs and selective COX-2 inhibitors increase the risk of cardiovascular events.503 The cardiovascular safety profiles of the individual NSAIAs compared with placebo varied depending on the specific outcome.503 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).503 Naproxen appeared to have the least harmful cardiovascular effects of the 7 NSAIAs.503
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.505,511,512 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.505,511,512 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.505,508 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).500,508,511 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.508,511 Similar patterns were observed for the composite end point of coronary death or nonfatal recurrent myocardial infarction.511
In these Danish registry studies, the most commonly used NSAIAs were ibuprofen and diclofenac, followed by celecoxib, rofecoxib, and naproxen.505,511,512 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).512 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.512
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.508 (See Experience with Other COX-2 Inhibitors under Cautions.)
Limited data are available regarding cardiovascular risks associated with use of NSAIAs in patients with stable atherothrombotic disease.516,517 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).516 Results of the PRECISION trial in osteoarthritis or rheumatoid arthritis patients with, or at high risk for, cardiovascular disease indicated that celecoxib was not inferior to ibuprofen or naproxen with respect to risk of cardiovascular events.1,168 (See Celecoxib Experience under Cautions.)
Data from observational studies indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.500,504,507,508 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.1,500,504,508 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.1,500,501,508 Fluid retention and edema also have been observed in some patients receiving NSAIAs.508
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.504 Risks associated with the 5 most commonly used NSAIAs were analyzed separately.504 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.504 With ibuprofen and naproxen, only higher dosages (exceeding 1.2 g or 500 mg daily, respectively) were associated with an increased risk of death.504 All 5 NSAIAs were associated with an increased risk of hospitalization for myocardial infarction or heart failure.504
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.133 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.133 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.133 FDA interpreted data on cardiovascular risk available in 2005 as being applicable to all NSAIAs, including selective COX-2 inhibitors and prototypical NSAIAs.133
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.133 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.133
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).133 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.121,133 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.133
Following completion of additional studies and analyses of pooled study data, FDA again reviewed the cardiovascular risks associated with NSAIAs.500,502 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 information500,501,502 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.500 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.500,502,505,506,508,510 Published observational studies also indicate that use of NSAIAs in patients who have had a myocardial infarction increases the risk of reinfarction and death.505,508,511,512 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.500,502,506,508 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.500 FDA directed manufacturers of prescription and nonprescription NSAIA preparations to revise the labeling of these preparations to include updated information regarding cardiovascular risk.500
There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,103,133,134,135,139,141,502,508 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.103,133,135,141
Dyspepsia,1,2,9 diarrhea,1,2,9 abdominal pain,1,2,9 nausea,1,9 or flatulence1,2 occurred in 8.8, 5.6, 4.1, 3.5, or 2.2%, respectively, of adults receiving usual dosages of celecoxib in clinical studies.1 In clinical trials in patients with migraine attacks, dysgeusia occurred in 3% of patients receiving celecoxib oral solution compared with 1% of those receiving placebo.161 Dry socket (alveolar osteitis) was reported in patients receiving celecoxib for postoperative dental pain in a clinical study.1 Abdominal pain,1 nausea,1 diarrhea,1 or vomiting1 has been reported in 3-8% of children receiving celecoxib in an active-controlled clinical study.1
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.1,2,3,9,21,24,28,33,65,66 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).1,2,3,21,28,33,65,66,99 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.1 Celecoxib was associated with a lower incidence of endoscopic ulcers than diclofenac (4% versus 15%) in one 6-month study.1 No consistent relationship between celecoxib dosage and the incidence of GI ulcers has been established in these studies.1 The correlation between endoscopic findings and the incidence of clinically important upper GI events remains to be determined.1
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]).1,33,79 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.33,79 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.33,72 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.79,81 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).1 Patients receiving celecoxib and low-dose aspirin experienced a fourfold higher rate of complicated ulcers compared with those receiving celecoxib alone.1,33 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.1 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.1 Low-dose aspirin did not have a clinically important effect on the rate of upper GI complications in patients receiving prototypical NSAIAs.33
Serious, sometimes fatal, 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.1,54 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.1,54 Longer duration of therapy with an NSAIA increases the likelihood of a serious adverse GI event.1 However, short-term therapy is not without risk.1 The frequency of NSAIA-associated upper GI ulcers, gross bleeding, or perforation is approximately 1% in patients receiving NSAIA therapy for 3-6 months and approximately 2-4% in those receiving therapy for one year.1 Therefore, clinicians should remain alert to the possible development of serious adverse GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy.1 Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored even more closely for evidence of GI bleeding.1 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.1 In patients with a suspected serious adverse GI event, evaluation should be initiated promptly and celecoxib should be discontinued until a serious adverse GI event is ruled out.1
Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than tenfold increased risk of developing GI bleeding than patients without these risk factors.1,54,87 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, anticoagulants, aspirin, or selective serotonin-reuptake inhibitors (SSRIs); longer duration of NSAIA therapy; smoking; alcohol use; older a and poor general health status.1,54,87 Risk of GI bleeding also is increased in patients with advanced liver disease and/or coagulopathy.1 Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis.30,54,87 In addition, most spontaneous reports of fatal GI effects have been in geriatric or debilitated patients.1
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.30,54,62,78 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.30,54,78 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.54 In addition, efficacy of usual dosages of H2-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established.54 Therefore, most clinicians do not recommend use of H2-receptor antagonists for the prevention of NSAIA-associated ulcers.30,54 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.30 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.100,101 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.100,101
Headache1,9 has been reported in about 16% of adults receiving celecoxib in clinical studies, whereas dizziness1 or insomnia1 occurred in 2 or 2.3% of these patients, respectively.1 Headache occurred in 10-13% of children receiving celecoxib in an active-controlled clinical study.1
Upper respiratory tract infection,1,2 sinusitis,1,2,9 pharyngitis,1,2 or rhinitis1,11 has occurred in 8.1, 5, 2.3, or 2%, respectively, of adults receiving usual dosages of celecoxib in clinical studies.1 1 Cough1 or nasopharyngitis1 has been reported in 5-7% of celecoxib-treated children.1
Dermatologic and Sensitivity Reactions
Rash occurred in 2.2% of adults receiving celecoxib in clinical studies.1,2 Adverse dermatologic effects occurring in 0.1-1.9% of adults receiving celecoxib include alopecia,1 dermatitis,1 dry skin,1 erythematous rash,1 maculopapular rash,1 photosensitivity reaction,1 pruritus,1 skin disorder,1 increased sweating,1 and urticaria.1 1
Anaphylactoid reactions and angioedema have occurred in patients receiving celecoxib. 1,83 Anaphylactic reactions have been reported in patients with or without known hypersensitivity to the drug, as well as in patients with aspirin-sensitivity asthma. 1
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.1,2,3,9,16,20,38 (See Hematologic Effects under Pharmacology.)
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.38 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.56,57 (See Anticoagulants under Drug Interactions.)
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.1
Renal, Electrolyte, and Genitourinary Effects
Like prototypical NSAIAs, celecoxib has been associated with adverse renal effects.1,2,3,58,59,100,101 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).100 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.100 The incidence of adverse renal effects was increased in patients with preexisting renal impairment.100
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.100 Hyperkalemia also has been reported in patients receiving NSAIAs, including in individuals without renal impairment.1
Long-term administration of NSAIAs has resulted in renal papillary necrosis and other renal injury.1
Back pain has been reported in 2.8% of adults receiving celecoxib.1 Arthralgia has been reported in 3-7% of children receiving celecoxib in an active-controlled clinical study.1
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.1 Substantial increases in serum concentrations of liver enzymes occurred in approximately 0.2 or 0.3% of patients receiving the drug or placebo, respectively, while borderline elevations of these enzymes occurred in 6 or 5% of patients receiving these respective treatments.1,2 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 or AST have occurred in approximately 1% of patients receiving NSAIAs in controlled clinical studies.1 These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.1 Hepatitis,1,85 jaundice,1 or liver failure1 has been reported in patients receiving celecoxib during postmarketing surveillance.1
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.1,500,508
Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.1
NSAIAs, including selective COX-2 inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events.103,104,113,116,122,123,129,130,131,134,135,137,138,139,140,141,500,502,508 (See Cardiovascular Effects under Cautions.) 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,146,147,148,151,500,501,502,503,506 FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 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.41,51,52,53,112,121,128,130,133,143,503,505,506,511,517 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.112,121,128,145 Some clinicians also suggest that it is prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 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.508 Additional studies, preferably randomized controlled trials, are required to more fully assess cardiovascular risks associated with individual NSAIAs in patients with established cardiovascular disease.505,511,512,517
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.1,500,508 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.1,500,508 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.1,500,508
There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,103,133,134,135,139,141,502,508 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.103,133,135,141 Concomitant use of aspirin and celecoxib increases the risk for serious GI events.1 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)
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.1 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.1,508 Blood pressure should be monitored closely during initiation of celecoxib therapy and throughout therapy.1
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.508 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.507 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.508 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).508 (See Drug Interactions.)
Use of celecoxib for longer than 6 months in children has not been systematically studied.1 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.508,508
The risk of potentially serious adverse GI effects should be considered in patients receiving celecoxib, particularly in patients receiving chronic therapy with the drug.1 (See GI Effects under Cautions.) Because peptic ulceration and/or GI bleeding have been reported in patients receiving the drug,1 patients should be advised to report promptly signs or symptoms of GI ulceration or bleeding to their clinician.1
To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed, and use of more than one NSAIA at a time should be avoided.1 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.) In addition, use of NSAIAs should be avoided in patients at higher risk (see GI Effects under Cautions) unless the benefits of therapy are expected to outweigh the increased risk of bleeding; for patients who are at high risk, as well as for those with active GI bleeding, alternative therapy other than an NSAIA should be considered.1
Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration, and the drugs should be used concomitantly with caution.51
Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.1 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.1 Patients at greatest risk of this reaction are those with impaired renal function,1 heart failure,1 or hepatic dysfunction;1 those with extracellular fluid depletion (e.g., patients receiving diuretics);1 those taking an ACE inhibitor1 or angiotensin II antagonist1,46 concomitantly; and geriatric patients.1 Fluid depletion should be corrected prior to initiation of celecoxib therapy, and renal function should be monitored during celecoxib therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.1 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.1 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1
Celecoxib has not been evaluated in patients with severe renal impairment, and the renal effects of the drug may hasten the progression of renal dysfunction in patients with preexisting renal disease.1 The manufacturers state that use of celecoxib is not recommended in patients with advanced renal disease.1,161 If celecoxib therapy must be used in patients with advanced renal disease, close monitoring of renal function is recommended.1
Patients who experience signs and/or symptoms suggestive of liver dysfunction while receiving celecoxib should be evaluated for evidence of the development of a severe hepatic reaction.1 Severe, sometimes fatal, reactions, including fulminant hepatitis, liver necrosis, and hepatic failure, have been reported rarely in patients receiving NSAIAs.1 Celecoxib should be discontinued immediately if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations (e.g., eosinophilia, rash) occur.1 (See Hepatic Effects under Cautions.) 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).1 In addition, patients should be advised to discontinue celecoxib and contact their clinician immediately if any of these manifestations occur.1
The manufacturers state that celecoxib has not been evaluated in patients with severe hepatic impairment, and use of the drug in such patients is not recommended.1,161
In patients with the cytochrome P-450 isoenzyme 2C9 (CYP2C9) poor metabolizer phenotype, metabolism of celecoxib may be decreased substantially; the half-life of celecoxib is prolonged and higher plasma concentrations of the drug may increase the likelihood and/or severity of adverse effects.1,520 Metabolism of celecoxib may be moderately reduced in CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1 and mildly reduced in those with an AS of 1.5.520 Higher plasma concentrations of the drug in intermediate metabolizers with an AS of 1 may increase the likelihood of adverse effects.520 The presence of other factors affecting clearance of the drug (e.g., hepatic impairment, advanced age) also may increase the risk of adverse effects in intermediate metabolizers.520 (See Pharmacogenomic Dosage Considerations under Dosage and Administration and also see Elimination under Pharmacokinetics.) The Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs should be consulted for additional information on interpretation of CYP2C9 genotype testing.520
Precautions Related to Dermatologic and Hypersensitivity Reactions
Anaphylactoid reactions have been reported in patients receiving celecoxib.1 Patients receiving celecoxib should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.1
Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis) can occur in patients receiving celecoxib.1,144 These serious skin reactions can occur without warning and in patients without a history of sulfonamide sensitivity reactions; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.1 Celecoxib should be discontinued at the first appearance of rash or any other sign of hypersensitivity.1
Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1,1201 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1201 Symptoms may resemble those of an acute viral infection.1201 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1201 If such signs or symptoms develop, celecoxib should be discontinued and the patient evaluated immediately.1201
Use of NSAIAs, including celecoxib, has been associated with modest prolongation of activated partial thromboplastin time (aPTT) in children with systemic onset juvenile rheumatoid arthritis.1 Because of the risk of disseminated intravascular coagulation in children with systemic onset juvenile rheumatoid arthritis who are receiving celecoxib, these children should be monitored for clinical signs or symptoms of abnormal clotting or bleeding and with coagulation tests.1
NSAIAs, including celecoxib, may increase the risk of bleeding.1 Patients with certain coexisting conditions such as coagulation disorders and those receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk and should be monitored for signs of bleeding.1 (See Drug Interactions.)
If signs and/or symptoms of anemia or blood loss occur during therapy with celecoxib, hemoglobin concentration and hematocrit should be determined.1
The possibility that the anti-inflammatory and, perhaps, antipyretic effects of NSAIAs may mask the usual signs and symptoms of infection should be considered.1
Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of celecoxib, serotonin type 1 [5-HT1] receptor agonists, ergotamine, opiate analgesics, or certain analgesic combinations on a regular basis for 10 or more days per month) may result in migraine-like daily headaches or a marked increase in the frequency of migraine attacks.161 Detoxification, including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often include transient worsening of headaches), may be necessary.161 Patients should be encouraged to record the frequency of migraine headaches and medication use and to contact their clinician if the frequency of migraine attacks increases.161
Because of similarity in spelling of Celexa® (citalopram hydrobromide), Celebrex® (celecoxib), and Cerebyx® (fosphenytoin sodium), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.34
Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.1
When the fixed combination of celecoxib and amlodipine is used, the cautions, precautions, contraindications, and drug interactions associated with both drugs must be considered.1201 For additional information on precautions and drug interactions related to use of amlodipine, see Amlodipine 24:28.08.
The manufacturer states that celecoxib is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug or any ingredient in the formulation.1 In addition, celecoxib should not be given to patients who have experienced allergic-type reactions to sulfonamides.1 NSAIAs, including celecoxib, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, because there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients.1 Because patients with asthma may have aspirin-sensitivity asthma, patients with asthma but without known aspirin sensitivity who are receiving celecoxib should be monitored for changes in manifestations of asthma.1 In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad.1
Celecoxib is contraindicated in the setting of CABG surgery.1,508
Celecoxib is used for the management of the signs and symptoms of juvenile rheumatoid arthritis in children 2 years of age or older; safety and efficacy of celecoxib therapy beyond 6 months in pediatric patients with juvenile arthritis have not been established.1 Celecoxib has been evaluated in pediatric patients 2-17 years of age with pauciarticular course, polyarticular course, or systemic onset juvenile rheumatoid arthritis in one clinical study.1 Celecoxib has not been studied in pediatric patients younger than 2 years of age, those weighing less than 10 kg, or children with active systemic disease.1 Alternative therapies for juvenile rheumatoid arthritis should be considered in pediatric patients known to be CYP2C9 poor metabolizers.1
Safety and efficacy of celecoxib for the acute treatment of attacks of migraine have not been established in pediatric patients.161 In addition, safety and efficacy of celecoxib in fixed combination with amlodipine have not been established in pediatric patients.1201
Recommended pediatric dosages of celecoxib should achieve plasma concentrations of the drug that are similar to those achieved in the clinical study that demonstrated efficacy.1
In the clinical study in pediatric patients with pauciarticular course, polyarticular course, or systemic onset juvenile rheumatoid arthritis (active systemic disease not present at study entry), children with systemic onset juvenile rheumatoid arthritis appeared to be at risk for the development of abnormal coagulation test results.1 Use of NSAIAs, including celecoxib, has been associated with modest prolongation of activated partial thromboplastin time (aPTT) in children with systemic onset juvenile rheumatoid arthritis.1 Because of the risk of disseminated intravascular coagulation in children with systemic onset juvenile rheumatoid arthritis who are receiving celecoxib, these children should be monitored for clinical signs or symptoms of abnormal clotting or bleeding and with coagulation tests.1
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.508 (See Cardiovascular Effects under Cautions.)
Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects.1,161 In clinical trials evaluating celecoxib for acute treatment of migraine attacks, approximately 70 patients were 65 years of age or older, while in clinical trials evaluating celecoxib for other indications, more than 3300 patients were 65-74 years of age and about 1300 were 75 years of age and older.1,161 No overall differences in efficacy of celecoxib were observed between geriatric and younger patients.1,161 Although results from clinical studies indicated that renal (i.e., glomerular filtration rate, blood urea nitrogen, creatinine) and platelet function (i.e., bleeding time, platelet aggregation) in geriatric individuals receiving celecoxib did not differ from those in younger individuals, more of the spontaneous reports of fatal adverse GI effects and acute renal failure have been in geriatric individuals than in younger individuals.1 If it is determined that the anticipated benefits of celecoxib therapy outweigh the potential risks, celecoxib should be initiated at the lower end of the dosing range and patients should be monitored for adverse effects;1 if used for the acute treatment of migraine attacks, celecoxib should be used for the fewest possible number of days per month.161
Peak plasma concentration and area under the plasma concentration-time curve (AUC) were increased 40 and 50%, respectively, in geriatric individuals (i.e., older than 65 years of age), but dosage adjustment in this age group based solely on age generally is not required.1 However, in geriatric patients weighing less than 50 kg, celecoxib therapy should be initiated at the lowest recommended dosage.1
Pregnancy, Fertility, and Lactation
Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.1200,1201 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.1200,1201 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.1200,1201 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.1200,1201
Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.1202
Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1200,1201 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1200,1201 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1200,1201 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1200,1201 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1200,1201 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.1201 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1201 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.1201
Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1201 In animal studies, inhibitors of prostaglandin synthesis, such as celecoxib, were associated with increased pre- and post-implantation losses.1201 Prostaglandins also have an important role in fetal kidney development.1201 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1201
An increased incidence of fetuses with ventricular septal defects, sternebral fusion, rib fusion, and sternebrae abnormality was observed in reproduction studies in rabbits receiving oral celecoxib dosages of 150 mg/kg daily or more throughout organogenesis (exposure approximately twice the usual human dosage of 200 mg twice daily, expressed in terms of AUC [0-24 hours]).1,50 A dose-dependent increase in diaphragmatic hernias was observed in rats receiving oral celecoxib dosages of 30 mg/kg or more daily throughout organogenesis (exposure approximately sixfold the usual human dosage of 200 mg twice daily, expressed in terms of AUC [0-24 hours]).1 Reproduction studies in rats using oral dosages up to 100 mg/kg daily (exposure approximately sevenfold the usual human dosage of 200 mg twice daily, expressed in terms of AUC [0-24 hours]) did not reveal evidence of delayed labor or parturition.1 In rats receiving oral celecoxib dosages of 50 mg/kg or more daily (exposure approximately sixfold the usual human dosage of 200 mg twice daily, expressed in terms of AUC [0-24 hours]), pre- and post-implantation losses and reduced embryonic/fetal survival were observed.1
The effects of celecoxib on labor and delivery are unknown.1 In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, increased the incidence of dystocia, delayed parturition, and decreased pup survival.1
Use of NSAIAs, including celecoxib, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.1 Therefore, withdrawal of celecoxib should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1
Studies in female and male rats using celecoxib dosages up to 600 mg/kg daily (exposure approximately 11-fold the usual human dosage of 200 mg twice daily, expressed in terms of AUC [0-24 hours]) have not revealed evidence of impaired fertility.1
Celecoxib is distributed into milk in small amounts.1,161,1201 Limited data obtained from nursing women receiving celecoxib indicate that the calculated average infant exposure to the drug is 10-40 mcg/kg daily, which is less than 1% of the weight-based therapeutic dosage for a 2-year-old child.1,161,1201 Maternal use of celecoxib was not associated with adverse effects in 2 breast-fed infants 17 and 22 months of age.1,161,1201 It is not known whether celecoxib affects milk production.161,1201 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for celecoxib and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1,161
Drugs Affecting or Metabolized by 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, thereby increasing celecoxib exposure and toxicity.1,3,44 Drugs that induce CYP2C9 (e.g., rifampin) may reduce efficacy of celecoxib.1 Adjustment of celecoxib dosage may be required in patients receiving concomitant therapy with CYP2C9 inhibitors or inducers.1
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, atomoxetine, and some antiarrhythmics (e.g., encainide, flecainide), potentially increasing exposure to and toxicity of these drugs.1,3,6,44 Dosage adjustments may be required.1
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.1
Concomitant administration of celecoxib with fluconazole can result in substantially increased plasma concentrations of celecoxib.1,50 This pharmacokinetic interaction appears to occur because fluconazole inhibits the CYP2C9 isoenzyme involved in celecoxib metabolism.1 In one study, concomitant administration of fluconazole (200 mg daily) and celecoxib (a single 200-mg dose) increased plasma concentrations of celecoxib twofold.1,50
Other Drugs Affecting Hepatic Microsomal Enzymes
In clinical studies, concomitant administration of celecoxib with glyburide, ketoconazole, phenytoin, or tolbutamide did not alter the pharmacokinetics and/or pharmacodynamics of these drugs, and no clinically important interactions have been reported.1
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.1,50 However, the manufacturer makes no specific recommendation for administration of the drug with regard to antacids because these effects are not considered clinically important.1,50
Anticoagulants, such as warfarin, and nonsteroidal anti-inflammatory agents (NSAIAs) have synergistic effects on GI bleeding.1 Concomitant use of celecoxib and anticoagulants is associated with a higher risk of serious bleeding compared with use of either agent alone.1 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).50,55 However, during postmarketing surveillance, bleeding complications associated with increases in PT were reported in some (mainly geriatric) patients receiving celecoxib concomitantly with warfarin.1,56,57 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, and for signs of bleeding.1,56,57
Because reduced CYP2C9 function is associated with an increased risk of major bleeding or supratherapeutic international normalized ratio (INR) in patients receiving concomitant therapy with warfarin (a CYP2C9 substrate) and NSAIAs, some experts state that concomitant use of warfarin and NSAIAs should be avoided in patients who are CYP2C9 intermediate or poor metabolizers.520
Concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents may reduce the blood pressure response to the antihypertensive agent.1,153 Therefore, blood pressure should be monitored to ensure that target blood pressure is achieved.1,153
Concomitant use of celecoxib with ACE inhibitors or angiotensin II receptor antagonists in geriatric patients or patients with volume depletion or renal impairment may result in reversible deterioration of renal function, including possible acute renal failure; such patients should be monitored for signs of worsening renal function.1 Patients receiving concomitant therapy with celecoxib and ACE inhibitors or angiotensin II receptor antagonists should be adequately hydrated, and renal function should be assessed when concomitant therapy is initiated and periodically thereafter.1
Concomitant use of celecoxib and corticosteroids may increase the risk of GI ulceration or bleeding.1 Patients should be monitored for signs of bleeding.1
Concomitant use of celecoxib and cyclosporine may increase cyclosporine-associated nephrotoxicity.1 Patients should be monitored for signs of worsening renal function.1
Concomitant use of celecoxib and digoxin has been reported to result in increased serum concentrations and prolonged half-life of digoxin.1 Serum digoxin concentrations should be monitored.1
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).1 (See Renal, Electrolyte, and Genitourinary Effects under Cautions and also see Renal Effects under Pharmacology.) Patients receiving concomitant celecoxib and diuretic therapy should be monitored for signs of worsening renal function and for adequacy of diuretic and antihypertensive effects.1
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.1
Celecoxib and other NSAIAs can decrease renal clearance of lithium, which may lead to increased serum or plasma lithium concentrations.1,36 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.36 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.1 Patients receiving lithium and celecoxib concomitantly should be monitored for signs of lithium toxicity.1
Concomitant use of NSAIAs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).1 Although concomitant administration of celecoxib with methotrexate during clinical studies did not alter the pharmacokinetics of methotrexate, patients receiving concomitant celecoxib and methotrexate therapy should be monitored for methotrexate toxicity.1
Nonsteroidal Anti-inflammatory Agents
In controlled clinical trials, concomitant use of NSAIAs and analgesic dosages of aspirin did not produce any greater therapeutic effect than use of NSAIAs alone.1 However, concomitant use of aspirin and an NSAIA increases the risk for bleeding and serious GI events.1 Because of the potential for increased adverse effects, concomitant use of celecoxib with other NSAIAs or with analgesic dosages of aspirin generally is not recommended.1
Patients receiving celecoxib should be advised not to take low-dose aspirin without consulting their clinician.1 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.1,33,79 (See GI Effects under Cautions.) Celecoxib is not a substitute for low-dose aspirin therapy for prophylaxis of cardiovascular events, and patients receiving antiplatelet agents such as aspirin concomitantly with celecoxib should be monitored closely for bleeding.1 In studies in healthy individuals and in patients with osteoarthritis and established heart disease, celecoxib (200-400 mg daily) did not interfere with the cardioprotective antiplatelet effect of aspirin (100-325 mg).1,163,164 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,103,133,134,139,141,502,508
Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.1 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.1 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.1 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant celecoxib and pemetrexed therapy.1
Serotonin release by platelets plays an important role in hemostasis.1 Results of case-control and epidemiologic cohort studies indicate that concomitant use of NSAIAs and drugs that interfere with serotonin reuptake may potentiate the risk of bleeding beyond that associated with an NSAIA alone.1 Patients receiving concomitant therapy with celecoxib and selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) should be monitored for signs of bleeding.1
Limited information is available on the acute toxicity of celecoxib in humans.1 Serious toxicity was not observed in 12 individuals who received celecoxib 2.4 g daily for 10 days.1
Overdosage of NSAIAs can cause lethargy, drowsiness, nausea, vomiting, and epigastric pain; these manifestations generally are reversible with supportive care.1 GI bleeding also has been reported.1 Rarely, hypertension, acute renal failure, respiratory depression, and coma may occur.1
Treatment of NSAIA overdosage involves symptomatic and supportive care; there is no specific antidote for NSAIA overdosage.1 During the first 4 hours after overdosage, emesis and/or administration of activated charcoal (60-100 g in adults or 1-2 g/kg in children) and/or an osmotic cathartic may be useful in symptomatic patients or in those who reportedly ingested a large overdosage.1 It is not known whether celecoxib is removed by hemodialysis, but the drug's extensive protein binding suggests that forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion is likely to be ineffective in removing substantial amounts of celecoxib from the body.1
Celecoxib is a selective inhibitor of the cyclooxygenase-2 (COX-2) isoform of prostaglandin endoperoxide synthase (prostaglandin G/H synthase, PGHS)1,2,3,4,5,7,8,10,48,53,80 and exhibits many of the pharmacologic actions of prototypical NSAIAs, including anti-inflammatory, analgesic, and antipyretic activity.1,2 NSAIAs appear to inhibit prostaglandin synthesis via inhibition of cyclooxygenase (COX);1,2,3,4,8,11,19,38,40,41,48,53 at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as PGHS-1 and -2, respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway.1,2,3,4,5,8,9,10,11,17,19,38,41,48 Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa.2,3,4,8,11,38,40,41,102 While prototypical NSAIAs are nonselective, inhibiting both COX-1 and COX-2 to varying degrees,2,3,4,5,8,11,38,40,41,53 celecoxib's highly selective inhibition of COX-2 potentially may be associated with a decreased risk of certain adverse effects (e.g., on GI mucosa);1,2,3,4,8,9,10,11,38,40,41 however, additional experience is needed to evaluate fully the adverse effect profile of the drug.2,3,5,8,9,10
COX-1 is a constitutive enzyme that is expressed in most tissues, blood monocytes, and platelets; COX-1 is involved in thrombogenesis (e.g., promotion of platelet aggregation), maintenance of the gastric mucosal barrier, and renal function (e.g., maintenance of renal perfusion).2,3,19,38,40,53 COX-2 is an inducible enzyme that is found principally at sites of inflammation, although it also is expressed constitutively in the brain, kidney, and reproductive organs.2,3,19,38,40,53 COX-2 is expressed within 2-12 hours in response to cytokines and growth factors.2,19 At clinically relevant concentrations, celecoxib inhibits COX-2 in a slow, time-dependent manner involving formation of a tight enzyme-inhibitor complex that is noncovalent but only slowly dissociable.2,4,41 The celecoxib IC50s (concentrations that inhibit enzyme activity by 50%) for COX-1 and COX-2 are 15 and 0.04 µ M , respectively; the ED50 (dose that results in an effect in 50% of individuals tested) for COX-1 exceeds 200 mg/kg and, for COX-2, 0.2 mg/kg.2 The ratios of the IC50s and ED50s for COX-1 and COX-2 are 375 and greater than 1000, respectively, indicating that celecoxib is a highly selective COX-2 inhibitor.2,3,4,8,11,40,41 When celecoxib is administered in the management of osteoarthritis and rheumatoid arthritis, the principal physiologic action of the drug is inhibition of COX-2; celecoxib does not inhibit COX-1 when given in recommended dosages.1,2,3,41
Anti-inflammatory, Analgesic, and Antipyretic Effects
The anti-inflammatory, analgesic, and antipyretic effects of celecoxib and prototypical NSAIAs appear to result from inhibition of prostaglandin synthesis.1,2,3,4,5,8,9,10,11,37,38,39,40,41,53,80 While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.1,2,3,4,5,8,9,10,11,37,38,39,40,41,53 Evidence supporting the role of COX-2 in inflammation includes up-regulation of COX-2 expression by mediators of inflammation, including cytokines and bacterial endotoxin.5,9,10,37,39 In addition, anti-inflammatory glucocorticoids can selectively inhibit cytokine and endotoxin induction of COX-2 while having no effect on expression of COX-1.5,9,10,17,37,39 Selective inhibitors of COX-2 block prostaglandin production and acute tissue inflammation in vivo, and studies in animals suggest that the anti-inflammatory and analgesic properties of selective COX-2 inhibitor NSAIAs are similar to those of prototypical NSAIAs that inhibit both COX-1 and COX-2.5,9,10,37,39 Clinical evidence also indicates that COX-2 has an important role in joint inflammation because highly selective COX-2 inhibitor NSAIAs are as effective as prototypical NSAIAs in the management of rheumatoid arthritis and osteoarthritis.1,2,38
The precise mechanism of action by which celecoxib exerts therapeutic effects in the acute treatment of migraine attacks is not fully understood but may involve inhibition of prostaglandin synthesis, primarily via inhibition of COX-2.161
Studies in animals indicate that celecoxib exerts antipyretic activity at concentrations that inhibit COX-2 in vitro.2
NSAIAs have been associated with reductions in renal blood flow and glomerular filtration rate (GFR) and with sodium retention and hyperkalemia.1,2,38,53 These effects have been attributed to inhibition of renal prostaglandin synthesis in states of low renal reserve when prostaglandin-related physiologic mechanisms are needed to support renal function.2,38,53 Hyperkalemia also has occurred in some patients without renal impairment, and these effects have been attributed to a hyporenin-hypoaldosterone state.1
COX-1 is located in the arteries and arterioles, glomeruli, and collecting ducts of the kidney and is believed to be important in the maintenance of renal blood flow.2 The location and role of COX-2 in the human kidney remains to be determined, but results of animal studies indicate that COX-2 may be important in the regulation of sodium, volume, and blood pressure homeostasis, and in postnatal renal development.2,80 Although the effects of celecoxib on renal function were expected to differ from those of prototypical NSAIAs, results of renal pharmacodynamic and clinical studies indicate that the renal effects of selective inhibitors of COX-2 (e.g., celecoxib) are similar to those of prototypical NSAIAs with respect to renal regulation of sodium excretion, blood pressure, and GFR.2,51,59 In healthy geriatric adults (65-85 years of age), a group likely to have compromised renal function, and in patients with renal impairment (serum creatinine 1.3-3 mg/dL, GFR 40-60 mL/minute per 1.73 m2), celecoxib had minimal effects on renal function.2
Current evidence suggests that primary dysmenorrhea is mediated by prostaglandins.88,89,90,91 Substantially higher concentrations of prostaglandins have been found in the endometrium and menstrual fluid of women with primary dysmenorrhea (painful menses without demonstrable pelvic abnormality) compared with women without primary dysmenorrhea, and the amount of prostaglandin F2 in menstrual fluid correlates with symptom severity (i.e., cramps, pain).88,89,90 Whether increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or -2 remains to be determined.88 Prototypical NSAIAs that inhibit COX-1 and -2 and selective inhibitors of COX-2 (e.g., celecoxib) have been effective in relieving menstrual pain.1,88
Limited evidence indicates that inhibition of COX-2 might interfere with ovulation.54,88,92
Therapy with prototypical NSAIAs has been associated with gastric mucosal dama these effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.1,2,3,4,5,8,9,10,11,38,39,40,41,53,54 Other factors possibly involved in NSAIA-induced gastropathy include local irritation, promotion of acid back-diffusion into gastric mucosa, uncoupling of oxidative phosphorylation, and enterohepatic recirculation of the drugs.40,54 Because celecoxib is a selective inhibitor of COX-2, the drug is not expected to produce gastric mucosal damage typical of prototypical NSAIAs.2,3,4,5,8,9,10,11,38,39,40,41 Short-term administration of celecoxib has been associated with a lower incidence of adverse upper GI effects and endoscopically confirmed GI ulcer than prototypical NSAIAs.1,2,3,9,21,22,24,28,29,38 Whether long-term therapy with celecoxib is associated with a better GI safety profile than therapy with prototypical NSAIAs remains to be established.79 Limited evidence (e.g., from animal studies) indicates that COX-2 may contribute to healing of GI ulcers and that inhibition of COX-2 might interfere with epithelial cell proliferation, angiogenesis, and maturation of granular tissue at regions of ulcer repair and thus may delay healing of gastric ulcers.54,70,71,72,73,80
The effect, if any, of selective COX-2 inhibitors in patients with inflammatory bowel disease remains to be established.69
Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.15,38,53,60,61,75,76,77 The exact mechanism by which NSAIAs may inhibit colon carcinogenesis has not been fully determined, and inhibition of COX-1 and/or COX-2 or inhibition of other cellular targets of NSAIAs may be involved.15,38,60,61,75 Several lines of evidence suggest that inhibition of COX-2 by NSAIAs may play an important role in this effect, although pathways that do not involve cyclooxygenase also may be involved.60,75,76 Overexpression of COX-2 has been observed in colon tumors in rodents and humans and there is evidence that COX-2 contributes to tumorigenesis.15,60,61,75 Although the specific cellular pathways responsible for the effects of COX-2 on tumorigenesis remain to be determined, the enzyme apparently mediates mitogenic growth factor signaling and down-regulates apoptosis, thus promoting tumor growth.60 Biopsy specimens from patients with colorectal cancer (adenocarcinomas) indicate that COX-2 is present in and around colorectal tumors and the degree of expression of COX-2 correlates positively with Duke's stage and tumor size; COX-2 was not present in control tissue from patients without colorectal cancer.61 The distribution of COX-2 in colorectal tumors suggests that inhibition of COX-2 has the potential to restore apoptosis and prevent proliferation of colon cancer cells.15,75,76,77 Induction of apoptosis by inhibition of COX-2 may be important in reducing the number of adenomatous colorectal polyps in patients with familial adenomatous polyposis (FAP), a disorder in which apoptosis is believed to be attenuated,60 and there is some evidence that celecoxib and some other NSAIAs can reduce the size and number of colorectal polyps in patients with FAP.60,76 Studies using genetic and carcinogen-induced rodent models of colon cancer indicate that NSAIAs can decrease both the incidence and multiplicity of colon tumors and decrease the overall colon tumor burden15,75,76,77 and that celecoxib is more effective than prototypical NSAIAs (e.g., aspirin, ibuprofen, piroxicam, sulindac) in these models.15,38,61
Unlike prototypical NSAIAs, celecoxib administered in single doses up to 800 mg and in multiple doses of 600 mg twice daily for up to 7 days does not appear to inhibit platelet aggregation or prolong bleeding time.1,3,9,20 However, bleeding complications have been reported during postmarketing surveillance in some patients with elevated PTs receiving concomitant warfarin therapy.56,57 (See Anticoagulants under Drug Interactions.)
It has been postulated that selective COX-2 inhibitors may increase cardiovascular thrombotic risk because they block synthesis of prostacyclin (which is antithrombotic) but leave generation of thromboxane A2 (which is prothrombotic) unaffected, thereby allowing platelet aggregation and hemostasis to occur unopposed; in contrast, prototypical NSAIAs suppress synthesis of both prostacyclin and thromboxane A2.102,105,112,117,121 However, individual prototypical NSAIAs vary in degree of selectivity for COX-1 relative to COX-2,519 and both selective COX-2 inhibitors and prototypical NSAIAs have been associated with increased risk of cardiovascular events.103,104,113,129,130,131,500,502,508 Because NSAIAs differ in their selectivity for the COX-2 enzyme and their potency as inhibitors of COX-2, effects of individual NSAIAs on the balance between suppression of prostacyclin and thromboxane A2 may differ.102,105,519 Rofecoxib is one of the most potent COX-2 inhibitors; rofecoxib also is one of the most selective COX-2 inhibitors in vitro.102,117 Celecoxib is less selective than rofecoxib or valdecoxib.102,117 The clinical relevance of differences in COX-2 selectivity and potency of individual NSAIAs with regard to cardiovascular thrombotic risk remains to be fully determined.102,105,112,503,510,512,519
The pharmacokinetics of celecoxib have been studied principally in healthy adults and in adults with acute pain, rheumatoid arthritis, or osteoarthritis.1,2 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.1 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.1,50 Limited data indicate that the pharmacokinetics of celecoxib are affected by advanced age, renal and/or hepatic function, and race.1,2 (See Absorption under Pharmacokinetics.)
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.1,2,23 Absolute bioavailability of celecoxib has not been determined.1 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.1,2 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.1,2 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.2 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.1 Following oral administration of celecoxib at recommended dosages (200-400 mg daily), steady-state plasma concentrations are achieved within 5 days.1,2 Drug accumulation has not been observed in individuals receiving celecoxib 400 mg twice daily.1,2
Following oral administration of tablets containing celecoxib in fixed combination with amlodipine, peak concentrations of celecoxib were attained within 2 hours, and the rate and extent of absorption of celecoxib were similar under fed and fasting conditions.1201
Celecoxib oral solution has a faster rate of absorption and increased bioavailability as compared with celecoxib oral capsules.166 Following administration of celecoxib 120 mg as an oral solution in healthy, fasting individuals, the median time to peak plasma concentration was 1 hour.161,166 When the oral solution was administered with a high-fat meal, the median time to peak plasma concentration was delayed by 2 hours and peak plasma concentration was decreased by approximately 50% compared with administration under fasting conditions, with no change in total exposure (AUC).161 However, in the principal clinical trials establishing efficacy of celecoxib oral solution for acute treatment of migraine, the drug was administered without regard to food.161
Following oral administration of celecoxib capsules 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.1,2,161 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.1,2 Analysis of pooled pharmacokinetic data indicates that the AUC of celecoxib, administered as capsules, is about 40% higher in Blacks compared with Whites; the cause and clinical importance of this finding are not known.1,2,161
Limited information is available on the pharmacokinetics of celecoxib in patients with mild to moderate hepatic and/or renal impairment.1,2 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, receiving celecoxib as capsules compared with that in healthy adults with normal hepatic function.1,2,161 In adults with chronic renal insufficiency (glomerular filtration rates of 35-60 mL/minute), AUC of celecoxib administered as capsules reportedly was 40% lower than that in adults with normal renal function.1,2,161
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.1,2
At therapeutic plasma concentrations, celecoxib is about 97% bound to plasma proteins, principally albumin and to a lesser extent, α1-acid glycoprotein.1,2,23 Celecoxib is not preferentially bound to erythrocytes in blood.1,2,23
It is not known whether celecoxib crosses the placenta in humans.1,2 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.1
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.1,2 The mean apparent elimination half-life of celecoxib following administration as an oral solution is approximately 6 hours independent of dosing condition and is similar to that observed for celecoxib capsules administered under fed conditions.161 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.50
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 2C9.1,2,23 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.1,2,23 The carboxylic acid metabolite is conjugated with glucuronic acid to some extent, forming the 1- O -glucuronide.1,2 Metabolites of celecoxib do not have pharmacologic activity as cyclooxygenase-1 (COX-1) or COX-2 inhibitors.2
In patients with the CYP2C9 poor metabolizer phenotype, the metabolic clearance of celecoxib may be decreased substantially and plasma concentrations may be increased.1,520 Metabolism may be moderately or mildly decreased in patients with the CYP2C9 intermediate metabolizer phenotype with a diplotype activity score (AS) of 1 or 1.5, respectively.520 (See Pharmacogenomic Precautions under Cautions.) Limited data indicate that celecoxib concentrations are increased threefold to sevenfold in individuals with the homozygous CYP2C9*3/*3 diplotype compared with individuals with a diplotype of CYP2C9*1/*1 or CYP2C9*1/*3.1 Data are lacking in individuals with other CYP2C9 polymorphisms, such as *2, *5, *6, *9, and *11.1
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.1
Celecoxib is excreted in urine and feces principally as metabolites; less than 3% of the dose is excreted unchanged.1,2,23 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.1,2,50 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.1,2
Celecoxib, a diaryl substituted pyrazole derivative containing a sulfonamide substituent, is a nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,5,8,11,41 Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX-2).1,2,8,52 Because the goal of selective inhibitors of COX-2 is to inhibit COX-2 but not COX-1, the drugs also have been referred to as COX-1-sparing NSAIAs. Celecoxib differs chemically and, to some extent, pharmacologically from prototypical NSAIAs, which inhibit cyclooxygenase-1 (COX-1) and -2 (COX-2).1,2,3,4,5,8,11,41
Celecoxib consists of a central pyrazole ring, 2 substituted aromatic rings, and a benzenesulfonamide attached to one of the rings.1,2,8,11,41 Spatial orientation of the 2 aromatic rings relative to the central ring is important for cyclooxygenase inhibitory activity; the 2 aromatic rings must reside at adjacent positions on the central ring for COX-2 activity.11 Unlike most prototypical NSAIAs, celecoxib does not contain a carboxylate group; it has been postulated that absence of such a group may contribute to the drug's high COX-2 selectivity.41,53
Although the overall structures of COX-1 and COX-2 are similar, a principal difference between the 2 isoforms of cyclooxygenase is the presence of a much larger NSAIA binding site on COX-2 compared with the NSAIA binding site on COX-1.8,41,50,51,53 The larger binding site on COX-2 results from the substitution of valine for isoleucine at position 523 in COX-2.8,41,48,53 It has been postulated that the smaller valine molecule, unlike the larger isoleucine molecule in COX-1, gives access to a side pocket that may be the binding site for many selective COX-2 inhibitors, including celecoxib.8,41,48 It appears that the benzenesulfonamide moiety of celecoxib binds to the side pocket, although diaryl heterocyclic compounds, including celecoxib, may have multiple modes of binding to cyclooxygenases.8,41
Celecoxib occurs as an odorless, white to off-white crystalline powder.50 The aqueous solubility of celecoxib at a pH less than 9 is about 5 mcg/mL at 5-40°C.50 Solubility of the drug increases in strongly basic solutions; celecoxib has a solubility of 0.8 mg/mL in water at 40°C and pH 12.50 The drug has a solubility of 111 mg/mL in alcohol at room temperature.50
Commercially available celecoxib capsules should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.1 When stored as directed, the capsules have an expiration date of 2 years following the date of manufacture.1,50 When a celecoxib capsule is opened and the contents mixed with applesauce, the mixture is stable for 6 hours when refrigerated.1
The commercially available celecoxib oral solution should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.161 The oral solution should not be refrigerated or frozen, and any unused portion remaining in the disposable unit-dose glass bottle should be discarded immediately after use.161
Tablets containing celecoxib in fixed combination with amlodipine should be stored at 20-25°C.1201
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Capsules | 50 mg* | ||
Celecoxib Capsules | ||||
100 mg* | CeleBREX® | Pfizer | ||
Celecoxib Capsules | ||||
200 mg* | CeleBREX® | Pfizer | ||
Celecoxib Capsules | ||||
400 mg* | CeleBREX® | Pfizer | ||
Celecoxib Capsules | ||||
Solution | 120 mg/4.8 mL | Elyxyb® | Dr. Reddy's |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets | 56 mg with tramadol hydrochloride 44 mg | Seglentis® (C-IV) | Kowa |
200 mg with Amlodipine Besylate 2.5 mg (of amlodipine) | Consensi® | Burke | ||
200 mg with Amlodipine Besylate 5 mg (of amlodipine) | Consensi® | Burke | ||
200 mg with Amlodipine Besylate 10 mg (of amlodipine) | Consensi® | Burke |
1. Pfizer. Celebrex® (celecoxib) capsules prescribing information. New York, NY; 2019 May.
2. G.D. Searle & Co. Celebrex® (celecoxib) formulary information. Skokie, IL; 1999 Feb 8.
3. Anon. Celecoxib for arthritis. Med Lett Drugs Ther . 1999; 41:11-2. [PubMed 9949762]
4. Gierse JK, McDonald JJ, Hauser SD et al. A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J Biol Chem . 1996; 271:15810-4. [PubMed 8663121]
5. Seibert K, Zhang Y, Leahy K et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA . 1994; 91:12013-7. [PubMed 7991575]
6. Funck-Brentano C, Thomas G, Jacqz-Aigrain E et al. Polymorphism of dextromethorphan metabolism: relationships between phenotype, genotype and response to the administration of encainide in humans. J Pharmacol Exp Ther . 1992; 263:780-6. [PubMed 1432700]
7. McAdam BF, Catella-Lawson F, Mardini IA et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA . 1999; 96:272-7. [PubMed 9874808]
8. Hawkey CJ. COX-2 inhibitors. Lancet . 1999; 353:307-14. [PubMed 9929039]
9. Simon LS, Lanza FL, Lipsky PE et al. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum . 1998; 41:1591-602. [PubMed 9751091]
10. Lipsky PE, Isakson PC. Outcome of specific COX-2 inhibition in rheumatoid arthritis. J Rheumatol . 1997; 24(Suppl 49):9-14. [PubMed 9002004]
11. Penning TD, Talley JJ, Bertenshaw SR et al. Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H -pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib). J Med Chem . 1997; 40:1347-65. [PubMed 9135032]
12. Markind JE (G. D. Searle, Skokie, Ill): Personal communication; 1999 May 7.
13. G.D. Searle. Response to Wall Street Journal article regarding Celebrex. Skokie, Ill; 1999 Apr 20. Press release from website ([Web]).
14. Anon. Searle responds to Journal report on Celebrex side effects. Skokie, Ill; 1999 Apr 22. Press release from website ([Web]).
15. Kawamori T, Rao CV, Seibert K et al. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res . 1998; 58:409-12. [PubMed 9458081]
16. McAdam BF, Kapoor S, Catella-Lawson F et al. Selective inhibition of monocyte COX-2 vs platelet COX-1 in humans. Circulation . 1997; 96(Suppl):I-557.
17. Crofford LJ, Wilder RL, Ristimäki AP et al. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues: effects of interleukin-1β, phorbol ester, and corticosteroids. J Clin Invest . 1994; 93:1095-101. [PubMed 8132748]
18. Lane NE. Pain management in osteoarthritis: the role of COX-2 inhibitors. J Rheumatol . 1997; 24(Suppl 49):20-4. [PubMed 9002006]
19. DeWitt DL, Bhattacharyya D, Lecomte M et al. The differential susceptibility of prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs: aspirin derivatives as selective inhibitors. Med Chem Res . 1995; 5:325-43.
20. Mengle-Gaw L, Hubbard RC, Karim A et al. A study of the platelet effects of SC-58635, a novel COX-2-selective inhibitor. Arthritis Rheum . 1997; 40:S93.
21. Geis GS, Hubbard R, Callison D et al. Safety and efficacy of celecoxib, a specific COX-2 inhibitor, in patients with rheumatoid arthritis. Arthritis Rheum . 1998; 41:S364.
22. Hubbard RC, Koepp R, Yu SS et al. Pilot efficacy of SC-58635, a COX-2-selective inhibitor, in rheumatoid arthritis. Arthritis Rheum . 1997; 40:S51.
23. Karim A, Tolbert D, Burton E et al. SC-58635 (celecoxib): a highly selective inhibitor of cyclooxygenase-2, disposition kinetics in man and identification of its major CYP450 isozyme in its biotransformation. Pharm Res . 1997; 14(Suppl):S617.
24. Geis GS, Stead H, Morant S et al. Efficacy and safety of celecoxib, a specific COX-2 inhibitor, in patients with rheumatoid arthritis. Arthritis Rheum . 1998; 41:S316.
25. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum . 1995; 38:727-35. [PubMed 7779114]
26. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum . 1993; 36:729-40. [PubMed 8507213]
27. Felson DT, Anderson JJ, Lange MLM et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? Arthritis Rheum . 1998; 41:1564-70. (IDIS 411264)
28. Hubbard RC, Geis GS, Callison DA et al. Efficacy and safety of celecoxib, a specific COX-2 inhibitor, in osteoarthritis (OA) and rheumatoid (RA). J Rheumatol . 1998; 25(Suppl 52):6. [PubMed 9458195]
29. Hubbard R, Geis GS, Woods E et al. Efficacy, tolerability, and safety of celecoxib, a specific COX-2 inhibitor, in osteoarthritis. Arthritis Rheum . 1998; 41:S196.
30. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum . 2002; 46:328-46. [PubMed 11840435]
31. Lane NE, Thompson JM. Management of osteoarthritis in the primary-care setting: an evidence-based approach to treatment. Am J Med . 1997; 103(Suppl 6A):25-30S. [PubMed 9236482]
32. Kolasinski SL, Neogi T, Hochberg MC et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol . 2020; 72:220-233. [PubMed 31908163]
33. Silverstein FE, Faich G, Goldstein JL et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumtoid arthritis. The CLASS study: a randomized controlled trial. JAMA . 2000; 284:1247-55. [PubMed 10979111]
34. Sharpe R. Monsanto, FDA are trying to overcome confusion over name of arthritis drug. Wall St J . 1999 Apr 15.
35. Anon. Celebrex wins unclear advantage from FDA: backhanded ok for GI safety. F-D-C Rep . 1999; Jan 4:33-4.
36. Lithium interactions. In: Hansten PD, Horn JR. Drug interactions analysis and management. Vancouver, WA: Applied Therapeutics, Inc; 1997:223, 327, 332, 358, 367-369, 371.
37. Smith CJ, Zhang Y, Koboldt CM et al. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA . 1998; 95:13313-8. [PubMed 9789085]
38. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenasea review. Prostaglandins Lipid Mediators . 1998; 56:341-61.
39. Anderson GD, Hauser SD, McGarity KL et al. Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J Clin Invest . 1996; 97:2672-9. [PubMed 8647962]
40. Riendeau D, Charleson S, Cromlish W et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol . 1997; 75:1088-95. [PubMed 9365818]
41. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature . 1996; 384:644-8. [PubMed 8967954]
42. Hubbard RC, Mehlisch DR et al. SC-58635, a highly selective inhibitor of COX-2, is an effective analgesic in an acute post surgical pain model. J Invest Med . 1996; 44:293A.
43. Mehlisch DR, Hubbard RC, Isakson P et al. Analgesic efficacy and plasma levels of a highly selective inhibitor of COX-2 (SC-58635; SC) in patients with post-surgical dental pain. Clin Pharmacol Ther . 1997; 61:195.
44. Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy . 1998; 18:84-112. [PubMed 9469685]
45. Angiotensin-converting enzyme inhibitor interactions: nonsteroidal anti-inflammatory drugs (NSAIDSs). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:131-2.
46. Novartis Pharmaceuticals. Diovan® (valsartan) capsules prescribing information (dated 1997 Apr). In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:2013-5.
47. Lanza FL, Rack MF, Callison DA et al. A pilot endoscopic study of the gastroduodenal effects of SC-58635, a novel COX-2 selective inhibitor. Gastroenterology . 1997; 112:A194.
48. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med . 1999; 106:37S-42. [PubMed 10390126]
49. Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? J Rheumatol . 1999; 26(Suppl 56):31-6.
50. Pfizer, New York, NY: Personal communication.
51. Reviewers' comments (personal observations).
52. Merck & Co. Vioxx® (rofecoxib) tablets and oral suspension prescribing information. Whitehouse Station, NJ: 2000 Jul.
53. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Ann Rev Pharmacol Toxicol . 1998; 38:97-120.
54. Wolfe MM, Lichtenstein DR, Singh G. Gastroinestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med . 1999; 340:1888-99. [PubMed 10369853]
55. Karim A, Tolbert D, Piergies A et al. Celecoxib, a specific COX-2 inhibitor, lacks significan drug-drug interactions with methotrexate or warfarin. Arthritis Rheum . 1998; 41(Suppl):S315.
56. Bello A. Dear health care professional letter regarding updated labeling for Celebrex® (celecoxib) on prothrombin time increases with concomitant warfarin therapy. Skokie, IL: Searle; 1999 May.
57. Food and Drug Administration Center for Drug Evaluation and Research: questions and answers about Celebrex® labeling changewarfarin interaction. 1999; June 1.
58. Perazella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis . 2000: 35:937-40.
59. Dunn MJ. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis . 2000: 35:976-7. Editorial.
60. Steinbach G, Lynch PM, RKS Phillips et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med . 2000; 342:1946-52. [PubMed 10874062]
61. Sheehan KM, Sheahan K, O'Donoghue DP et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA . 1999; 282:1254-7. [PubMed 10517428]
62. Lanza FL, and the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol . 1998; 93:2037-46. [PubMed 9820370]
63. Goldstein JL, Silverstein FE, Agrawal NM et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol . 2000; 95:1681-90. [PubMed 10925968]
64. Bensen WG, Fiechtner JJ, McMillen JI et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc . 1999; 74:1095-1105. [PubMed 10560596]
65. Emery P, Zeidler H, Kvien TK et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomized double-blind comparison. Lancet . 1999; 354:2106-11. [PubMed 10609815]
66. Simon LS, Weaver AL, Graham DY et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled study. JAMA . 1999; 282:1921-8. [PubMed 10580457]
67. Pincus T, O'Dell JR, Kremer JM. Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy. Ann Intern Med . 1999; 131:768-74. [PubMed 10577301]
68. Reviewer comments (personal observations) on etanercept.
69. Peterson WL, Cryer B. Cox-1-sparing NSAIDs-is the enthusiasm justified? JAMA . 1999; 282:1961-3. Editorial.
70. Beejay U, Wolfe MM. Cyclooxygenase 2 selective inhibitors: panacea or flash in the pan? Gastroenterology . 1999; 117:1002-14. Editorial.
71. Mizuno H, Sakamoto C, Matsuda K et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology . 1997; 112:387-97. [PubMed 9024292]
72. Stenson WF. Cyclooxygenase 2 and wound healing in the stomach. Gastroenterology . 1997; 112:645-8. [PubMed 9024317]
73. Schmassmann A, Peskar BM, Stettler C et al. Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br J Pharmacol, . 1998; 123:795-804.
74. Anon. Selective COX-2 inhibitors and bleeding risk: an additional note. Med Lett Drugs Ther . 2000; 42:92.
75. Reddy BS, Hirose Y, Lubet R et al. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res . 2000; 60:293-7. [PubMed 10667579]
76. Fournier DB, Gordon GB. COX-2 and colon cancer: potential targets for chemoprevention. J Cell Biochem . 2000; 34:97-102.
77. Jacoby RF, Seibert K, Cole CE et al. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res . 2000; 60:5040-4. [PubMed 11016626]
78. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther . 2000; 42:57-64. [PubMed 10887424]
79. Food and Drug Administration. CLASS Advisory Committee meeting. Rockville, MD; Feb 2001. From FDA web site ([Web])
80. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med . 2001; 345:433-42. [PubMed 11496855]
81. Gottlieb S. Researchers deny any attempt to mislead public over JAMA article on arthritis drug. BMJ . 2001; 323:301. [PubMed 11498480]
82. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA . 2001; 286:954-9. [PubMed 11509060]
83. Levy MB, Fink JN. Anaphylaxis to celecoxib. Ann Allergy Asthma Immunol . 2001; 87:72-3. [PubMed 11476468]
84. Fye KH, Crowley E, Berger TG et al. Celecoxib-induced Sweet's syndrome. J Am Acad Dermatol . 2001; 45:300-2. [PubMed 11464196]
85. O'Beirne JP, Cairns SR. Cholestatic hepatitis in association with celecoxib. BMJ . 2001; 323:23. [PubMed 11440939]
86. Graham MG. Acute renal failure related to high-dose celecoxib. Ann Intern Med . 2001; 135:69-70. [PubMed 11434756]
87. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol . 1999; 26(suppl 56):18-24.
88. Morrison BW, Daniels SE, Kotey P et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled trial. Obstet Gynecol . 1999; 94:504-8. [PubMed 10511349]
89. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol . 1993; 169:1255-65. [PubMed 8238194]
90. Bieglmayer C, Hofer G, Kainz C et al. Concentrations of various arachidonic acid metabolites in menstrual fluid are associated with menstrual pain and are influenced by hormonal contraceptives. Gynecol Endocrinol . 1995; 9:307-12. [PubMed 8629459]
91. Chan WY, Fuchs F, Powell AM. Effects of naproxen sodium on menstrual prostaglandin and primary dysmenorrhea. Obstet Gynecol . 1983; 61:285-91. [PubMed 6571974]
92. Lim H, Paria BC, Das SK et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell . 1997; 91:197-208. [PubMed 9346237]
93. in't Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med . 2001; 345:1515-21. [PubMed 11794217]
94. Breitner JCS, Zandi PP. Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer's disease? N Engl J Med . 2001; 345:1567-8. Editorial.
95. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology . 1996; 47:425-32. [PubMed 8757015]
96. Beard CM, Waring SC, O'sBrien PC et al. Nonsteroidal anti-inflammatory drug use and Alzheimer's disease : a case-control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc . 1998; 73:951-5. [PubMed 9787743]
97. in't Veld BA, Launer LJ, Hoes AW et al. NSAIDs and incident Alzheimer's disease: the Rotterdam Study. Neurobiol Aging . 1998; 19:607-11. [PubMed 10192221]
98. Stewart WF, Kawas C, Corrada M et al. Risk of Alzheimer's disease and duration of NSAID use. Neurology . 1997; 48:626-32. [PubMed 9065537]
99. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomized controlled trials. BMJ ; 325:619-23.
100. Chan FKL, Hung LCT, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med . 2002; 347:2104-10. [PubMed 12501222]
101. Graham DY. NSAIDs, Helicobacter pylori , and Pandora's box. N Engl J Med . 2002; 347:2162-4. [PubMed 12501230]
102. Clark DWJ, Layton D, Shakir SAW. Do some inhibitors of COX-2 increase the risk of thromboembolic events? Drug Safety . 2004; 27:427-56.
103. Bresalier RS, Sandler RS, Quan H. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352:1092-102. (IDIS 529764) Correction: N Engl J Med. 2006; 355:221. [PubMed 15713943]
104. Merck. Merck announces voluntary worldwide withdrawal of Vioxx®. Whitehouse Station, NJ; 2004 Sep 30. Press release.
105. Couzin J. Drug safety: withdrawal of Vioxx casts a shadow over COX-2 inhibitors. Science . 2004; 306:384-5. [PubMed 15486258]
106. Pfizer. Pfizer to sponsor major new Celebrex clinical trial. New York, NY; 2004 Oct 18. Press release.
107. Solomon D, Kavanaugh A, Matteson E L. Cardiovascular complications related to COX-2 inhibitors. From the American College of Rheumatology website ([Web]). Accessed 2004 Oct 25.
108. Solomon DH, Schneeweiss S, Glynn RJ et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation . 2004; 109:2068-73. [PubMed 15096449]
109. Food and Drug Administration. Consultation NDA 21-042, S-007: review of cardiovascular safety data: rofecoxib. Rockville, MD: 2001 Feb 1. From the FDA website ([Web]). Accessed 2004 Oct 25.
110. Food and Drug Administration. CLASS Advisory Committee briefing document. Rockville, MD: 2001 Feb 7. From the FDA website ([Web]). Accessed 2004 Oct 25.
111. Pfizer. Comparative studies with Vioxx (rofecoxib) in cardiovascular safety. New York, NY; 2004 Aug.
112. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med . 2004: 351:1709-11.
113. Ott E, Nussmeier NA, Duke P C et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg . 2003; 125:1481-92. [PubMed 12830070]
114. Pfizer. The overall cardiovascular safety profile: Bextra®. New York, NY; 2004 Nov 1.
115. White WB, Strand V, Roberts R et al. Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther . 2004; 11:244-50. [PubMed 15266215]
116. Bombardier C, Laine L, Reicin et al. Compariosn of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med . 2000; 343:1520-8. [PubMed 11087881]
117. Anon. What about Celebrex? Med Lett Drugs Ther . 2004; 46:87-8.
118. Juni P, Nartey L, Reichenbach S et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet . 2004; 364:2021-9. [PubMed 15582059]
119. White WB, Raich G, Borer JS et al. Cardiovascular events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol . 2003; 92:411-8. [PubMed 12914871]
120. Pfizer. Pfizer provides information to healthcare professionals about its Cox-2 medicine Bextra® (valdecoxib). New York, NY: 2004 Oct 15. Press release.
121. Reviewers' comments (personal observations) on COX-2 inhibitors and issue of potential cardiovascular risk.
122. Ray WA, Stein CM, Daugherty JR et al. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet . 2002; 360:1071-3. [PubMed 12383990]
123. Graham DJ, Campen D, Hui R et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet . 2005; 365:475-81. [PubMed 15705456]
124. Bing RJ. Cyclooxygenase-2 inhibitors: is there an association with coronary or renal events? Current Atherosclerosis Rep . 2003; 5:114-7.
125. White WB, Faich G, Whelton A et al. Comparison of thromboembolic events in patients treated with celecoxib , a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac . Am J Cardiol . 2002; 89:425-30. [PubMed 11835924]
126. Pfizer, New York, NY. Personal communication on COX-2 inhibitors and issue of potential cardiovascular risk.
127. Kimmel SE, Berlin JA, Reilly M et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med . 2005; 142:157-64. [PubMed 15684203]
128. Finckh A, Aronson MD. Cardiovascular risks of cyclooxygenase-2 inhibitors: where we stand now. Ann Intern Med . 2005; 142:212-4. [PubMed 15684210]
129. Burklow J, Ralbovsky D. NIH Halts use of COX-2 inhibitor in large cancer prevention trial. NIH News . 2004 Dec 17.
130. US Food and Drug Administration. FDA statement on the halting of a clinical trial of the Cox-2 inhibitor Celebrex. Press release. Rockville, MD; 2004 Dec 17.
131. Pfizer. Pfizer statement on new information regarding cardiovascular safety of Celebrex. Press release. New York, NY; 2004 Dec 17.
132. Dougados M, Behier JM, Jolchine I et al. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum . 2001; 44:180-5. [PubMed 11212158]
133. Food and Drug Administration. Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6.
134. Lévesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med . 2005; 142:481-9. [PubMed 15809459]
135. Solomon SD, McMurray JJV, Pfeffer MA et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med . 2005; 352:1071-80. [PubMed 15713944]
136. Anon. Use of non-steroidal anti-inflammatory drugs suspended in large Alzheimer's disease prevention trial. NIH News . 2004 Dec 20.
137. Nussmeier NA, Whelton AA, Brown MT et al. Complications of the COX-2 inhibitors paracoxib and valdecoxib after cardiac surgery. N Engl J Med . 2005; 352:1081-91. [PubMed 15713945]
138. Shaya FT, Blume SW, Blanchette CM et al. Selective cyclooxygenase-2 inhibition and cardiovascular effects: an observational study of a Medicaid population. Arch Intern Med . 2005; 165:181-6. [PubMed 15668364]
139. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ . 2005; 330:1366-72. [PubMed 15947398]
140. Johnson SP, Larsson H, Tarone RE et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-controlled study. Arch Intern Med . 2005; 165:978-84. [PubMed 15883235]
141. Farkouh ME, Kirshner H, Harrington RA et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet . 2004; 364:675-84. [PubMed 15325832]
142. Cush JJ. The safety of COX-2 inhibitors: deliberations from the February 16-18, 2005, FDA meeting. From the American College of Rheumatology website ([Web]). Accessed 2005 Oct 12.
143. Bennett JS, Daugherty A, Herrington D et al. The use of nonsteroidal anti-inflammatory drugs (NSAIDs); a Science Advisory from the American Heart Association. Circulation . 2005; 111:1713-16. [PubMed 15781731]
144. La Grenade L, Lee L, Weaver J et al. Comparison of reporting of Stevens-Johnson syndrome and toxic epidermal necrosis in association with selective COX-2 inhibitors. Drug Saf . 2005; 28:917-24. [PubMed 16180941]
145. Shaya FT, Samant N, Skolasky R et al. Modeling risk of gastrointestinal events among Medicaid NSAID users using propensity scores. Expert Rev Pharmacoeconomics Outcomes Res . 2005; 5:625-32.
146. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA . 2006; 296; 1633-44. [PubMed 16968831]
147. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ . 2006; 332; 1302-5. [PubMed 16740558]
148. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense. JAMA . 2006; 296:1653-6. [PubMed 16968830]
149. Bertagnolli MM, Eagle CJ, Zauber A et al., for the APC study investigators. Celecoxib for the prevention of sporadic colorectal adenomas. N Eng J Med . 2006; 355:873-84. [PubMed 16943400]
150. Arber N, Eagle CJ, Spicak J, et al., for the PreSAP trial investigators. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med . 2006; 355; 885-95. [PubMed 16943401]
151. Chou R, Helfand M, Peterson K et al. Comparative effectiveness and safety of analgesics for osteoarthritis. Comparative effectiveness review no. 4. (Prepared by the Oregon evidence-based practice center under contract no. 290-02-0024.) . Rockville, MD: Agency for Healthcare Research and Quality. 2006 Sep. Available at: [Web].
152. Solomon SD, Pfeffer MA, McMurray JJV, et al., for the APC and PreSAP trial investigators. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation . 2006; 114: 1028-35. [PubMed 16943394]
153. Merck & Co. Clinoril® (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.
154. Boulos P, Dougados M, MacLeod SM et al. Pharmacological treatment of ankylosing spondylitis. A systematic review. Drugs . 2005; 65:2111-27. [PubMed 16225367]
155. Zochling Z, van der Heijde D, Braun J et al. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis . 2006; 65:423-32. [PubMed 16126792]
156. Zochling Z, van der Heijde D, Burgos-Vargas R et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis . 2006; 65:442-52. [PubMed 16126791]
157. Gislason GH, Jacobsen S, Rasmussen JN et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation . 2006; 113:2906-13. [PubMed 16785336]
158. Andersohn F, Suissa A, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction. Circulation . 2006; 113:1950-57. [PubMed 16618816]
159. Giannini EH, Ruperto N, Ravelli A et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum . 1997; 40:1202-9. [PubMed 9214419]
160. Ilowite NT. Current treatment of juvenile rheumatoid arthritis. Pediatrics . 2002; 109:109-115. [PubMed 11773549]
161. Dr. Reddy's Laboratories. Elyxyb® (celecoxib) oral solution prescribing information. Hyderabad, Telangana, India; 2020 May.
162. Pfizer. Celebrex® (celecoxib) capsules prescribing information. New York, NY; 2006 Dec.
163. Wilner KD, Rushing M, Walden C et al. Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers. J Clin Pharmacol . 2002; 42:1027-30. [PubMed 12211219]
164. Renda G, Tacconelli S, Capone ML et al. Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease. Clin Pharmacol Ther . 2006; 80:264-74. [PubMed 16952493]
165. Lipton RB, Munjal S, Brand-Schieber E et al. Efficacy, Tolerability, and Safety of DFN-15 (Celecoxib Oral Solution, 25 mg/mL) in the Acute Treatment of Episodic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study. Headache . 2020; 60:58-70. [PubMed 31647577]
166. Pal A, Shenoy S, Gautam A et al. Pharmacokinetics of DFN-15, a Novel Oral Solution of Celecoxib, Versus Celecoxib 400-mg Capsules: A Randomized Crossover Study in Fasting Healthy Volunteers. Clin Drug Investig . 2017; 37:937-946. [PubMed 28748412]
167. Ruschitzka F, Borer JS, Krum H et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial. Eur Heart J . 2017; 38:3282-3292. [PubMed 29020251]
168. Nissen SE, Yeomans ND, Solomon DH et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med . 2016; 375:2519-29. [PubMed 27959716]
169. Food and Drug Administration. Pfizer, Inc.; Withdrawal of approval of familial adenomatous polyposis indication for Celebrex. Notice. [Docket No. FDA-2012-N-0494] Fed Regist . 2012; 77:34052.
170. European Medicines Agency. European Medicines Agency concludes on use of celecoxib in familial adenomatous polyposis; celecoxib not to be used off-label following Onsenal withdrawal. London, United Kingdom; 2011 May 20. Press release. [Web]
171. Syngal S, Brand RE, Church JM et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol . 2015; 110:223-62; quiz 263. [PubMed 25645574]
172. Kowa Pharmaceuticals. Seglentis® (celecoxib and tramadol hydrochloride) tablets prescribing information. Montgomery, AL; 2021 Oct.
500. Food and Drug Administration. Drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Silver Spring, MD; 2015 Jul 9. From the FDA website. Accessed 2016 Mar 22. [Web]
501. Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet . 2013; 382:769-79. [PubMed 23726390]
502. Food and Drug Administration. FDA briefing document: Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee, February 10-11, 2014. From FDA web site [Web]
503. Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ . 2011; 342:c7086. [PubMed 21224324]
504. Gislason GH, Rasmussen JN, Abildstrom SZ et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med . 2009; 169:141-9. [PubMed 19171810]
505. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation . 2011; 123:2226-35. [PubMed 21555710]
506. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med . 2011; 8:e1001098. [PubMed 21980265]
507. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2013; 62:e147-239. [PubMed 23747642]
508. Pfizer. Celebrex® (celecoxib capsules) prescribing information. New York, NY; 2016 May.
510. Helin-Salmivaara A, Virtanen A, Vesalainen R et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland. Eur Heart J . 2006; 27:1657-63. [PubMed 16731535]
511. Olsen AM, Fosbøl EL, Lindhardsen J et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation . 2012; 126:1955-63. [PubMed 22965337]
512. Olsen AM, Fosbøl EL, Lindhardsen J et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study. PLoS One . 2013; 8:e54309.
513. Combe B, Swergold G, McLay J et al. Cardiovascular safety and gastrointestinal tolerability of etoricoxib vs diclofenac in a randomized controlled clinical trial (The MEDAL study). Rheumatology (Oxford) . 2009; 48:425-32. [PubMed 19223284]
514. Baron JA, Sandler RS, Bresalier RS et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet . 2008; 372:1756-64. [PubMed 18922570]
515. ADAPT Research Group. Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). PLoS Clin Trials . 2006; 1:e33.
516. Bavry AA, Khaliq A, Gong Y et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med . 2011; 124:614-20. [PubMed 21596367]
517. Kohli P, Steg PG, Cannon CP et al. NSAID use and association with cardiovascular outcomes in outpatients with stable atherothrombotic disease. Am J Med . 2014; 127:53-60.e1. [PubMed 24280110]
518. Solomon SD, Wittes J, Finn PV et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation . 2008; 117:2104-13. [PubMed 18378608]
519. Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res . 2015; 8:105-18. [PubMed 25759598]
520. Theken KN, Lee CR, Gong L et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther . 2020; 108:191-200. [PubMed 32189324]
1200. US Food and Drug Administration. FDA drug safety communication: FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid. 2020 Oct 15. From the FDA website. [Web]
1201. Burke Therapeutics. Consensi® (amlodipine and celecoxib) tablets prescribing information. Hot Springs, AR; 2020 Nov.
1202. Actavis Pharma. Sulindac tablets prescribing information. Parsippany, NJ; 2020 Oct.