celecoxib

Celecoxib is indicated for the treatment of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, acute pain, musculoskeletal pain, painful menstruation, ankylosing spondylitis, juvenile rheumatoid arthritis, and to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis. It may be used in children with juvenile rheumatoid arthritis who are older than two years of age and weigh more than 10 kg (22 lb).

For postoperative pain, it is more or less equal to ibuprofen.{{cite journal | vauthors = Derry S, Moore RA | title = Single dose oral celecoxib for acute postoperative pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD004233 | date = October 2013 | pmid = 24150982 | doi = 10.1002/14651858.CD004233.pub4 | pmc = 4161494 }} For pain relief, it is similar to paracetamol (acetaminophen) at 3990 mg per day,{{cite journal | vauthors = Yelland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM | title = Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials | journal = Rheumatology | volume = 46 | issue = 1 | pages = 135–40 | date = January 2007 | pmid = 16777855 | doi = 10.1093/rheumatology/kel195 | doi-access = free | hdl = 10072/15035 | hdl-access = free }} which is the first line treatment for osteoarthritis.{{cite journal | vauthors = Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P | title = OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence | journal = Osteoarthritis and Cartilage | volume = 15 | issue = 9 | pages = 981–1000 | date = September 2007 | pmid = 17719803 | doi = 10.1016/j.joca.2007.06.014 | doi-access = free }}{{cite journal | vauthors = Flood J | title = The role of acetaminophen in the treatment of osteoarthritis | journal = The American Journal of Managed Care | volume = 16 | issue = Suppl | pages = S48–54 | date = March 2010 | pmid = 20297877 }}

Evidence of effects is not clear as several studies done by the manufacturer have not been released for independent analysis.{{cite journal | vauthors = Puljak L, Marin A, Vrdoljak D, Markotic F, Utrobicic A, Tugwell P | title = Celecoxib for osteoarthritis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | pages = CD009865 | date = May 2017 | issue = 7 | pmid = 28530031 | pmc = 6481745 | doi = 10.1002/14651858.CD009865.pub2 }}

It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer, so it is not a good choice for this reason.

• Cardiovascular events: NSAIDs are associated with an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including myocardial infarction and stroke. Risk may be increased with duration of use or pre-existing cardiovascular risk factors or disease. Individual cardiovascular risk profiles should be evaluated before prescribing. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may impair response to thiazide or loop diuretics), and may contribute to cardiovascular events; monitor blood pressure and use with caution in patients with hypertension. Celecoxib may cause sodium and fluid retention, so its use in patients with edema or heart failure warrants caution. Long-term cardiovascular risk in children has not been evaluated. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce the risk of cardiovascular events; alternative therapies should be considered for patients at high risk.{{cite journal | vauthors = Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M | title = Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1071–80 | date = March 2005 | pmid = 15713944 | doi = 10.1056/NEJMoa050405 | doi-access = free }} The increased risk is about 37%.
• Gastrointestinal events: NSAIDs may increase the risk of serious gastrointestinal (GI) ulceration, bleeding, and perforation (may be fatal). These events may occur at any time during therapy and without warning. Use caution with a history of GI disease (bleeding or ulcers), concurrent therapy with aspirin, anticoagulants and/or corticosteroids, smoking, use of alcohol, and the elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce the risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with ≤325 mg of aspirin, a substantial increase in the risk of gastrointestinal complications (e.g., ulcer) occurs; concomitant gastroprotective therapy (e.g., proton pump inhibitors) is recommended.{{cite web | title=Celebrex- celecoxib capsule | website=DailyMed | date=31 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8d52185d-421f-4e34-8db7-f7676db2a226 | access-date=5 May 2020 | archive-date=24 February 2021 | archive-url=https://web.archive.org/web/20210224181140/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8d52185d-421f-4e34-8db7-f7676db2a226 | url-status=live }} The increased risk is about 81%.
• Hematologic effects: Anemia may occur; monitor hemoglobin or hematocrit in people on long-term treatment. Celecoxib does not usually affect prothrombin time, partial thromboplastin time, or platelet counts; it does not inhibit platelet aggregation at approved doses.

People with a prior history of ulcer disease or GI bleeding require special precautions. Moderate to severe liver impairment or GI toxicity can occur with or without warning symptoms in people treated with NSAIDs.

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.{{cite press release | title=FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications | website=U.S. Food and Drug Administration (FDA) | date=15 October 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications | access-date=15 October 2020 | archive-date=16 October 2020 | archive-url=https://web.archive.org/web/20201016180003/https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications | url-status=dead }} {{PD-notice}}{{cite web | title=NSAIDs may cause rare kidney problems in unborn babies | website=U.S. Food and Drug Administration | date=21 July 2017 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic | access-date=15 October 2020 | archive-date=17 October 2020 | archive-url=https://web.archive.org/web/20201017014419/https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic | url-status=dead }} {{PD-notice}}

Celecoxib contains a sulfonamide moiety and may cause allergic reactions in those allergic to other sulfonamide-containing drugs. This is in addition to the contraindication in people with severe allergies to other NSAIDs. However, it has a low (reportedly 4%) chance of inducing cutaneous reactions among persons who have a history of such reactions to aspirin or nonselective NSAIDs. NSAIDs may cause serious skin adverse events, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis; events may occur without warning and in patients without prior known sulfa allergy. Use should be discontinued at the first sign of rash (or any other hypersensitivity).

A 2013 meta-analysis of hundreds of clinical trials found that coxibs (the class of drugs that includes celecoxib) increase the risk of major cardiovascular problems by about 37% over placebo.{{cite journal | vauthors = Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C | title = Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials | journal = Lancet | volume = 382 | issue = 9894 | pages = 769–79 | date = August 2013 | pmid = 23726390 | pmc = 3778977 | doi = 10.1016/S0140-6736(13)60900-9 }} In 2016, a randomized trial provided strong evidence that treatment with celecoxib is not more likely to result in poor cardiovascular outcomes than treatment with naproxen or ibuprofen.{{cite journal | vauthors = Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME, Graham DY, Borer JS, Wisniewski LM, Wolski KE, Wang Q, Menon V, Ruschitzka F, Gaffney M, Beckerman B, Berger MF, Bao W, Lincoff AM | title = Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis | journal = The New England Journal of Medicine | volume = 375 | issue = 26 | pages = 2519–29 | date = December 2016 | pmid = 27959716 | doi = 10.1056/NEJMoa1611593 | doi-access = free }} As a result, in 2018 an FDA advisory panel concluded that celecoxib poses no greater risk for causing heart attacks and strokes than the commonly-used NSAIDs ibuprofen or naproxen and recommended that the FDA consider changing its advice to physicians regarding celecoxib's safety.

The COX-2 inhibitor rofecoxib (Vioxx) was removed from the market in 2004 due to its risk. Like all NSAIDs on the US market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association warned that with respect to "patients with a prior history of or at high risk for cardiovascular disease... use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives, and then, only in the lowest dose and for the shortest duration necessary."

In 2005, a study published in the Annals of Internal Medicine found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug.{{cite journal | vauthors = Kimmel SE, Berlin JA, Reilly M, Jaskowiak J, Kishel L, Chittams J, Strom BL | title = Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction | journal = Annals of Internal Medicine | volume = 142 | issue = 3 | pages = 157–64 | date = February 2005 | pmid = 15684203 | doi = 10.7326/0003-4819-142-3-200502010-00005 | doi-access = free }} Other COX-2-selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib.{{cite journal | vauthors = Mukherjee D, Nissen SE, Topol EJ | title = Risk of cardiovascular events associated with selective COX-2 inhibitors | journal = JAMA | volume = 286 | issue = 8 | pages = 954–9 | year = 2001 | pmid = 11509060 | doi = 10.1001/jama.286.8.954 }} In April 2005, after an extensive review of data, the FDA concluded it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs".{{cite web |vauthors=Jenkins JK, Seligman PJ | title=Analysis and recommendations for Agency action regarding nonsteroidal anti-inflammatory drugs and cardiovascular risk [decision memorandum] | url=https://www.fda.gov/cder/drug/infopage/cox2/NSAIDdecisionMemo.pdf | archive-url=https://web.archive.org/web/20050909082236/https://www.fda.gov/cder/drug/infopage/cox2/NSAIDdecisionMemo.pdf | url-status=dead | archive-date=9 September 2005 | date=6 April 2005 | publisher=U.S. Food and Drug Administration (FDA) }} In a 2006 meta-analysis of randomized control studies, the cerebrovascular events associated with COX-2 inhibitors were examined, but no significant risks were found when compared to nonselective NSAIDs or placebos.{{cite journal | vauthors = Chen LC, Ashcroft DM | title = Do selective COX-2 inhibitors increase the risk of cerebrovascular events? A meta-analysis of randomized controlled trials | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 31 | issue = 6 | pages = 565–76 | date = December 2006 | pmid = 17176361 | doi = 10.1111/j.1365-2710.2006.00774.x | s2cid = 40738580 | doi-access = free }}

Celecoxib undergoes metabolism primarily by the enzymes CYP2C9 and CYP3A4, but it also interacts with CYP2D6, inhibiting its activity without being metabolized by it.{{cite journal | vauthors = Shkundin A, Wheeler HE, Sinacore J, Halaris A | title = BDNF/BDNF-AS Gene Polymorphisms Modulate Treatment Response and Remission in Bipolar Disorder: A Randomized Clinical Trial | journal = Journal of Personalized Medicine | volume = 15 | issue = 2 | pages = 62 | year = 2025 | doi = 10.3390/jpm15020062 | doi-access = free| pmid = 39997339 | pmc = 11856652 }} The CYP2C9 gene exhibits considerable genetic variability, with common polymorphisms, such as rs1799853 and rs1057910, linked to reduced enzyme activity and altered pharmacokinetics of celecoxib. Additionally, the influence of CYP2D6 on celecoxib metabolism is inconsistent, with its effect varying depending on the individual’s CYP2C9 genetic profile.

Caution must be exercised with concomitant use of 2C9 inhibitors, such as fluconazole, which can greatly elevate celecoxib serum levels. If used concomitantly with lithium, celecoxib increases lithium plasma levels. If used concomitantly with warfarin, celecoxib may result in an increased risk of bleeding complications. The risk of bleeding and gastric ulcers also increases further when selective serotonin reuptake inhibitors (SSRI) are used in combination with celecoxib.{{cite journal | vauthors = Turner MS, May DB, Arthur RR, Xiong GL | title = Clinical impact of selective serotonin reuptake inhibitors therapy with bleeding risks | journal = Journal of Internal Medicine | volume = 261 | issue = 3 | pages = 205–213 | date = March 2007 | pmid = 17305643 | doi = 10.1111/j.1365-2796.2006.01720.x | s2cid = 41772614 | doi-access = free }} The drug may increase the risk of kidney failure with angiotensin-converting enzyme-inhibitors, such as lisinopril, and diuretics, such as hydrochlorothiazide.

A highly selective reversible inhibitor of the COX-2 isoform of cyclooxygenase, celecoxib inhibits the transformation of arachidonic acid to prostaglandin precursors. Therefore, it has analgesic and anti-inflammatory properties. Nonselective NSAIDs (such as aspirin, naproxen, and ibuprofen) inhibit both COX-1 and COX-2. Inhibition of COX-1 (which celecoxib does not inhibit at therapeutic concentrations) inhibits the production of prostaglandins and the production of thromboxane A2, a platelet activator. COX-1 is traditionally defined as a constitutively expressed "housekeeping" enzyme and plays a role in the protection of the gastrointestinal mucosa, kidney hemodynamics, and platelet thrombogenesis.{{cite journal | vauthors = Mathew ST, Devi SG, Prasanth VV, Vinod B | title = Efficacy and Safety of COX-2 Inhibitors in the Clinical Management of Arthritis: Mini Review | journal = ISRN Pharmacology | volume = 2011 | pages = 480291 | date = 2011 | pmid = 22084715 | pmc = 3197256 | doi = 10.5402/2011/480291 | doi-access = free }}{{cite book| vauthors = Katzung BG |title=Basic & clinical pharmacology |date=2007 |publisher=McGraw-Hill Medical |location=New York |isbn=9780071451536 |page=579 |edition=10th }} COX-2, on the contrary, is extensively expressed in cells involved in inflammation and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters.{{cite journal | vauthors = Shi S, Klotz U | title = Clinical use and pharmacological properties of selective COX-2 inhibitors | journal = European Journal of Clinical Pharmacology | volume = 64 | issue = 3 | pages = 233–52 | date = March 2008 | pmid = 17999057 | doi = 10.1007/s00228-007-0400-7 | s2cid = 24063728 }} Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1.{{cite journal | vauthors = Conaghan PG | title = A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity | journal = Rheumatology International | volume = 32 | issue = 6 | pages = 1491–502 | date = June 2012 | pmid = 22193214 | pmc = 3364420 | doi = 10.1007/s00296-011-2263-6 }} It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site.{{cite book | vauthors = Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM |title=Pharmacotherapy A Pathophysiologic Approach |date=2008 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-147899-1 |edition=7th}} In theory, this selectivity allows celecoxib and other COX-2 inhibitors to reduce inflammation (and pain) while minimizing gastrointestinal adverse drug reactions (e.g. stomach ulcers) that are common with nonselective NSAIDs.{{cite journal | vauthors = Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM, Harrington RA, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Hlatky MA, Kaul S, Lindner JR, Moliterno DJ, Mukherjee D, Schofield RS, Rosenson RS, Stein JH, Weitz HH, Wesley DJ | title = ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents | journal = Journal of the American College of Cardiology | volume = 52 | issue = 18 | pages = 1502–17 | date = October 2008 | pmid = 19017521 | doi = 10.1016/j.jacc.2008.08.002 | doi-access = free }}

For its use in reducing colon polyps, celecoxib affects genes and pathways involved in inflammation and malignant transformation in tumors, but not normal tissues.{{cite journal | vauthors = Half E, Arber N | title = Colon cancer: preventive agents and the present status of chemoprevention | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 2 | pages = 211–9 | date = February 2009 | pmid = 19236194 | doi = 10.1517/14656560802560153 | s2cid = 72411967 }}

Celecoxib binds to Cadherin-11 (which may explain the reduction in cancer progression).{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

File:Monosubstituted 1,5-diarylpyrazoles.jpg

File:Enzyme data for monosubstituted 5-aryl analogs.jpg

File:Enzyme data for 4-substituted analogs.jpg

File:In vitro cox-I and cox-II enzyme data for disubstituted 5-aryl analogs.jpg

The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX-2 inhibition. Various modifications can be made to the 1,5-diarylpyrazole moiety to deduce the structure-activity relationship of celecoxib.{{cite journal | vauthors = Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC | title = Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib) | journal = Journal of Medicinal Chemistry | volume = 40 | issue = 9 | pages = 1347–65 | date = April 1997 | pmid = 9135032 | doi = 10.1021/jm960803q }} A para-sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is known to be necessary for COX-2 inhibition. For instance, replacing either of these entities with a –SO₂NHCH₃ substituent diminishes COX-2 inhibitory activity as noted with a very high inhibitory concentration-50 (see structures 3 – 5). At the 3-position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9).

Celecoxib is compound 22; the 4-sulfamoylphenyl on the 1-pyrazol substituent is required for COX-2 inhibition and the 4-methyl on the 5-pyrazol system has low steric hindrance to maximising potency, while the 3-trifluoromethyl group provides superior selectivity and potency. To explain the selectivity of celecoxib, it is necessary to analyze the free energy of binding difference between the drug molecule and COX-1 compared to COX-2 enzymes. The structural modifications highlight the importance of binding to residue 523 in the side binding pocket of the cyclooxygenase enzyme, which is an isoleucine in COX-1 and a valine in COX-2.{{cite journal | vauthors = Price ML, Jorgensen WL | title = Rationale for the observed COX-2/COX-1 selectivity of celecoxib from Monte Carlo simulations | journal = Bioorganic & Medicinal Chemistry Letters | volume = 11 | issue = 12 | pages = 1541–4 | date = June 2001 | pmid = 11412976 | doi = 10.1016/s0960-894x(00)00522-9 }} This mutation appears to contribute to COX-2 selectivity by creating steric hindrance between the sulfonamide oxygen and the methyl group of Ile523 that effectively destabilizes the celecoxib-COX-1 complex.

{{See also|Discovery and development of cyclooxygenase 2 inhibitors}}

It was initially marketed by Pfizer for arthritis. Celecoxib and other COX-2 selective inhibitors, valdecoxib, parecoxib, and mavacoxib, were discovered by a team at the Searle division of Monsanto led by John Talley.{{cite news| vauthors = Langreth R |title=The Chemical Cobbler|url=https://www.forbes.com/global/2003/0623/050.html|work=Forbes|date=23 June 2003|access-date=15 April 2018|archive-date=16 April 2018|archive-url=https://web.archive.org/web/20180416013759/https://www.forbes.com/global/2003/0623/050.html|url-status=live}}{{cite journal|title=Dr. John Talley: 2001 St. Louis Awardee|journal=Chemical Bond|date=May 2001|volume=52|issue=5|page=2|url=http://www.stlacs.org/Bonds/2001May.pdf|archive-url=https://web.archive.org/web/20180415180802/http://www.stlacs.org/Bonds/2001May.pdf|archive-date=15 April 2018}}

Two lawsuits arose over the discovery of celecoxib. Daniel L. Simmons of Brigham Young University (BYU) discovered the COX-2 enzyme in 1988,{{cite web | url = http://www.the-scientist.com/news/display/25408/ | title = University sues Pfizer over COX-2 research | author = Yajnik J | date = 27 October 2006 | work = The Scientist | access-date = 11 November 2010 | archive-date = 3 February 2009 | archive-url = https://web.archive.org/web/20090203140727/http://www.the-scientist.com/news/display/25408/ | url-status = dead }} and in 1991, BYU entered into a collaboration with Monsanto to develop drugs to inhibit it. Monsanto's pharmaceutical division was later purchased by Pfizer, and in 2006, BYU sued Pfizer for breach of contract, claiming Pfizer did not properly pay contractual royalties back to BYU.{{cite web |work=Deseret News |date=28 October 2009 |url=http://www.deseretnews.com/article/705340277/Judge-orders-Pfizer-to-pay-BYU-852K-for-suit-delays.html |title=Judge orders Pfizer to pay BYU $852K for suit delays |author=Linda Thomson |access-date=23 November 2009 |archive-date=31 October 2009 |archive-url=https://web.archive.org/web/20091031124503/http://www.deseretnews.com/article/705340277/Judge-orders-Pfizer-to-pay-BYU-852K-for-suit-delays.html |url-status=dead }} A settlement was reached in April 2012, in which Pfizer agreed to pay $450 million.{{cite news | vauthors = Harvey T |title=Pfizer, BYU settle Celebrex lawsuit for $450M |work=The Salt Lake Tribune |date=1 May 2012 |url=http://www.sltrib.com/sltrib/entertainment/54024947-79/byu-pfizer-settlement-simmons.html.csp |access-date=22 July 2012 |archive-date=3 March 2016 |archive-url= https://web.archive.org/web/20160303220047/http://www.sltrib.com/sltrib/entertainment/54024947-79/byu-pfizer-settlement-simmons.html.csp |url-status=live }}{{cite news | title=Pfizer Settles B.Y.U. Lawsuit Over Development of Celebrex | website=The New York Times | date=1 May 2012 | url=https://www.nytimes.com/2012/05/02/health/pfizer-settles-byu-lawsuit-over-development-of-celebrex.html | agency=Associated Press | access-date=5 May 2020 | archive-date=27 December 2017 | archive-url=https://web.archive.org/web/20171227132546/http://www.nytimes.com/2012/05/02/health/pfizer-settles-byu-lawsuit-over-development-of-celebrex.html | url-status=live }} Other important discoveries in COX-2 were made at University of Rochester, which patented the discoveries.{{US patent | 6048850}} When the patent was issued, the university sued Searle (later Pfizer) in a case called, University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2, and therefore the patent was invalid.{{cite web |url=http://www.hodgsonruss.com/Home/Practice_Areas/Alphabetical_Listing/Intellectual_Property_Technology/Articles/20012004Articles/Reach-ThroughClaimsDeclaredInvalid |title=Reach-Through Claims Declared Invalid |access-date=31 December 2012 |archive-date=22 February 2014 |archive-url=https://web.archive.org/web/20140222060537/http://www.hodgsonruss.com/Home/Practice_Areas/Alphabetical_Listing/Intellectual_Property_Technology/Articles/20012004Articles/Reach-ThroughClaimsDeclaredInvalid |url-status=live }}Ranjana Kadle (2004) [https://web.archive.org/web/20130721100341/http://www.kayescholer.com/professionals/sobel_gerald_extras/misc/01_Rochester2_FedCir_Affirm.pdf CAFC Court Decision Reach-Through Claims Declared Invalid]

According to the National Academy of Sciences, Philip Needleman, who was vice president of Monsanto in 1989 and president of Searle in 1993 oversaw research into COX-2 that led to the development of the anti-inflammatory drug celecoxib (Celebrex). He became senior executive vice president and chief scientist of Pharmacia from 2000 to 2003.{{cite web | url=http://www.nasonline.org/news-and-multimedia/podcasts/interviews/philip-needleman.html?referrer=https://www.google.ca/ | title=Philip Needleman | publisher=National Academy of Sciences | date=15 June 2015 | access-date=28 December 2015 | archive-date=7 January 2016 | archive-url=https://web.archive.org/web/20160107133428/http://www.nasonline.org/news-and-multimedia/podcasts/interviews/philip-needleman.html?referrer=https%3A%2F%2Fwww.google.ca%2F | url-status=live }} Celecoxib was discovered and{{US patent | 5466823}} developed by G. D. Searle & Company and was approved by the FDA on 31 December 1998.{{cite web | title=Drug Approval Package: Celebrex (Celecoxib) NDA# 20-998 | website=U.S. Food and Drug Administration (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20998.cfm | access-date=5 May 2020 | archive-date=27 March 2019 | archive-url=https://web.archive.org/web/20190327103438/https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20998.cfm | url-status=live }} It was co-promoted by Monsanto Company (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia, from which the Medical Research Division was acquired by Pfizer, giving Pfizer ownership of Celebrex. The drug was at the core of a major patent dispute that was resolved in Searle's favor (later Pfizer) in 2004. In University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004), the University of Rochester claimed that United States Pat. No. 6,048,850 (which claimed a method of inhibiting COX-2 in humans using a compound, without actually disclosing what that compound might be) covered drugs such as celecoxib. The court ruled in favor of Searle, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2, and therefore the patent was invalid.

After the withdrawal of rofecoxib from the market in September 2004, celecoxib enjoyed a robust increase in sales. However, the results of the APC trial in December of that year raised concerns that Celebrex might carry risks similar to those of rofecoxib, and Pfizer announced a moratorium on direct-to-consumer advertising of Celebrex soon afterward. Sales reached $2 billion in 2006. Before its availability in generic form, it was one of Pfizer's "best-selling drugs, amounting to more than $2.5 billion in sales [by 2012], and was prescribed to 2.4 million" people in 2011. By 2012, 33 million Americans had taken celecoxib.{{cite news | url=https://www.nytimes.com/2012/06/25/health/in-documents-on-pain-drug-celebrex-signs-of-doubt-and-deception.html | title=In Documents on Pain Drug, Signs of Doubt and Deception | work=The New York Times | date=24 June 2012 | access-date=27 December 2015 | vauthors = Thomas K | archive-date=3 January 2016 | archive-url=https://web.archive.org/web/20160103151323/http://www.nytimes.com/2012/06/25/health/in-documents-on-pain-drug-celebrex-signs-of-doubt-and-deception.html | url-status=live }}

Pfizer resumed advertising Celebrex in magazines in 2006,{{cite news |author=Berenson A |title=Celebrex Ads Are Back, Dire Warnings and All |work=The New York Times |date=29 April 2006 |url=https://www.nytimes.com/2006/04/29/business/media/29celebrex.html |access-date=21 February 2017 |archive-date=7 January 2016 |archive-url=https://web.archive.org/web/20160107133428/http://www.nytimes.com/2006/04/29/business/media/29celebrex.html |url-status=live }} and resumed television advertising in April 2007 with an unorthodox, {{frac|2|1|2}}-minute advertisement which extensively discussed the adverse effects of Celebrex in comparison with other anti-inflammatory drugs. The ad drew criticism from the consumer advocacy group Public Citizen, which called the ad's comparisons misleading.{{cite news |author=Saul S |title=Celebrex Commercial, Long and Unconventional, Draws Criticism |work=The New York Times |date=10 April 2007 |url=https://www.nytimes.com/2007/04/10/business/media/10celebrex.html |access-date=21 February 2017 |archive-date=17 January 2018 |archive-url=https://web.archive.org/web/20180117060825/http://www.nytimes.com/2007/04/10/business/media/10celebrex.html |url-status=live }} Pfizer responded to Public Citizen's concerns with assurances that they are truthfully advertising the risk and benefits of Celebrex as set forth by the FDA.

In 2025, Australian Therapeutic Goods Administration decided to include celecoxib 200mg as the first Schedule 3 (Pharmacist Only Medicine) selective COX-2 inhibitor in a primary pack containing not more than 10 dosage units for the short-term treatment of acute pain due to primary dysmenorrhoea or musculoskeletal or soft tissue injury in adults.

Pfizer and its partner, Pharmacia presented findings from their study that Celebrex was "better in protecting the stomach from serious complications than other drugs." This became Celebrex's main selling point. However, following federal investigations it was revealed that Pfizer and Pharmacia "only presented the results from the first six months of a year-long study rather than the whole thing." These partial results were then published in The Journal of the American Medical Association. In 2001, the US Food and Drug Administration (FDA) released the full results of the Pfizer and Pharmacia study which showed that they had withheld crucial data. By 2012, a federal judge unsealed "thousands of pages of internal documents and depositions" in a "long-running securities fraud case against Pfizer."

In March 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Massachusetts, revealed that the data for 21 studies he had authored for the efficacy of the drug (along with others such as Vioxx) had been fabricated. The analgesic effects of the drugs had been exaggerated. Reuben was also a former paid spokesperson for Pfizer. Although from 2002 to 2007 Pfizer underwrote much of Dr. Reuben's research and "many of his trials found that Celebrex and Lyrica, Pfizer drugs, were effective against postoperative pain," Pfizer was not aware of the fraudulent data.{{cite news |url=https://www.nytimes.com/2009/03/11/health/research/11pain.html |title=Doctor Admits Pain Studies Were Frauds, Hospital Says |work=The New York Times |date=11 March 2009 |access-date=27 December 2015 | vauthors = Harris G |archive-date=17 May 2017 |archive-url=https://web.archive.org/web/20170517184147/http://www.nytimes.com/2009/03/11/health/research/11pain.html |url-status=live }}{{Failed verification|date=August 2018}} None of the retracted studies were submitted to either the US Food and Drug Administration or the European Union's regulatory agencies before the drug's approval. Although Pfizer issued a public statement declaring, "It is very disappointing to learn about Dr. Scott Reuben's alleged actions. When we decided to support Dr. Reuben's research, he worked for a credible academic medical center and appeared to be a reputable investigator",{{cite news | url=https://www.wsj.com/articles/SB123672510903888207 | work=The Wall Street Journal | title=Top Pain Scientist Fabricated Data in Studies, Hospital Says | vauthors = Winstein KJ | date=11 March 2009 | url-access=subscription | access-date=3 August 2017 | archive-date=30 August 2017 | archive-url=https://web.archive.org/web/20170830223401/https://www.wsj.com/articles/SB123672510903888207 | url-status=live }}{{cite web|title=Associated Press, Mar 11, 2009, Mass. doctor accused of faking pain pill data |url=https://www.google.com/hostednews/ap/article/ALeqM5jjpBsTFN9SEtQu-xyDltivC2GJ8AD96S2KVO0 |url-status=dead |archive-url=https://web.archive.org/web/20090316103119/https://www.google.com/hostednews/ap/article/ALeqM5jjpBsTFN9SEtQu-xyDltivC2GJ8AD96S2KVO0 |archive-date=16 March 2009 }} the documents unsealed in 2012, revealed that by February 2000, Pharmacia employees had devised a strategy to present the findings.

Pfizer markets celecoxib under the brand name Celebrex, and it is available as oral capsules containing 50, 100, 200, or 400 mg of celecoxib.

It is legally available in many jurisdictions as a generic under several brand names.{{cite web | title=Celecoxib | website=Drugs.com | date=4 May 2020 | url=https://www.drugs.com/international/celecoxib.html | access-date=5 May 2020 | archive-date=10 March 2016 | archive-url=https://web.archive.org/web/20160310184046/http://www.drugs.com/international/celecoxib.html | url-status=live }} In the US, celecoxib was covered by three patents, two of which expired on 30 May 2014, and one of which (US RE44048{{cite web |url=https://patents.google.com/patent/USRE44048 |title=US Re-issued Patent RE44048 |access-date=10 November 2016 |archive-date=9 January 2017 |archive-url=https://web.archive.org/web/20170109190350/https://www.google.com/patents/USRE44048 |url-status=live }}) was due to expire 2 December 2015. On 13 March 2014, that patent was found to be invalid for double patenting.{{cite web | vauthors = Parloff R | title=Judge cuts 18 months off patent life of Pfizer's Celebrex | website=Fortune | date=13 March 2014 | url=https://fortune.com/2014/03/13/judge-cuts-18-months-off-patent-life-of-pfizers-celebrex/ | access-date=5 May 2020 | archive-date=25 July 2017 | archive-url=https://web.archive.org/web/20170725162355/http://fortune.com/2014/03/13/judge-cuts-18-months-off-patent-life-of-pfizers-celebrex/ | url-status=live }} Upon the patent expiry on 30 May 2014, the FDA approved the first versions of generic celecoxib.{{cite press release | title=FDA approves first generic versions of celecoxib | website=U.S. Food and Drug Administration (FDA) | date=31 May 2014 | url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm399428.htm | archive-url=https://web.archive.org/web/20140531020104/https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm399428.htm | archive-date=31 May 2014 | url-status=dead | access-date=5 May 2020}}

In the US, Celebrex is marketed by Viatris after Upjohn was spun off from Pfizer.{{cite web | title=Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan | publisher=Pfizer | via=Business Wire | date=16 November 2020 | url=https://www.businesswire.com/news/home/20201116005378/en/ | access-date=17 June 2024}}{{cite web | title=Celebrex | website=Pfizer | url=https://www.pfizer.com/products/product-detail/celebrex | access-date=17 June 2024}}{{cite web | title=Brands | website=Viatris | date=16 November 2020 | url=https://www.viatris.com/en/products/brands | access-date=17 June 2024}}

On the theory that inflammation plays a role in the pathogenesis of major mental disorders, celecoxib has been trialed for a number of psychiatric disorders, including major depression, bipolar disorder, and schizophrenia.{{cite journal | vauthors = Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G | title = Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials | journal = Journal of Psychiatric Research | date = September 2021 | volume = 143 | pages = 230–238 | doi = 10.1016/j.jpsychires.2021.09.018| pmid = 34509090 | s2cid = 237485915 }}{{cite journal | vauthors = Müller N, Myint AM, Krause D, Weidinger E, Schwarz MJ | title = Anti-inflammatory treatment in schizophrenia | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 42 | pages = 146–53 | date = April 2013 | pmid = 23178230 | doi = 10.1016/j.pnpbp.2012.11.008 | s2cid = 22078590 }}{{cite journal | vauthors = Na KS, Lee KJ, Lee JS, Cho YS, Jung HY | title = Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 48 | pages = 79–85 | date = January 2014 | pmid = 24056287 | doi = 10.1016/j.pnpbp.2013.09.006 | s2cid = 35885429 }}{{cite journal | vauthors = Rosenblat JD, Cha DS, Mansur RB, McIntyre RS | title = Inflamed moods: a review of the interactions between inflammation and mood disorders | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 53 | pages = 23–34 | date = August 2014 | pmid = 24468642 | doi = 10.1016/j.pnpbp.2014.01.013 | s2cid = 32289214 }}{{cite journal | vauthors = Fond G, Hamdani N, Kapczinski F, Boukouaci W, Drancourt N, Dargel A, Oliveira J, Le Guen E, Marlinge E, Tamouza R, Leboyer M | title = Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review | journal = Acta Psychiatrica Scandinavica | volume = 129 | issue = 3 | pages = 163–79 | date = March 2014 | pmid = 24215721 | doi = 10.1111/acps.12211 | s2cid=23482349 }} A 2014 meta-analysis concluded that adjunctive treatment with celecoxib improved depressive symptoms, response, and remission rates compared to placebo.

A meta-analysis considering trials of celecoxib as an adjunctive treatment in bipolar disorder was inconclusive citing low evidence quality.

It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer, so it is not a good choice for this reason.

The use of celecoxib to reduce the risk of colorectal cancer has been investigated, but neither celecoxib nor any other drug is indicated for this use.{{cite journal | vauthors = Rial NS, Zell JA, Cohen AM, Gerner EW | title = Clinical end points for developing pharmaceuticals to manage patients with a sporadic or genetic risk of colorectal cancer | journal = Expert Review of Gastroenterology & Hepatology | volume = 6 | issue = 4 | pages = 507–17 | date = August 2012 | pmid = 22928902 | pmc = 3587976 | doi = 10.1586/egh.12.23 }} Small-scale clinical trials in very high-risk people (belonging to FAP families) showed celecoxib can prevent polyp growth. Hence, large-scale randomized clinical trials were undertaken.{{cite journal | vauthors = Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Wittes J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, Macrae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Gordon GB, Hawk ET | title = Celecoxib for the prevention of sporadic colorectal adenomas | journal = The New England Journal of Medicine | volume = 355 | issue = 9 | pages = 873–84 | date = August 2006 | pmid = 16943400 | doi = 10.1056/NEJMoa061355 | doi-access = free }} Results show a 33 to 45% polyp recurrence reduction in people treated with celecoxib each day. However, serious cardiovascular events were significantly more frequent in the celecoxib-treated groups. Aspirin shows a similar (and possibly larger) protective effect,{{cite journal | vauthors = Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F, van Stolk RU | title = A randomized trial of aspirin to prevent colorectal adenomas | journal = The New England Journal of Medicine | volume = 348 | issue = 10 | pages = 891–9 | date = March 2003 | pmid = 12621133 | doi = 10.1056/NEJMoa021735 | doi-access = free }}{{cite journal | vauthors = Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, Petrelli N, Pipas JM, Karp DD, Loprinzi CL, Steinbach G, Schilsky R | title = A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer | journal = The New England Journal of Medicine | volume = 348 | issue = 10 | pages = 883–90 | date = March 2003 | pmid = 12621132 | doi = 10.1056/NEJMoa021633 | doi-access = free }}{{cite journal | vauthors = Bosetti C, Talamini R, Franceschi S, Negri E, Garavello W, La Vecchia C | title = Aspirin use and cancers of the upper aerodigestive tract | journal = British Journal of Cancer | volume = 88 | issue = 5 | pages = 672–4 | date = March 2003 | pmid = 12618872 | pmc = 2376339 | doi = 10.1038/sj.bjc.6600820 }} has demonstrated cardioprotective effects and is significantly cheaper, but no head-to-head clinical trials have compared the two drugs.

Different from cancer prevention, cancer treatment is focused on the therapy of tumors that have already formed and have established themselves inside the patient. Many studies are going on to determine whether celecoxib might be useful for this latter condition.{{cite journal | vauthors = Dannenberg AJ, Subbaramaiah K | title = Targeting cyclooxygenase-2 in human neoplasia: rationale and promise | journal = Cancer Cell | volume = 4 | issue = 6 | pages = 431–6 | date = December 2003 | pmid = 14706335 | doi = 10.1016/S1535-6108(03)00310-6 | doi-access = free }} However, during molecular studies in the laboratory, it became apparent that celecoxib could interact with other intracellular components besides its most famous target, COX-2. The discovery of these additional targets has generated much controversy, and the initial assumption that celecoxib reduces tumor growth primarily by the inhibition of COX-2 became contentious.{{cite journal | vauthors = Schönthal AH | title = Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy | journal = British Journal of Cancer | volume = 97 | issue = 11 | pages = 1465–8 | date = December 2007 | pmid = 17955049 | pmc = 2360267 | doi = 10.1038/sj.bjc.6604049 }}

Certainly, the inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of celecoxib. However, whether inhibition of COX-2 also plays a dominant role in this drug's anticancer effects is unclear. For example, a recent study with malignant tumor cells showed celecoxib could inhibit the growth of these cells in vitro, but COX-2 played no role in this outcome; even more strikingly, the anticancer effects of celecoxib were also obtained with the use of cancer cell types that do not even contain COX-2.{{cite journal | vauthors = Chuang HC, Kardosh A, Gaffney KJ, Petasis NA, Schönthal AH | title = COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro | journal = Molecular Cancer | volume = 7 | issue = 1 | pages = 38 | date = May 2008 | pmid = 18485224 | pmc = 2396175 | doi = 10.1186/1476-4598-7-38 | doi-access = free }} Karen Seibert and colleagues have published research showing antiangiogenic and antitumor activity of celecoxib in animal models.{{cite journal | vauthors = Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K | title = Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors | journal = Cancer Research | volume = 60 | issue = 5 | pages = 1306–1311 | date = March 2000 | pmid = 10728691 | url = https://aacrjournals.org/cancerres/article/60/5/1306/507043/Antiangiogenic-and-Antitumor-Activities-of }}

Additional support for the idea that other targets besides COX-2 are important for celecoxib's anticancer effects has come from studies with chemically modified versions of celecoxib. Several dozen analogs of celecoxib were generated with small alterations in their chemical structures.{{cite journal | vauthors = Zhu J, Song X, Lin HP, Young DC, Yan S, Marquez VE, Chen CS | title = Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents | journal = Journal of the National Cancer Institute | volume = 94 | issue = 23 | pages = 1745–57 | date = December 2002 | pmid = 12464646 | doi = 10.1093/jnci/94.23.1745 | doi-access = free }} Some of these analogs retained COX-2 inhibitory activity, whereas many others did not. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing the inhibition of COX-2 was not required for the anticancer effects.{{cite journal | vauthors = Schönthal AH, Chen TC, Hofman FM, Louie SG, Petasis NA | title = Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs | journal = Expert Opinion on Investigational Drugs | volume = 17 | issue = 2 | pages = 197–208 | date = February 2008 | pmid = 18230053 | doi = 10.1517/13543784.17.2.197 | s2cid = 21093404 }} One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually displayed stronger anticancer activity than celecoxib.{{cite journal | vauthors = Schönthal AH | title = Antitumor properties of dimethyl-celecoxib, a derivative of celecoxib that does not inhibit cyclooxygenase-2: implications for glioma therapy | journal = Neurosurgical Focus | volume = 20 | issue = 4 | pages = E21 | date = April 2006 | pmid = 16709027 | doi = 10.3171/foc.2006.20.4.14 | doi-access = free }}

{{reflist}}

{{refbegin}}

• {{cite book | title=Medical Genetics Summaries | chapter=Celecoxib Therapy and CYP2C9 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK379478/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=National Center for Biotechnology Information (NCBI) | year=2016 | pmid=28520369 | id=Bookshelf ID: NBK379478 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}
• {{cite journal |vauthors=Zhang J, Ding EL, Song Y |title=Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials |journal=JAMA |volume=296 |issue=13 |pages=1619–32 |date=October 2006 |pmid=16968832 |doi=10.1001/jama.296.13.jrv60015 }}

{{refend}}

• {{cite web | title=COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) | website=U.S. Food and Drug Administration (FDA) | date=15 July 2005 | url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-and-non-selective-non-steroidal-anti-inflammatory | archive-url=https://web.archive.org/web/20190928144031/https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-and-non-selective-non-steroidal-anti-inflammatory | url-status=dead | archive-date=28 September 2019 }}
• {{cite web | title=FDA Approves Labeling Supplement for Celebrex (celecoxib) | website=U.S. Food and Drug Administration (FDA) | date=28 June 2018 | url=https://www.fda.gov/drugs/drug-safety-and-availability/cder-statement-fda-approves-labeling-supplement-celebrex-celecoxib }}

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