AHFS Class:

• Cyclooxygenase-2 (COX-2) Inhibitors 28:08.04.08

Generic Name(s):

• Celecoxib

Celecoxib is a nonsteroidal anti-inflammatory agent (NSAIA)1,3,4,5,8,11,41 that is a selective inhibitor of cyclooxygenase-2 (COX-2).1,8

Osteoarthritis

Celecoxib is used for the management of the signs and symptoms of osteoarthritis.1

Clinical Experience

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.1,3,9,28,29,64

In controlled clinical studies in adults with osteoarthritis, therapy with celecoxib (100 mg twice daily or 200 mg once daily administered as capsules) resulted in improvement in the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index.1 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 occurred within 24-48 hours and therapy with the drug was 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.1,50 Celecoxib dosages of 200 mg twice daily did not appear to provide additional benefit compared with dosages of 100 mg twice daily or 200 mg once daily in these patients.1

A Cochrane review assessing the benefits and harms of celecoxib in the management of osteoarthritis concluded that celecoxib is slightly better than placebo and some traditional nonsteroidal anti-inflammatory agent (NSAIAs) in terms of reducing pain and improving physical function; however, it is unclear whether harms differ between celecoxib and placebo or traditional NSAIAs due to the risk of bias and low quality of evidence available for many outcomes.1999 Additionally, the authors reported that they were unable to access data for a large number of trial participants, which further hindered their ability to make firm conclusions on the relative benefits and harms of celecoxib.1999

Clinical Perspective

Medical management of osteoarthritis 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 in patients with osteoarthritis of the knee and/or hip who are overweight or obese, self-efficacy and self-management programs, tai chi, cane use, hand orthoses for first carpometacarpal joint osteoarthritis, knee bracing for knee osteoarthritis, 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 are recommended conditionally.32 Interventions for osteoarthritis and the order of their selection are patient specific.32 Factors to consider when making treatment decisions include patient values and preferences, risk of 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 associated with the least systemic exposure or toxicity.32 For some patients with limited disease, topical NSAIAs may be an appropriate initial choice of pharmacologic therapy; for other patients, particularly those with osteoarthritis of the hip or with polyarticular involvement, oral NSAIAs may be more appropriate.32

Rheumatoid Arthritis in Adults

Celecoxib is used for the management of the signs and symptoms of rheumatoid arthritis in adults.1

Clinical Experience

In double-blind, placebo-controlled studies in patients with rheumatoid arthritis, therapy with celecoxib (administered as the capsules) was associated with greater reduction in joint tenderness/pain and swelling than placebo.1 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.1,3,9,10,21,22,23,24,28,65,66 Clinical studies of celecoxib generally have included adults receiving standard therapy for rheumatoid arthritis (i.e., NSAIAs with or without disease-modifying antirheumatic drugs [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.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 ACR criteria for a 20% improvement (ACR 20 response) in measures of disease activity was used as the principal measure of clinical response in studies evaluating the efficacy of celecoxib in rheumatoid arthritis.1,25,26,27 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 randomized controlled studies comparing oral celecoxib with placebo, more patients who received celecoxib (200 or 400 mg daily) had clinically important rates of meeting the ACR 20 criteria than those who received placebo.1,2000 Studies comparing celecoxib and naproxen showed no statistically significant difference between the treatments in ACR 20 improvement criteria.1,2000 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

A Cochrane review assessing the benefits and harms of celecoxib in the management of rheumatoid arthritis concluded that celecoxib may improve clinical symptoms and alleviate pain compared to placebo, and may also slightly improve clinical symptoms compared to traditional NSAIAs.2000 However, results were inconclusive with regard to the effects of celecoxib on physical function.2000 Celecoxib was associated with a lower incidence of gastroduodenal ulcers ≥3 mm compared to traditional NSAIAs, but results for cardiovascular events were uncertain.2000

Clinical Perspective

The American College of Rheumatology (ACR) issued guidelines for the treatment of rheumatoid arthritis in 2021.2001 The ACR guideline recommends initiation of a DMARD (conventional DMARD, biologic DMARD, or targeted synthetic DMARD) in DMARD-naïve patients with rheumatoid arthritis.2001 Specific agents are selected according to current disease activity, prior therapies used, and the presence of comorbidities.2001 A “treat-to-target” approach is typically employed, with the goal of achieving a predefined target of low disease activity or remission.2001 The role of NSAIAs is not discussed in the current ACR guideline on rheumatoid arthritis.2001

Juvenile Rheumatoid Arthritis

Celecoxib is used for the management of the signs and symptoms of juvenile rheumatoid arthritis in children ≥2 years of age.1

Clinical Experience

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) capsules twice daily, celecoxib 6 mg/kg (up to a maximum dose of 300 mg) capsules twice daily, or naproxen 7.5 mg/kg (up to a maximum dose of 500 mg) twice daily.1,2002 Response was measured using the juvenile rheumatoid arthritis definition of improvement (i.e., a ≥30% improvement in at least 3 of 6 and a ≥30% 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 indicated that celecoxib was at least 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 Perspective

The American College of Rheumatology (ACR) and the Arthritis Foundation issued a joint guideline for the treatment of juvenile idiopathic (rheumatoid) arthritis manifesting as nonsystemic polyarthritis (including polyarticular disease), sacroiliitis, or enthesitis in 2019.2003 Several drug classes are used to treat juvenile idiopathic arthritis, including NSAIAs, systemic and intra-articular corticosteroids, conventional DMARDs (e.g., methotrexate, sulfasalazine, hydroxychloroquine, leflunomide), and biologic DMARDs (e.g., tumor necrosis factor [TNF] blocking agents, abatacept, tocilizumab, rituximab).2003 Specific agents for juvenile idiopathic arthritis treatment are selected according to the presence of certain risk factors (e.g., positive anti-cyclic citrullinated peptide antibodies, positive rheumatoid factor, joint damage), level of disease activity, involvement of specific joints, presence of certain comorbidities (e.g., uveitis), and prior therapies used.2003,2004 An individualized “treat-to-target” approach is typically employed, with the goal of achieving remission or minimal/low disease activity.2005

Initial therapy with a DMARD (e.g., methotrexate) is recommended over NSAIA monotherapy for children and adolescents with juvenile idiopathic arthritis and polyarthritis; NSAIAs may be used adjunctively for symptom management in patients with polyarthritis, particularly during initiation or escalation of therapy with DMARDs or biologics.2003 For patients with active sacroiliitis or enthesitis, initial treatment with an NSAIA is recommended, with no preference given to any particular NSAIA.2003

Ankylosing Spondylitis

Celecoxib is used for the management of the signs and symptoms of ankylosing spondylitis in adults.1

Clinical Experience

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 administered as the capsules) 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]).1,132,2006 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 [ASAS 20]).1 There was no change in responder rates after 6 weeks.1 Similar results were reported in a non-inferiority 12-week trial comparing celecoxib 200 mg once daily, celecoxib 200 mg twice daily, and diclofenac 75 mg twice daily; improvements were reported in pain and BASFI scores for all treatment groups.2007 An ASAS 20 response was observed in more patients treated with diclofenac (60.2%) or celecoxib 200 mg twice daily (59.7%) compared to celecoxib 200 mg once daily (46%).2007

Clinical Perspective

The American College of Rheumatology (ACR), the Spondylitis Association of America, and the Spondyloarthritis Research and Treatment Network issued a joint guideline for the treatment of ankylosing spondylitis in 2019.2008 Treatments for ankylosing spondylitis include NSAIAs, conventional DMARDs (e.g., methotrexate, sulfasalazine), biologic DMARDs (e.g., TNF blocking agents, secukinumab, ixekizumab), and/or targeted synthetic DMARDs (e.g., tofacitinib).2008 Specific agents for ankylosing spondylitis treatment are selected according to current disease activity, prior therapies, and the presence of comorbidities.2008 Goals of therapy in ankylosing spondylitis are to alleviate symptoms, improve functioning, maintain the ability to work, decrease complications, and prevent or slow skeletal damage.2008

Continuous NSAIA treatment is conditionally recommended in adults with active ankylosing spondylitis over on-demand treatment with NSAIAs, while on-demand treatment with NSAIAs is conditionally recommended over continuous NSAIA treatment in adults with stable ankylosing spondylitis.2008 No preference is given for one NSAIA over another.2008

Acute Pain

Celecoxib is used in the management of acute pain in adults.1

Clinical Experience

In acute analgesic models of post-oral surgery pain and post-orthopedic surgical pain, celecoxib (administered as the capsules) relieved moderate-to-severe pain, with single doses providing pain relief within 60 minutes.1

A Cochrane review evaluated the efficacy of single-dose celecoxib for moderate to severe postoperative pain (e.g., dental pain following tooth extraction, pain following uncomplicated orthopedic surgery).2009 Randomized, double-blind, placebo-controlled studies comparing celecoxib 200 or 400 mg to placebo were included in the analysis; the main outcome assessed was the proportion of patients achieving ≥50% pain relief over 4-6 hours.2009 Compared to placebo, celecoxib was substantially more effective for relief of acute postoperative pain; 33 or 43% of patients treated with celecoxib 200 or 400 mg, respectively, experienced ≥50% pain relief over 4-6 hours compared with 1-11% of patients who received placebo.2009 The percentage of patients requiring rescue medication at 24 hours was also less with celecoxib (74, 63, or 91% for celecoxib 200 mg, celecoxib 400 mg, or placebo, respectively).2009 The median time to use of rescue medication was prolonged with celecoxib compared with placebo (6.6, 8.4, or 2.3 hours for celecoxib 200 mg, celecoxib 400 mg, or placebo, respectively).2009

Clinical Perspective

A guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists recommends a multimodal approach to the treatment of postoperative pain, including both pharmacologic and nonpharmacologic interventions.2013 For most common surgeries, options for systemic pharmacologic therapy include opioids, NSAIAs and/or acetaminophen, IV ketamine, and gabapentin or pregabalin.2013 The guideline recommends the use of NSAIAs and/or acetaminophen as part of multimodal analgesia for postoperative pain in patients without contraindications.2013 When selecting therapy, the potential risks associated with NSAIAs (e.g., GI bleeding, ulceration, cardiovascular events, renal dysfunction) should be considered for individual patients; celecoxib may carry a lower risk of GI bleeding/ulceration compared with other NSAIAs.2013 If no contraindications are present, the guideline states that a preoperative dose of celecoxib (200-400 mg given 30-60 minutes prior to surgery) should be considered for adults undergoing major surgery, to reduce pain and opioid requirements after surgery.2013

Primary Dysmenorrhea

Celecoxib is used for the management of primary dysmenorrhea in adults.1

Clinical Experience

Celecoxib has been shown to relieve moderate to severe acute pain associated with primary dysmenorrhea.1 In 2 identical, randomized, double-blind, placebo-controlled crossover trials, women 18-44 years of age with a history of primary dysmenorrhea were randomly assigned to treatment with celecoxib (400 mg once, then 200 mg no sooner than 12 hours after the first dose and every 12 hours as needed, administered as capsules), naproxen sodium (550 mg once, then 550 mg no sooner than 12 hours after the first dose and every 12 hours as needed), or placebo on days 1-3 of their menstrual cycle.2014 The primary outcomes assessed were total pain relief and summed pain intensity difference during the first 8 hours after the initial dose of study drug.2014 A total of 303 patients were enrolled in the 2 studies.2014 At 8 hours, total pain relief was substantially greater with both celecoxib and naproxen compared to placebo in studies 1 and 2; naproxen provided greater relief than celecoxib in study 2 only.2014 For summed pain intensity difference, both active treatments were more effective than placebo in both studies, and naproxen was more effective than celecoxib in both studies.2014

Clinical Perspective

First-line treatment options for primary dysmenorrhea include combined oral contraceptives, progesterone-only contraceptives, and NSAIAs; treatment selection should be based on patient-specific considerations (e.g., comorbidities, desire/need for contraception).2012,2015 The American College of Obstetricians and Gynecologists includes celecoxib as a potential NSAIA for use in patients ≥18 years of age with primary dysmenorrhea, but does not recommend one NSAIA over another.2012

Migraine

Celecoxib is used for the acute treatment of migraine with or without aura in adults; the oral solution is specifically FDA-labeled for this use.161 Celecoxib should not be used for the preventive treatment of migraine.161

Clinical Experience

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 40.6 years) who were experiencing a migraine attack causing moderate to severe pain.161,2021,2022,2023 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 (35.1 versus 21%) but not in the other study (32.4 versus 25.3%).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 (56.8 versus 43.9% and 58 versus 44.4%).161

Clinical Perspective

Guidelines from the American Headache Society (AHS) provide recommendations for the acute treatment of migraine attacks.2024 The guidelines include NSAIAs (aspirin, celecoxib oral solution, diclofenac, ibuprofen, naproxen) as one of several classes of drugs with established efficacy in the acute treatment of migraine.2024 Nonspecific analgesic therapies such as NSAIAs are used for mild-to-moderate attacks, while migraine-specific therapies (e.g., triptans, ergotamine derivatives, small-molecule calcitonin gene-related peptide [CGRP] receptor antagonists [gepants], lasmiditan) are used for moderate-to-severe attacks or mild-to-moderate attacks that respond poorly to nonspecific therapy.2024 Selection of an agent for acute treatment should be based on patient-specific factors such as comorbid disease states, individual treatment history, and concomitant medications.2024

Colorectal Polyps

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 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 this2024 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 of the rectum and 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

The American Society of Colon and Rectal Surgeons guideline for the management of inherited adenomatous polyposis syndromes states that patients with FAP or MAP ( MutY homolog-associated polyposis) with retained colon or rectum may be considered for adenoma chemoprevention.2017 The guideline does not recommend a specific agent for chemoprevention, but mentions 2 NSAIAs (sulindac and celecoxib) as potential chemoprevention agents.2017

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 Institutes 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

General

Patient Monitoring

• Monitor blood pressure during initiation of celecoxib and throughout therapy.1,161
• Monitor patients (including those without previous symptoms of cardiovascular disease) for the possible development of cardiovascular events throughout therapy.1,161
• Monitor for signs and symptoms of GI bleeding or ulceration.1,161
• Monitor for signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritis, jaundice, right upper quadrant tenderness, flu-like symptoms).1,161
• Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.1,161
• Monitor for changes in asthma signs and symptoms when using celecoxib in patients with preexisting asthma.1,161
• Perform periodic CBC and chemistry profiles in patients receiving long-term celecoxib therapy.1,161
• Monitor hemoglobin or hematocrit if signs and/or symptoms of anemia occur during therapy with celecoxib.1,161
• Monitor pediatric patients with systemic onset juvenile rheumatoid arthritis receiving celecoxib for clinical signs and symptoms of abnormal clotting or bleeding.1,161

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) includes Celebrex^® (celecoxib), Celexa^® (citalopram hydrobromide), and Cerebyx^® (fosphenytoin sodium) on their ISMP List of Confused Drug Names, and recommends using special safeguards to ensure the accuracy of prescriptions for these drugs.34

Other General Considerations

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.1
• When used for migraine, use for the fewest number of days per month, as needed.161

Administration

Celecoxib is administered orally.1,161 The drug is commercially available as capsules and an oral solution; the oral solution is FDA-labeled for the treatment of migraine only.1,161

Capsules

The manufacturer states that celecoxib capsules may be administered without regard to meals.1

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

Store capsules at 20-25°C (excursions permitted between 15-30°C).1

Oral Solution

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

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 oral solution.161

Store the oral solution at 20-25°C (excursions permitted between 15-30°C).161 Do not refrigerate or freeze.161 Discard any unused portion remaining in the disposable unit-dose glass bottle immediately after use.161

Dosage

Pediatric Patients

Juvenile Rheumatoid Arthritis

For the symptomatic management of juvenile rheumatoid arthritis in children ≥2 years of age weighing >10 kg to <25 kg, the recommended dosage of celecoxib is 50 mg twice daily, and the recommended dosage for children ≥2 years of age weighing >25 kg is 100 mg twice daily.1

Adults

Osteoarthritis

For the symptomatic treatment of osteoarthritis, the recommended adult dosage of celecoxib is 200 mg daily given as a single dose or in 2 equally divided doses.1 Celecoxib dosages exceeding 200 mg daily (e.g., 200 mg twice daily) do not appear to provide additional therapeutic benefit.1

Rheumatoid Arthritis

For the symptomatic treatment of rheumatoid arthritis, the recommended adult dosage of celecoxib is 100-200 mg twice daily.1 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 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

Ankylosing Spondylitis

For the symptomatic treatment of ankylosing spondylitis, the recommended 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

Acute Pain

For the relief of acute pain, the recommended 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

Primary Dysmenorrhea

For the treatment of primary dysmenorrhea, the recommended 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

Migraine

For the acute treatment of migraine with or without aura, the recommended adult dosage of celecoxib (as the oral solution) is a single 120-mg dose.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

Special Populations

Hepatic Impairment

No dosage adjustment of celecoxib oral solution is necessary when used for acute treatment of migraine attacks in patients with mild hepatic impairment (Child-Pugh Class A).161

In patients with moderate hepatic impairment (Child-Pugh class B), the manufacturer of celecoxib capsules 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 oral solution is 60 mg.161

The use of celecoxib is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).1,161

Renal Impairment

When celecoxib oral solution is used for the acute treatment of migraine attacks in patients with mild or moderate renal impairment, no dosage adjustment is required.161 The manufacturer of celecoxib capsules makes no specific recommendations for dosage modification in patients with chronic renal insufficiency receiving celecoxib for other indications.1

Celecoxib has not been studied in patients with severe renal impairment, and is not recommended for use in such patients.1,161

Geriatric Patients

Dosage adjustment in geriatric patients based solely on age generally is not required.1,161 However, for geriatric patients weighing <50 kg, celecoxib therapy should be initiated at the lowest recommended dosage.1

Pharmacogenomic Considerations in Dosing

The manufacturer of celecoxib capsules 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 adult 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 oral solution 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

The 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

Contraindications

• Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug, sulfonamides, or any ingredient in the formulation.1,161
• History of asthma, urticaria, or other sensitivity reactions after taking aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs).1,161
• Contraindicated in the setting of coronary artery bypass graft (CABG) surgery.1,161

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Events

A boxed warning regarding the increased risk of serious cardiovascular thrombotic events is included in the prescribing information for celecoxib.1,161 NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction (MI) and stroke (which can be fatal).1,161 Because findings from clinical trials of celecoxib, other selective COX-2 inhibitors, and nonselective NSAIAs of up to 3 years' duration have shown an increased risk of serious cardiovascular thrombotic events, MI, and stroke, all NSAIAs are considered to be potentially associated with this risk.1,161 It is unclear based on available evidence if the thrombotic risk differs among NSAIAs.1,161 Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with duration of use.1,161 An increase in risk has been observed most consistently at higher NSAIA dosages.1,161 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease (CVD) or risk factors for CVD, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with CVD or risk factors for CVD because of their elevated baseline risk.1,161 In the Adenoma Prevention with Celecoxib (APC) trial, dosages of 400 mg twice daily or 200 mg twice daily increased the composite endpoint of cardiovascular death, MI, or stroke by 3-fold compared to placebo therapy.1,161 This increase in cardiovascular events among patients receiving celecoxib was primarily driven by the increased incidence of MI.1,161 In the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial, celecoxib 100 mg twice daily demonstrated noninferiority to naproxen 375-500 mg twice daily and ibuprofen 600-800 mg 3 times daily for the composite endpoint of cardiovascular death (including hemorrhagic death), non-fatal MI, and non-fatal stroke.1 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.1,161 In patients receiving celecoxib for migraine, the drug should be used as needed for the fewest possible number of days per month.161 Patients receiving NSAIAs (including those without previous symptoms of CVD) should be monitored for the possible development of cardiovascular events throughout therapy.1,161 Patients should be informed about the signs and symptoms of serious cardiovascular events and instructed to seek immediate medical attention if such symptoms occur.1,161 There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,161 Concomitant use of aspirin and celecoxib increases the risk for serious GI events.1,161 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 MI and stroke was increased.1,161 Do not use NSAIAs (including celecoxib) in the setting of CABG.1,161 Observational studies utilizing data from the Danish National Registry have examined the cardiovascular risk associated with use of NSAIAs in patients post-MI.1,161 Results from these studies indicate that patients who received NSAIAs in the post-MI period were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.1,161 Patients who received NSAIAs had a higher mortality rate in the first year post-MI compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).1,161 Although the absolute mortality rate declined somewhat after the first year following the MI, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.1,161 Celecoxib should be avoided in patients with recent MI unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if celecoxib is used in such patients, monitor for signs of cardiac ischemia.1,161

GI Bleeding, Ulceration, and Perforation

A boxed warning regarding the increased risk of serious GI events is included in the prescribing information for celecoxib.1,161 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.1,161 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.1,161 Longer duration of therapy with an NSAIA increases the likelihood of a serious adverse GI event.1,161 However, short-term therapy is not without risk.1,161 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.1,161 Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than 10-fold increased risk of developing GI bleeding than patients without these risk factors.1,161 In addition to a history of ulcer disease, other risk factors for GI bleeding include the concomitant use of oral corticosteroids, anticoagulants, antiplatelet agents (including aspirin), or selective serotonin-reuptake inhibitors (SSRIs); longer duration of NSAIA therapy; smoking; alcohol use; older a and poor general health status.1,161 Risk of GI bleeding also is increased in patients with advanced liver disease and/or coagulopathy.1,161 Most spontaneous reports of fatal GI effects have been in geriatric or debilitated patients.1,161 In a prospective, long-term safety study, the incidence of complicated, symptomatic ulcers at 9 months was 0.78% for all patients and 2.19% for the subgroup of patients receiving concomitant low-dose aspirin.1 The incidence of complicated, symptomatic ulcer was 1.4% in geriatric patients ≥65 years of age and 3.06% in geriatric patients ≥65 years of age receiving concomitant low-dose aspirin.1 Clinicians should remain alert to the possible development of serious adverse GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy.1,161 Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored even more closely for evidence of GI bleeding.1,161 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.1,161 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.1,161 In addition, use of NSAIAs should be avoided in patients at higher risk 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.1,161

Other Warnings/Precautions

Hepatotoxicity

Elevations in serum ALT or AST of more than 3 times the upper limit of normal (ULN) were reported in approximately 1% of patients receiving NSAIAs in controlled clinical studies.1,161 ALT or AST elevations of less than 3 times the ULN may occur in up to 15% of patients treated with NSAIAs, including celecoxib.1,161 In controlled clinical studies of celecoxib capsules in adults, notable increases in serum liver enzyme concentrations 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

Severe, sometimes fatal, reactions, including fulminant hepatitis, liver necrosis, and hepatic failure, have been reported rarely in patients receiving NSAIAs.1,161 Celecoxib should be discontinued immediately if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations (e.g., eosinophilia, rash) occur.1,161 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, diarrhea, pruritus, jaundice, right upper quadrant tenderness, flu-like symptoms).1,161

Hypertension

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.1,161 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.1,161 Blood pressure should be monitored closely during initiation of celecoxib therapy and throughout therapy.1,161

Heart Failure and Edema

Results from a study utilizing Danish National Registry data indicated that use of NSAIAs in patients with heart failure was associated with an increase in the risk of death, MI, and hospitalization for heart failure.1,161 In addition, findings from a meta-analysis of randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or nonselective NSAIAs was associated with an approximate 2-fold increase in the risk of hospitalization for heart failure.1,161 Fluid retention and edema also have been observed in some patients receiving NSAIAs.1,161

In a clinical trial of celecoxib, dosages of 400 mg twice daily (4-fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis dosages, respectively) resulted in a peripheral edema incidence of 4.5% at 9 months, compared to 6.9% with ibuprofen (800 mg three times daily) and 4.7% with diclofenac (75 mg twice daily).1,161

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.1,161 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).1,161

Renal Toxicity and Hyperkalemia

Long-term administration of NSAIAs has resulted in renal papillary necrosis and other renal injury.1,161

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.1,161 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.1,161 Patients at greatest risk of this reaction are those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II receptor antagonist concomitantly; and geriatric patients.1,161 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.1,161 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.1,161

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.1,161 The manufacturer states that use of celecoxib is not recommended in patients with advanced renal disease unless the benefits of therapy are expected to outweigh the potential risk of worsening renal function.1,161 If celecoxib is used in patients with advanced renal disease, clinicians should monitor for signs of worsening renal function.1

Hyperkalemia also has been reported in patients receiving NSAIAs, including in individuals without renal impairment, which has been attributed to a hyporenin-hypoaldosterone state in such patients.1,161

Anaphylactic Reactions

Anaphylactic reactions have been reported in patients receiving celecoxib.1 Celecoxib is a sulfonamide; both NSAIAs and sulfonamides may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.1 Use of celecoxib is contraindicated in patients with known hypersensitivity to celecoxib or any components of the formulation; it is also contraindicated in patients with known sulfonamide allergy or a history of asthma, urticaria, or other allergic-type reactions to aspirin or other NSAIAs.1,161 Patients should seek emergency medical assistance if any anaphylactic reaction occurs.1

Exacerbations of Asthma Related to Aspirin Sensitivity

Some patients with asthma may have aspirin-sensitive asthma, which may manifest as chronic rhinosinusitis with nasal polyps; episodes of severe, potentially fatal, bronchospasm; and/or intolerance to aspirin and other NSAIAs.1,161 Because cross-reactivity between aspirin and other NSAIAs has been reported in aspirin-sensitive patients, celecoxib is contraindicated in patients with this form of aspirin sensitivity.1,161 Monitor for changes in signs and symptoms of asthma when celecoxib is prescribed to patients with pre-existing asthma (without known aspirin sensitivity).1,161

Serious Skin Reactions

Serious skin reactions (e.g., erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis) have occurred in patients receiving celecoxib.1,161 These serious skin reactions can occur without warning and may be fatal.1,161

Celecoxib is contraindicated in patients with previous serious skin reactions to NSAIAs.1,161 Patients should be advised on the signs and symptoms of serious skin reactions.1,161 Celecoxib should be discontinued at the first appearance of rash or any other sign of hypersensitivity.1,161

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

DRESS, a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1,161 Although the clinical presentation of DRESS is highly variable, patient presentation typically involves eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).1,161 Symptoms can sometimes resemble an acute viral infection.1,161 Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) can present without an evident rash.1 If DRESS is suspected, celecoxib should be discontinued and the patient should undergo immediate evaluation.1,161

Hematologic Toxicity

Use of NSAIAs, including celecoxib, may cause occult or gross blood loss, fluid retention, or incompletely described effects on erythropoiesis that can result in anemia.1,161 In clinical trials of celecoxib capsules, the incidence of anemia was 0.6% in patients receiving celecoxib and 0.4% with placebo.1,161 If signs and/or symptoms of anemia or blood loss occur during therapy with celecoxib, check hemoglobin and hematocrit.1,161

NSAIAs, including celecoxib, may increase the risk of bleeding.1,161 Patients with certain coexisting conditions, such as coagulation disorders, and those receiving concomitant therapy with anticoagulants, antiplatelet agents, SSRIs, or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) may be at increased risk and should be monitored for signs of bleeding.1,161

Disseminated Intravascular Coagulation (DIC)

Because there is a risk of DIC with the use of celecoxib in children with systemic onset juvenile rheumatoid arthritis, these children should be monitored for clinical signs or symptoms of abnormal clotting or bleeding; inform the patients and their caregivers to report symptoms as soon as possible.1,161

Laboratory Monitoring

Patients receiving long-term NSAIA treatment should be monitored periodically with a CBC and chemistry profile, as serious GI bleeding, hepatotoxicity, and renal injury may occur without warning symptoms or signs.1,161

In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib capsules than in patients receiving placebo; this laboratory abnormality also was seen in those who received comparator NSAIAs in these studies.1,161 The clinical significance of this abnormality has not been established.1

Masking of Inflammation and Fever

The possibility that the anti-inflammatory and, perhaps, antipyretic effects of NSAIAs may mask the usual signs and symptoms of infection should be considered.1,161

Medication Overuse Headache

Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of NSAIAs, serotonin type 1 [5-HT₁] receptor agonists, ergotamine, opiate analgesics, or certain analgesic combinations on a regular basis for ≥10 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

Fetal/Neonatal Morbidity and Mortality

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus; 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.1,161 Fetal renal dysfunction has been observed, on average, after days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1,161 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.1,161 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1,161 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1,161 Some cases of neonatal renal dysfunction have required treatment with invasive procedures, such as exchange transfusion or dialysis.1,161

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1,161 In animal studies, inhibitors of prostaglandin synthesis, such as celecoxib, were associated with increased pre- and post-implantation losses.1,161 Prostaglandins also have an important role in fetal kidney development.1,161 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1,161

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.1,161 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.1,161

Specific Populations

Pregnancy

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.1,161 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.1,161 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.1,161

Fetal renal dysfunction has been observed, on average, after days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1,161 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.1,161 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1,161 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1,161 Some cases of neonatal renal dysfunction have required treatment with invasive procedures, such as exchange transfusion or dialysis.1,161

Observational data regarding other embryofetal risks with NSAIAs during the first or second trimester of pregnancy are not conclusive.1,161 An increased incidence of fetuses with ventricular septal defects, sternebral fusion or abnormality, and rib fusion was observed in reproduction studies in rabbits receiving oral celecoxib dosages ≥150 mg/kg daily throughout organogenesis (exposure approximately twice the usual human dosage of 200 mg twice daily, expressed in terms of AUC [0-24 hours]).1 A dose-dependent increase in diaphragmatic hernias was observed in rats receiving oral celecoxib dosages ≥30 mg/kg daily throughout organogenesis (exposure approximately 6-fold 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 7-fold 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 ≥50 mg/kg daily (exposure approximately 6-fold 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

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1,161 In animal studies, inhibitors of prostaglandin synthesis, such as celecoxib, were associated with increased pre- and post-implantation losses.1,161 Prostaglandins also have an important role in fetal kidney development.1,161 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1,161

The effects of celecoxib on labor and delivery are unknown.1 In animal studies, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased stillbirth.1,161

Lactation

Celecoxib is distributed into milk in small amounts.1,161 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 Maternal use of celecoxib was not associated with adverse effects in 2 breast-fed infants 17 and 22 months of age.1,161 It is not known whether celecoxib affects milk production.161 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

Females and Males of Reproductive Potential

Use of prostaglandin-mediated NSAIAs, including celecoxib, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1,161 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.1,161 Therefore, withdrawal of celecoxib should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1,161

Pediatric Use

Celecoxib is used for the management of the signs and symptoms of juvenile rheumatoid arthritis in pediatric patients ≥2 years of a safety and efficacy of celecoxib therapy have not been established beyond 6 months in pediatric patients with juvenile rheumatoid arthritis.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 <10 kg, or those with active systemic disease.1 Alternative therapies should be considered in pediatric patients known to be CYP2C9 poor metabolizers.1

In the pediatric clinical study for juvenile rheumatoid arthritis, patients 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 mild prolongation of activated partial thromboplastin time (aPTT) but not prothrombin time in pediatric patients with systemic onset juvenile rheumatoid arthritis.1 Because of the risk of disseminated intravascular coagulation in pediatric patients with systemic onset juvenile rheumatoid arthritis who are receiving celecoxib, these patients should be monitored for clinical signs or symptoms of abnormal clotting or bleeding and with coagulation tests.1

Long-term cardiovascular toxicity has not been evaluated in pediatric patients, and it is not known whether long-term risks may be similar to those observed in adults exposed to celecoxib and other NSAIAs.1

Safety and efficacy of celecoxib for the acute treatment of migraine attacks have not been established in pediatric patients.161

Geriatric Use

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, 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.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 function (measured by glomerular filtration rate, blood urea nitrogen, and creatinine) and platelet function (measured by bleeding time and platelet aggregation) in geriatric individuals receiving celecoxib did not differ from those in younger individuals, spontaneous postmarketing reports of fatal adverse GI effects and acute renal failure have occurred more often in geriatric individuals than in younger individuals.1,161 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 AUC of celecoxib (as the oral capsules) were increased 40 and 50%, respectively, in geriatric individuals (i.e., ≥65 years of age), but dosage adjustment in this age group based solely on age generally is not required.1,161 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.1,161 In geriatric patients weighing <50 kg, celecoxib therapy should be initiated at the lowest recommended dosage.1

Hepatic Impairment

AUC of celecoxib at steady state reportedly was increased 40 or 180% in individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, respectively, receiving celecoxib as capsules compared with that in healthy adults with normal hepatic function.1,161 Therefore, in patients with moderate hepatic impairment (Child-Pugh class B), the manufacturer of celecoxib capsules recommends that celecoxib dosage be reduced by approximately 50%.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

Renal Impairment

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.1,161

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.1,161 The manufacturers state that use of celecoxib is not recommended in patients with advanced renal disease unless the benefits of therapy are expected to outweigh the potential risk of worsening renal function.1,161

Pharmacogenomic Considerations

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 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

Common Adverse Effects

Adverse effects reported in >2% of adult patients receiving celecoxib for osteoarthritis and rheumatoid arthritis in clinical trials include abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, and rash.1 Adverse events reported in adult patients receiving celecoxib for ankylosing spondylitis, analgesia, and dysmenorrhea in clinical trials were similar to those reported in the osteoarthritis and rheumatoid arthritis trials.1

In the clinical trial of celecoxib in pediatric patients with juvenile rheumatoid arthritis, the most commonly occurring (≥5%) adverse events in celecoxib-treated patients were headache, pyrexia, upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea, and vomiting.1

The most common adverse effect reported in ≥3% of adult patients receiving celecoxib for migraine is dysgeusia.161

Celecoxib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 2C9.1 In vitro studies indicate that celecoxib is an inhibitor of CYP2D6, but not an inhibitor of CYP2C9, 2C19, or 3A4.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Metabolism of celecoxib is predominantly mediated by CYP2C9, and the possibility exists that drugs that inhibit this enzyme (e.g., fluconazole) may affect the pharmacokinetics of celecoxib, thereby increasing celecoxib exposure and toxicity.1,161 Drugs that induce CYP2C9 (e.g., rifampin) may reduce efficacy of celecoxib.1,161 Adjustment of celecoxib dosage may be required in patients receiving concomitant therapy with CYP2C9 inhibitors or inducers.1,161

In addition, celecoxib inhibits CYP2D6, and the possibility exists that celecoxib may alter the pharmacokinetics of drugs metabolized by this isoenzyme (e.g., atomoxetine), potentially increasing exposure to and toxicity of these drugs.1,161 Dosage adjustments may be required.1,161

Fluconazole

Concomitant administration of celecoxib with fluconazole can result in substantially increased plasma concentrations of celecoxib.1,161 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 increased plasma concentrations of celecoxib 2-fold.1,161

Other Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In clinical studies, concomitant administration of celecoxib with glyburide, ketoconazole, or phenytoin did not alter the pharmacokinetics and/or pharmacodynamics of these drugs, and no clinically important interactions have been reported.1,161

Antacids

Administration of an antacid containing magnesium or aluminum with celecoxib decreased peak plasma concentrations of celecoxib by 37% and the AUC by 10% in clinical studies.1 However, the manufacturer makes no specific recommendation for administration of the drug with regard to antacids.1

Anticoagulants and Antiplatelet Agents

Anticoagulants, such as warfarin, and nonsteroidal anti-inflammatory agents (NSAIAs) have synergistic effects on GI bleeding.1,161 Concomitant use of celecoxib and anticoagulants is associated with a higher risk of serious bleeding compared with use of either agent alone.1,161 Patients receiving concomitant anticoagulant or antiplatelet therapy should be monitored appropriately for signs of bleeding.1,161

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

Antihypertensive Agents

Concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents (including propranolol) may reduce the blood pressure response to the antihypertensive agent.1,161 Therefore, blood pressure should be monitored to ensure that target blood pressure is achieved.1,161

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.1,161 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.1,161

Corticosteroids

Concomitant use of celecoxib and corticosteroids may increase the risk of GI ulceration or bleeding.1,161 Patients should be monitored for signs of bleeding.1,161

Cyclosporine

Concomitant use of celecoxib and cyclosporine may increase cyclosporine-associated nephrotoxicity.1,161 Patients should be monitored for signs of worsening renal function.1,161

Digoxin

Concomitant use of celecoxib and digoxin has been reported to result in increased serum concentrations and prolonged half-life of digoxin.1,161 Serum digoxin concentrations should be monitored.1,161

Diuretics

NSAIAs may interfere with the natriuretic response to diuretics with activity that depends in part on prostaglandin-mediated alterations in renal blood flow (e.g., loop diuretics [e.g., furosemide], thiazide diuretics).1,161 Patients receiving concomitant celecoxib and diuretic therapy should be monitored for signs of worsening renal function and for adequacy of diuretic and antihypertensive effects.1,161

Glyburide

In clinical studies, concomitant administration of celecoxib with glyburide did not alter the pharmacokinetics and/or pharmacodynamics of glyburide, and no clinically important interactions have been reported.1,161

Lithium

Celecoxib and other NSAIAs can decrease renal clearance of lithium, which may lead to increased serum or plasma lithium concentrations.1,161 The mechanism involved has been attributed to NSAIA inhibition of prostaglandin synthesis.1,161 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.1,161 Patients receiving lithium and celecoxib concomitantly should be monitored for signs of lithium toxicity.1,161

Methotrexate

Concomitant use of NSAIAs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).1,161 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.1,161

Nonsteroidal Anti-inflammatory Agents and Salicylates

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.1,161 However, concomitant use of aspirin and an NSAIA increases the risk for bleeding and serious GI events.1,161 Because of the potential for increased adverse effects, concomitant use of celecoxib with analgesic dosages of aspirin generally is not recommended.1,161 Concomitant use of celecoxib with other NSAIAs or salicylates (e.g., diflunisal, salsalate) is also not recommended, as it increases the risk of GI toxicity with little to no increase in efficacy.1,161

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.1,161 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.1,161 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).1,161 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.1,161 In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding and inform patients of the increased risk for, and the signs and symptoms of, GI bleeding.1

Pemetrexed

Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.1,161 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.1,161 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.1,161 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.1,161

Serotonin-reuptake Inhibitors

Serotonin release by platelets plays an important role in hemostasis.1,161 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.1,161 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.1,161

Description

Celecoxib is a selective inhibitor of the cyclooxygenase-2 (COX-2) isoform of prostaglandin endoperoxide synthase (prostaglandin G/H synthase, PGHS)1,3,4,5,7,8,10,48,53,80 and exhibits many of the pharmacologic actions of nonselective NSAIAs, including anti-inflammatory, analgesic, and antipyretic activity.1 NSAIAs appear to inhibit prostaglandin synthesis via inhibition of cyclooxygenase (COX);1,3,4,8,11,19,38,40,41,48,53 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.1,3,4,5,8,9,10,11,19,38,41,48 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.3,4,8,11,38,40,41,102 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 While most NSAIAs are nonselective, inhibiting both COX-1 and COX-2 to varying degrees,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);1,3,4,8,9,10,11,38,40,41 however, additional experience is needed to evaluate fully the adverse effect profile of the drug.3,5,8,9,10

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.1,3,41

Certain pharmacokinetic parameters of celecoxib (i.e., peak plasma concentration, AUC) are approximately dose proportional when the drug is administered in capsule form 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 Limited data indicate that the pharmacokinetics of celecoxib are affected by advanced age, renal and/or hepatic function, and race.1

Celecoxib is well absorbed from the GI tract, and peak plasma concentrations of the drug generally are attained within 3 hours after dosing as capsules in fasting individuals.1 Absolute bioavailability of celecoxib has not been determined.1 Following administration of single doses of celecoxib, the onset of analgesia occurred within 60 minutes.1 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 capsules were administered with a high-fat meal.1 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

After once daily oral administration of 120 to 240 mg doses (2 times the recommended dosage) of celecoxib as the oral solution, a dose-proportional increase in exposure occurs.161 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 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 patients ≥65 years of age, peak plasma concentration and AUC were increased 40 and 50%, respectively, compared with younger adults.1,161 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 Analysis of pooled pharmacokinetic data indicates that the AUC of celecoxib, administered as capsules, is about 40% higher in Black patients compared with white patients; the cause and clinical importance of this finding are not known.1,161

At therapeutic plasma concentrations, celecoxib is about 97% bound to plasma proteins, principally albumin and to a lesser extent, α₁-acid glycoprotein.1,161 Celecoxib is not preferentially bound to erythrocytes in blood.1,161

The plasma elimination half-life of celecoxib following oral administration of a single 200-mg dose in capsule form under fasting conditions is about 11 hours; wide intraindividual variability is observed, presumably because the low aqueous solubility of celecoxib prolongs absorption.1 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

Celecoxib is primarily metabolized in the liver to inactive metabolites by the cytochrome P-450 (CYP) isoenzyme 2C9.1,161 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 Limited data indicate that celecoxib concentrations are increased 3-fold to 7-fold 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

In pediatric patients, 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.1,161 Following oral administration of a single dose of radiolabeled celecoxib, approximately 27 and 57% of the dose was excreted in urine and feces, respectively.1,161 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.1,161

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).1,161
• Advise patients to be alert for symptoms of serious cardiovascular thrombotic events (e.g., MI, stroke).1,161 Advise patients to seek immediate medical attention if signs and symptoms of a cardiovascular event (e.g., chest pain, dyspnea, weakness, slurred speech) occur.1,161
• Advise patients to report symptoms of GI ulcerations and bleeding (e.g., epigastric pain, dyspepsia, melena, hematemesis) to their healthcare provider.1,161 Inform patients receiving concomitant low-dose aspirin of the increased risk of GI bleeding.1,161
• Inform patients to stop taking celecoxib immediately if they develop any type of rash or fever and to promptly contact their clinician.1,161
• Advise patients to seek emergency medical attention if signs of an anaphylactic reaction occur (e.g., difficulty breathing, swelling of the face or throat).1,161
• Inform patients of the signs and symptoms of hepatotoxicity.1,161 Advise patients to discontinue therapy and contact their clinician immediately if signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.1,161
• Inform patients of the risk of heart failure or edema and the importance of reporting dyspnea, unexplained weight gain, or edema.1,161
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,161 Advise pregnant women to avoid NSAIAs beginning at 30 weeks' gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours' duration between about 20 and 30 weeks' gestation.1,161
• Inform women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.1,161
• Advise patients with migraine headaches that overuse of drugs intended for acute treatment of migraine attacks (e.g., use on ≥10 days per month) may exacerbate headaches; encourage patients to record the frequency of migraine headaches and medication use and to contact their clinician if the frequency of migraine attacks increases.161
• Advise patients on appropriate administration of celecoxib oral solution for acute treatment of migraine attacks.161
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1,161 Advise patients that concomitant use of other NSAIAs with celecoxib provides little or no increase in efficacy but increases risk of GI toxicity, and is not recommended.1,161 Advise patients not to use concomitant low-dose aspirin without consulting their clinician.1,161 Alert patients to the presence of NSAIAs in many OTC drugs.1,161
• Advise patients of other important precautionary information.1,161

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.

1. Viatris Specialty LLC. Celebrex^® (celecoxib) capsules prescribing information. Morgantown, WV; Feb 2023.

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. Drugs for Osteoarthritis. JAMA. 2021 Feb 9;325(6):581-582. doi: 10.1001/jama.2020.8395. PMID: 33560319.

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]

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.

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.

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]

34. Institute for Safe Medication Practices (ISMP). ISMP list of confused drug names. February 2023.

38. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenase—a review. Prostaglandins Lipid Mediators . 1998; 56:341-61.

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]

48. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med . 1999; 106:37S-42. [PubMed 10390126]

50. Pfizer, New York, NY: Personal communication.

53. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Ann Rev Pharmacol Toxicol . 1998; 38:97-120.

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]

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]

80. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med . 2001; 345:433-42. [PubMed 11496855]

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.

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]

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]

159. Giannini EH, Ruperto N, Ravelli A et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum . 1997; 40:1202-9. [PubMed 9214419]

161. Scilex Pharmaceuticals, Inc. Elyxyb^® (celecoxib) oral solution prescribing information. Palo Alto, CA; 2023 Jun.

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]

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]

1999. Puljak L, Marin A, Vrdoljak D, Markotic F, Utrobicic A, Tugwell P. Celecoxib for osteoarthritis. Cochrane Database Syst Rev. 2017;5(5):CD009865. Published 2017 May 22.

2000. Fidahic M, Jelicic Kadic A, Radic M, Puljak L. Celecoxib for rheumatoid arthritis. Cochrane Database Syst Rev. 2017;6(6):CD012095. Published 2017 Jun 9.

2001. Fraenkel L, Bathon J, England B, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924-939.

2002. Foeldvari I, Szer I, Zemel L, et al. A prospective study comparing celecoxib with naproxen in children with juvenile rheumatoid arthritis. J Rheumatol. 2009;36:174-182.

2003. Ringold S, Angeles-Han ST, Beukelman T et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis. Arthritis Care Res (Hoboken). 2019; 71:717-734.

2004. Angeles-Han ST, Ringold S, Beukelman T et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis. Arthritis Care Res (Hoboken). 2019; 71:703-716.

2005. Ravelli A, Consolaro A, Horneff G et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018; 77:819-828.

2006. Barkhuizen A, Steinfeld S, Robbins J, et al. Celecoxib is efficacious and well tolerated in treating signs and symptoms of ankylosing spondylitis. J Rheumatol. 2006;33:1805-1812.

2007. Sieper J, Klopsch T, Richter M, et al. Comparison of two different dosages of celecoxibwith diclofenac for the treatment of active ankylosing spondylitis: results of a 12-week randomised, double-blind, controlled study. Ann Rheum Dis. 2008;67:323-329.

2008. Ward MM, Deodhar A, Gensler LS et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2019; 71:1599-1613.

2009. Derry S, Moore RA. Single dose oral celecoxib for acute postoperative pain in adults. Cochrane Database Syst Rev. 2013;2013(10):CD004233.

2012. ACOG Committee Opinion No. 760: Dysmenorrhea and Endometriosis in the Adolescent. Obstet Gynecol. 2018;132(6):e249-e258.

2013. Chou R, Gordon D, de Leon-Casaola O, et al. Management of Postoperative Pain: A Clinical Practice Guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157.

2014. Daniels S, Robbins J, West C, et al. Celecoxib in the treatment of primary dysmenorrhea: results from two randomized, double-blind, active and placebo-controlled, crossover studies. Clin Ther. 2009;31(6):1192-1208.

2015. Ferries-Rowe E, Corey E, Archer J. Primary dysmenorrhea. Diagnosis and Therapy. Obstet Gynecol. 2020;136(5):1047-1058.

2017. Poylin V, Shaffer V, Felder S, et al. The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of inherited adenomatous polyposis syndromes. Dis Colon Rectum. 2024; 67:213-227.

2021. Lipton RB, Munjal S, Tepper SJ, Iaconangelo C, Serrano D. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Tolerability, and Safety of Celecoxib Oral Solution (ELYXYB) in Acute Treatment of Episodic Migraine with or without Aura. J Pain Res. 2021;14:2529-2542. Published 2021 Aug 19.

2022. Lipton RB, Munjal S, Dodick DW, Tepper SJ, Serrano D, Iaconangelo C. Acute Treatment of Migraine with Celecoxib Oral Solution: Results of a Randomized, Placebo-Controlled Clinical Trial. J Pain Res. 2021;14:549-560. Published 2021 Feb 25.

2023. Lipton RB, Munjal S, Brand-Schieber E, Tepper SJ, Dodick DW. 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(1):58-70.

2024. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. 2021;61(7):1021-1039.