Generic Name: Celecoxib
Class: Cyclooxygenase-2 (COX-2) Inhibitors
Chemical Name: 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
CAS Number: 184007-95-2
AUDIENCE: Health Professional, Consumer
ISSUE: FDA is strengthening an existing label warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the chance of a heart attack or stroke. Based on FDAs comprehensive review of new safety information, FDA is requiring updates to the drug labels of all prescription NSAIDs. As is the case with current prescription NSAID labels, the Drug Facts labels of over-the-counter (OTC) non-aspirin NSAIDs already contain information on heart attack and stroke risk. FDA will also request updates to the OTC non-aspirin NSAID Drug Facts labels. See the FDA Drug Safety Communication (Table 1) at: for a list of non-aspirin nonsteroidal anti-inflammatory drug products.
Prescription NSAID labels will be revised to reflect the following information:
The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.
The risk appears greater at higher doses.
It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.
NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied.
In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline.
Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.
There is an increased risk of heart failure with NSAID use.
BACKGROUND: The risk of heart attack and stroke with NSAIDs, either of which can lead to death, was first described in 2005 in the Boxed Warning and Warnings and Precautions sections of the prescription drug labels. Since then, FDA reviewed a variety of new safety information on prescription and OTC NSAIDs, including observational studies, a large combined analysis of clinical trials, and other scientific publications. These studies were also discussed at a joint meeting of the Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee held on February 10-11, 2014.
RECOMMENDATION: Patients and health care professionals should remain alert for heart-related side effects the entire time that NSAIDs are being taken. Patients taking NSAIDs should seek medical attention immediately if they experience symptoms such as chest pain, shortness of breath or trouble breathing, weakness in one part or side of their body, or slurred speech.
For more information visit the FDA website at: and .
- Cardiovascular Risk
Possible increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).1 Risk may increase with duration of use.1 Individuals with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.1 (See Cardiovascular Effects under Cautions.)
Contraindicated for the treatment of pain in the setting of CABG surgery.1
- GI Risk
Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).1 Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.1 Geriatric individuals are at greater risk for serious GI events.1 (See GI Effects under Cautions.)
Uses for Celebrex
Consider potential benefits and risks of celecoxib therapy as well as alternative therapies before initiating therapy with the drug.1 Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.1
Rheumatoid Arthritis in Adults
Reduction of the number of adenomatous colorectal polyps (colorectal adenomas) in adults with familial adenomatous polyposis (FAP); used as an adjunct to usual care.1 60 Not known whether celecoxib reduces the risk of colorectal, duodenal, or other FAP-related cancers.1
Has been investigated for the prevention of colorectal adenomas in patients without a history of FAP†.149 150 Use of celecoxib reduces the risk of recurrent colorectal adenomas;149 150 not known whether celecoxib reduces the risk of colorectal cancer.149 150 Routine use not recommended because of the potential for serious cardiovascular events.149
Cardiovascular Risk Reduction
Not a substitute for aspirin in the prevention of adverse cardiovascular events (MI).1 (See Cardiovascular Effects under Cautions.)
Celebrex Dosage and Administration
Consider potential benefits and risks of celecoxib therapy as well as alternative therapies before initiating therapy with the drug.1
Administer dosages up to 200 mg twice daily without regard to meals; administer higher dosages (400 mg twice daily) with food.1
For patients who have difficulty swallowing capsules, the capsule may be opened and the contents sprinkled onto a level teaspoonful of applesauce at room temperature or cooler, and the mixture swallowed immediately with water.1
To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.1
Attempt to titrate to the lowest effective dosage in adults with arthritis.1
Children ≥2 years of age weighing 10–25 kg: 50 mg twice daily.1
Children ≥2 years of age weighing >25 kg: 100 mg twice daily.1
No additional benefit from dosages >200 mg daily.1
Rheumatoid Arthritis in Adults
No additional benefit from higher dosages (400 mg twice daily).1
Initially, 200 mg daily as a single dose or in 2 equally divided doses.1 If no response observed after 6 weeks, increase to 400 mg daily.1 If no response observed after 400 mg daily for 6 weeks, response is unlikely; consider alternative therapies.1
Reduce dosage by 50% in patients with moderate hepatic impairment; not recommended in patients with severe impairment.1
Dosage adjustment based solely on age is not necessary; initiate at lowest recommended dosage in geriatric patients weighing <50 kg.1
Cautions for Celebrex
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Known hypersensitivity to celecoxib, sulfonamides, or any ingredient in the formulation.1
History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.1
Treatment of perioperative pain in the setting of CABG surgery.1
Selective COX-2 inhibitors have been associated with increased risk of cardiovascular events (e.g., MI, stroke) in certain situations.1 103 104 113 116 122 123 129 130 131 134 137 138 139 140 141 146 147 148 Several prototypical NSAIAs also have been associated with increased risk of cardiovascular events.146 147 148 Current evidence suggests that use of celecoxib at dosages >200 mg daily is associated with increased cardiovascular risk, while the potential risk is less clear at dosages of ≤200 mg daily.146 148 157 158
Short-term use to relieve acute pain, especially at low dosages, does not appear to be associated with increased risk of serious cardiovascular events (except immediately following CABG surgery).133
Not known whether long-term use in children is associated with increased cardiovascular risk.1
Use celecoxib with caution and careful monitoring (e.g., monitor for development of cardiovascular events).1 102 112 Until more data are available, a selective COX-2 inhibitor remains an appropriate choice for patients at low cardiovascular risk who have had serious GI events, especially while receiving a prototypical NSAIA.112 121 128 145 May be prudent to avoid use of selective COX-2 inhibitors in patients who have or are at risk for cardiovascular disease.112 121 124 128 142 143
No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.1 103 133 134 135 139 141 (See Specific Drugs under Interactions.)
Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.1 Use with caution in patients with hypertension; monitor BP.1 Impaired response to certain diuretics may occur.1 (See Specific Drugs under Interactions.)
Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.1
Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.1
Potential for overt renal decompensation.1 Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in patients with volume depletion, in geriatric patients, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.1 46 153 (See Renal Impairment under Cautions.)
Celecoxib not shown to reduce risk of GI cancer or need for prophylactic colectomy or other FAP-related surgery in patients with FAP; usual care (i.e., endoscopic surveillance, prophylactic colectomy, other FAP-related surgery) should not be altered.1
Anaphylactoid reactions (e.g., anaphylaxis, angioedema) reported.1
Immediate medical intervention and discontinuance for anaphylaxis.1
Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.1
Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning and in patients without a history of sulfonamide sensitivity.1 144 Discontinue at first appearance of rash or any other sign of hypersensitivity (blisters, fever, pruritus).1
Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.1
Elevations of serum ALT or AST reported.1
Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.1 Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.1
No effect on platelet counts, prothrombin time, or partial thromboplastin time; usual dosages do not affect platelet aggregation.1
Modest increases in aPTT reported in children with systemic onset juvenile rheumatoid arthritis (active systemic disease not present); risk of disseminated intravascular coagulation.1 Use with caution and monitor coagulation tests in these children.1
Potential for increased plasma celecoxib concentrations in patients with poor metabolizer phenotype of CYP2D6; use with caution in patients with known or suspected poor metabolizer phenotype.1
Prescribing and Dispensing Precautions
Ensure accuracy of prescription; similarity in spelling of Celebrex (celecoxib), Celexa (citalopram hydrobromide), and Cerebyx (fosphenytoin sodium) may result in errors.34
Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.1
May mask certain signs of infection.1
Obtain CBC and chemistry profile periodically during long-term use.1
Safety and efficacy in children 2–17 years of age with pauciarticular course, polyarticular course, or systemic onset juvenile rheumatoid arthritis supported by evidence from an active-controlled clinical study.1 Safety and efficacy not established in children <2 years of age, those weighing <10 kg, or children with active systemic disease.1 Not studied beyond 6 months.1
Children with systemic onset juvenile rheumatoid arthritis: Risk of abnormal coagulation test results; modest prolongation of aPTT reported.1 Risk of disseminated intravascular coagulation.1 Use with caution in these children; monitor coagulation tests.1
Use not recommended in patients with severe hepatic impairment.1
Reduced dosage recommended in patients with moderate hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)
Common Adverse Effects
Adults: Abdominal pain, diarrhea, dyspepsia, headache, nausea, sinusitis, upper respiratory tract infection.1
Children: Headache, fever, abdominal pain, cough, nasopharyngitis, nausea, arthralgia, diarrhea, vomiting.1
Interactions for Celebrex
Metabolized by CYP2C9.77
Inhibits CYP2D6; does not inhibit CYP2C9, CYP2C19, or CYP3A4.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Reduced BP response to ACE inhibitor1
Angiotensin II receptor antagonists
Reduced BP response to angiotensin II receptor antagonists153
Antacids (magnesium- or aluminum-containing)
Diuretics (furosemide, thiazides)
Reduced natriuretic effects1
Increased plasma celecoxib concentrations1
Initiate celecoxib at lowest recommended dosage1
Pharmacokinetic interaction unlikely1
Pharmacokinetic interaction unlikely1
Increased plasma lithium concentrations1
Monitor for lithium toxicity when initiating or discontinuing celecoxib1
Pharmacokinetics of methotrexate not altered1
Pharmacokinetic interaction unlikely1
Pharmacokinetic interaction unlikely1
Single doses provide pain relief within 60 minutes.1
Bioavailability increased 10–20% and time to reach peak plasma concentration delayed 1–2 hours when 200-mg capsule is administered with a high-fat meal.1 2 Administration of dosages of 400 mg twice daily with food improves absorption.1
Administration as mixture in applesauce does not alter AUC, peak plasma concentration, or time to peak plasma concentration.1
Not well characterized.1
Plasma Protein Binding
Pediatric patients: Oral clearance increases in less-than-proportional manner with increasing weight; clearance predicted to be 40 or 24% lower in pediatric patients weighing 10 or 25 kg, respectively, than in a 70-kg adult.1
11 hours under fasting conditions.1
25°C (may be exposed to 15–30°C).1
Mixture of capsule contents in applesauce is stable for 6 hours when refrigerated.1
Related structurally and pharmacologically to rofecoxib and valdecoxib (COX-2 inhibitors no longer commercially available in the US); differs structurally and, to some extent, pharmacologically from prototypical NSAIAs, which inhibit COX-1 and COX-2.1 2 3 4 5 8 11 41 52
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.1
Risk of serious cardiovascular events with long-term use.1
Risk of GI bleeding and ulceration.1
Risk of hepatotoxicity.1
Not a substitute for aspirin in the prevention of adverse cardiovascular events.1
Importance of notifying clinician if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.1
Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.1
Importance of discontinuing celecoxib and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.1 Importance of seeking immediate medical attention if an anaphylactic reaction occurs.1
Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1
For patients with FAP, importance of continuing usual care.1
Importance of informing patients of other important precautionary information. (See Cautions.)1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Celebrex (with povidone)
Celebrex (with povidone)
Celebrex (with povidone)
Celebrex (with povidone)
AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions May 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. Pfizer. Celebrex (celecoxib) capsules prescribing information. New York, NY; 2006 Dec.
2. G.D. Searle & Co. Celebrex (celecoxib) formulary information. Skokie, IL; 1999 Feb 8.
3. Anon. Celecoxib for arthritis. Med Lett Drugs Ther. 1999; 41:11-2. [PubMed 9949762]
4. Gierse JK, McDonald JJ, Hauser SD et al. A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J Biol Chem. 1996; 271:15810-4. [PubMed 8663121]
5. Seibert K, Zhang Y, Leahy K et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. 1994; 91:12013-7. [PubMed 7991575]
6. Funck-Brentano C, Thomas G, Jacqz-Aigrain E et al. Polymorphism of dextromethorphan metabolism: relationships between phenotype, genotype and response to the administration of encainide in humans. J Pharmacol Exp Ther. 1992; 263:780-6. [PubMed 1432700]
7. McAdam BF, Catella-Lawson F, Mardini IA et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA. 1999; 96:272-7. [PubMed 9874808]
8. Hawkey CJ. COX-2 inhibitors. Lancet. 1999; 353:307-14. [IDIS 418284] [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. [IDIS 411265] [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)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib). J Med Chem. 1997; 40:1347-65. [PubMed 9135032]
12. Markind JE (G. D. Searle, Skokie, Ill): Personal communication; 1999 May 7.
13. G.D. Searle. Response to Wall Street Journal article regarding Celebrex. Skokie, Ill; 1999 Apr 20. Press release from website (http://www.searlehealthnet.com/pr/042099.htm).
14. Anon. Searle responds to Journal report on Celebrex side effects. Skokie, Ill; 1999 Apr 22. Press release from website (http://www.pslgroup.com:80/dg/f8f2e.htm).
15. Kawamori T, Rao CV, Seibert K et al. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res. 1998; 58:409-12. [PubMed 9458081]
16. McAdam BF, Kapoor S, Catella-Lawson F et al. Selective inhibition of monocyte COX-2 vs platelet COX-1 in humans. Circulation. 1997; 96(Suppl):I-557.
17. Crofford LJ, Wilder RL, Ristimäki AP et al. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues: effects of interleukin-1β, phorbol ester, and corticosteroids. J Clin Invest. 1994; 93:1095-101. [PubMed 8132748]
18. Lane NE. Pain management in osteoarthritis: the role of COX-2 inhibitors. J Rheumatol. 1997; 24(Suppl 49):20-4. [PubMed 9002006]
19. DeWitt DL, Bhattacharyya D, Lecomte M et al. The differential susceptibility of prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs: aspirin derivatives as selective inhibitors. Med Chem Res. 1995; 5:325-43.
20. Mengle-Gaw L, Hubbard RC, Karim A et al. A study of the platelet effects of SC-58635, a novel COX-2-selective inhibitor. Arthritis Rheum. 1997; 40:S93.
21. Geis GS, Hubbard R, Callison D et al. Safety and efficacy of celecoxib, a specific COX-2 inhibitor, in patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:S364.
22. Hubbard RC, Koepp R, Yu SS et al. Pilot efficacy of SC-58635, a COX-2-selective inhibitor, in rheumatoid arthritis. Arthritis Rheum. 1997; 40:S51.
23. Karim A, Tolbert D, Burton E et al. SC-58635 (celecoxib): a highly selective inhibitor of cyclooxygenase-2, disposition kinetics in man and identification of its major CYP450 isozyme in its biotransformation. Pharm Res. 1997; 14(Suppl):S617.
24. Geis GS, Stead H, Morant S et al. Efficacy and safety of celecoxib, a specific COX-2 inhibitor, in patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:S316.
25. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]
26. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum. 1993; 36:729-40. [PubMed 8507213]
27. Felson DT, Anderson JJ, Lange MLM et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? Arthritis Rheum. 1998; 41:1564-70. (IDIS 411264)
28. Hubbard RC, Geis GS, Callison DA et al. Efficacy and safety of celecoxib, a specific COX-2 inhibitor, in osteoarthritis (OA) and rheumatoid (RA). J Rheumatol. 1998; 25(Suppl 52):6. [PubMed 9458195]
29. Hubbard R, Geis GS, Woods E et al. Efficacy, tolerability, and safety of celecoxib, a specific COX-2 inhibitor, in osteoarthritis. Arthritis Rheum. 1998; 41:S196.
30. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002; 46:328-46. [IDIS 476480] [PubMed 11840435]
31. Lane NE, Thompson JM. Management of osteoarthritis in the primary-care setting: an evidence-based approach to treatment. Am J Med. 1997; 103(Suppl 6A):25-30S. [IDIS 390389] [PubMed 9236482]
32. Altman RD, Hochberg MC, Moskowitz RW et al. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000; 43:1905-15. [IDIS 453740] [PubMed 11014340]
33. Silverstein FE, Faich G, Goldstein JL et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumtoid arthritis. The CLASS study: a randomized controlled trial. JAMA. 2000; 284:1247-55. [IDIS 453422] [PubMed 10979111]
34. Sharpe R. Monsanto, FDA are trying to overcome confusion over name of arthritis drug. Wall St J. 1999 Apr 15.
35. Anon. Celebrex wins “unclear” advantage from FDA: backhanded ok for GI safety. F-D-C Rep. 1999; Jan 4:33-4.
36. Lithium interactions. In: Hansten PD, Horn JR. Drug interactions analysis and management. Vancouver, WA: Applied Therapeutics, Inc; 1997:223, 327, 332, 358, 367-369, 371.
37. Smith CJ, Zhang Y, Koboldt CM et al. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA. 1998; 95:13313-8. [PubMed 9789085]
38. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenase—a review. Prostaglandins Lipid Mediators. 1998; 56:341-61.
39. Anderson GD, Hauser SD, McGarity KL et al. Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J Clin Invest. 1996; 97:2672-9. [PubMed 8647962]
40. Riendeau D, Charleson S, Cromlish W et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol. 1997; 75:1088-95. [PubMed 9365818]
41. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996; 384:644-8. [PubMed 8967954]
42. Hubbard RC, Mehlisch DR et al. SC-58635, a highly selective inhibitor of COX-2, is an effective analgesic in an acute post surgical pain model. J Invest Med. 1996; 44:293A.
43. Mehlisch DR, Hubbard RC, Isakson P et al. Analgesic efficacy and plasma levels of a highly selective inhibitor of COX-2 (SC-58635; SC) in patients with post-surgical dental pain. Clin Pharmacol Ther. 1997; 61:195.
44. Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy. 1998; 18:84-112. [IDIS 398636] [PubMed 9469685]
45. Angiotensin-converting enzyme inhibitor interactions: nonsteroidal anti-inflammatory drugs (NSAIDSs). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:131-2.
46. Novartis Pharmaceuticals. Diovan (valsartan) capsules prescribing information (dated 1997 Apr). In: Physicians’ desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:2013-5.
47. Lanza FL, Rack MF, Callison DA et al. A pilot endoscopic study of the gastroduodenal effects of SC-58635, a novel COX-2 selective inhibitor. Gastroenterology. 1997; 112:A194.
48. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med. 1999; 106:37S-42. [IDIS 430024] [PubMed 10390126]
49. Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? J Rheumatol. 1999; 26(Suppl 56):31-6.
50. Pfizer, New York, NY: Personal communication.
51. Reviewers’ comments (personal observations).
52. Merck & Co. Vioxx (rofecoxib) tablets and oral suspension prescribing information. Whitehouse Station, NJ: 2000 Jul.
53. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Ann Rev Pharmacol Toxicol. 1998; 38:97-120.
54. Wolfe MM, Lichtenstein DR, Singh G. Gastroinestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999; 340:1888-99. [IDIS 426864] [PubMed 10369853]
55. Karim A, Tolbert D, Piergies A et al. Celecoxib, a specific COX-2 inhibitor, lacks significan drug-drug interactions with methotrexate or warfarin. Arthritis Rheum. 1998; 41(Suppl):S315.
56. Bello A. Dear health care professional letter regarding updated labeling for Celebrex (celecoxib) on prothrombin time increases with concomitant warfarin therapy. Skokie, IL: Searle; 1999 May.
57. Food and Drug Administration Center for Drug Evaluation and Research: questions and answers about Celebrex labeling change—warfarin interaction. 1999; June 1.
58. Perazella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis. 2000: 35:937-40.
59. Dunn MJ. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis. 2000: 35:976-7. Editorial.
60. Steinbach G, Lynch PM, RKS Phillips et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000; 342:1946-52. [IDIS 448504] [PubMed 10874062]
61. Sheehan KM, Sheahan K, O’Donoghue DP et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA. 1999; 282:1254-7. [PubMed 10517428]
62. Lanza FL, and the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol. 1998; 93:2037-46. [IDIS 417402] [PubMed 9820370]
63. Goldstein JL, Silverstein FE, Agrawal NM et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol. 2000; 95:1681-90. [IDIS 450009] [PubMed 10925968]
64. Bensen WG, Fiechtner JJ, McMillen JI et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc. 1999; 74:1095-1105. [IDIS 440849] [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. [IDIS 439434] [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. [IDIS 436126] [PubMed 10580457]
67. Pincus T, O’Dell JR, Kremer JM. Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy. Ann Intern Med. 1999; 131:768-74. [IDIS 436171] [PubMed 10577301]
68. Reviewer comments (personal observations) on etanercept.
69. Peterson WL, Cryer B. Cox-1-sparing NSAIDs–is the enthusiasm justified? JAMA. 1999; 282:1961-3. Editorial.
70. Beejay U, Wolfe MM. Cyclooxygenase 2 selective inhibitors: panacea or flash in the pan? Gastroenterology. 1999; 117:1002-14. Editorial.
71. Mizuno H, Sakamoto C, Matsuda K et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology. 1997; 112:387-97. [PubMed 9024292]
72. Stenson WF. Cyclooxygenase 2 and wound healing in the stomach. Gastroenterology. 1997; 112:645-8. [PubMed 9024317]
73. Schmassmann A, Peskar BM, Stettler C et al. Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br J Pharmacol,. 1998; 123:795-804.
74. Anon. Selective COX-2 inhibitors and bleeding risk: an additional note. Med Lett Drugs Ther. 2000; 42:92.
75. Reddy BS, Hirose Y, Lubet R et al. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res. 2000; 60:293-7. [PubMed 10667579]
76. Fournier DB, Gordon GB. COX-2 and colon cancer: potential targets for chemoprevention. J Cell Biochem. 2000; 34:97-102.
77. Jacoby RF, Seibert K, Cole CE et al. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res. 2000; 60:5040-4. [PubMed 11016626]
78. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2000; 42:57-64. [PubMed 10887424]
79. Food and Drug Administration. CLASS Advisory Committee meeting. Rockville, MD; Feb 2001. From FDA web site ()
80. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001; 345:433-42. [IDIS 467602] [PubMed 11496855]
81. Gottlieb S. Researchers deny any attempt to mislead public over JAMA article on arthritis drug. BMJ. 2001; 323:301. [PubMed 11498480]
82. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001; 286:954-9. [IDIS 468025] [PubMed 11509060]
83. Levy MB, Fink JN. Anaphylaxis to celecoxib. Ann Allergy Asthma Immunol. 2001; 87:72-3. [IDIS 467027] [PubMed 11476468]
84. Fye KH, Crowley E, Berger TG et al. Celecoxib-induced Sweet’s syndrome. J Am Acad Dermatol. 2001; 45:300-2. [IDIS 467504] [PubMed 11464196]
85. O’Beirne JP, Cairns SR. Cholestatic hepatitis in association with celecoxib. BMJ. 2001; 323:23. [IDIS 467041] [PubMed 11440939]
86. Graham MG. Acute renal failure related to high-dose celecoxib. Ann Intern Med. 2001; 135:69-70. [IDIS 466428] [PubMed 11434756]
87. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999; 26(suppl 56):18-24.
88. Morrison BW, Daniels SE, Kotey P et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled trial. Obstet Gynecol. 1999; 94:504-8. [IDIS 437014] [PubMed 10511349]
89. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol. 1993; 169:1255-65. [IDIS 321917] [PubMed 8238194]
90. Bieglmayer C, Hofer G, Kainz C et al. Concentrations of various arachidonic acid metabolites in menstrual fluid are associated with menstrual pain and are influenced by hormonal contraceptives. Gynecol Endocrinol. 1995; 9:307-12. [PubMed 8629459]
91. Chan WY, Fuchs F, Powell AM. Effects of naproxen sodium on menstrual prostaglandin and primary dysmenorrhea. Obstet Gynecol. 1983; 61:285-91. [IDIS 166215] [PubMed 6571974]
92. Lim H, Paria BC, Das SK et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell. 1997; 91:197-208. [PubMed 9346237]
93. in’t Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med. 2001; 345:1515-21. [PubMed 11794217]
94. Breitner JCS, Zandi PP. Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer’s disease? N Engl J Med. 2001; 345:1567-8. Editorial.
95. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology. 1996; 47:425-32. [IDIS 371394] [PubMed 8757015]
96. Beard CM, Waring SC, O’sBrien PC et al. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease : a case-control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc. 1998; 73:951-5. [IDIS 416502] [PubMed 9787743]
97. in’t Veld BA, Launer LJ, Hoes AW et al. NSAIDs and incident Alzheimer’s disease: the Rotterdam Study. Neurobiol Aging. 1998; 19:607-11. [PubMed 10192221]
98. Stewart WF, Kawas C, Corrada M et al. Risk of Alzheimer’s disease and duration of NSAID use. Neurology. 1997; 48:626-32. [IDIS 383303] [PubMed 9065537]
99. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomized controlled trials. BMJ; 325:619-23.
100. Chan FKL, Hung LCT, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002; 347:2104-10. [IDIS 490812] [PubMed 12501222]
101. Graham DY. NSAIDs, Helicobacter pylori, and Pandora’s box. N Engl J Med. 2002; 347:2162-4. [IDIS 490815] [PubMed 12501230]
102. Clark DWJ, Layton D, Shakir SAW. Do some inhibitors of COX-2 increase the risk of thromboembolic events? Drug Safety. 2004; 27:427-56.
103. Bresalier RS, Sandler RS, Quan H et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005; 352:1092-102. [IDIS 529764] [PubMed 15713943]
104. Merck. Merck announces voluntary worldwide withdrawal of Vioxx. Whitehouse Station, NJ; 2004 Sep 30. Press release.
105. Couzin J. Drug safety: withdrawal of Vioxx casts a shadow over COX-2 inhibitors. Science. 2004; 306:384-5. [PubMed 15486258]
106. Pfizer. Pfizer to sponsor major new Celebrex clinical trial. New York, NY; 2004 Oct 18. Press release.
107. Solomon D, Kavanaugh A, Matteson E L. Cardiovascular complications related to COX-2 inhibitors. From the American College of Rheumatology website (). Accessed 2004 Oct 25.
108. Solomon DH, Schneeweiss S, Glynn RJ et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 2004; 109:2068-73. [IDIS 519280] [PubMed 15096449]
109. Food and Drug Administration. Consultation NDA 21-042, S-007: review of cardiovascular safety data: rofecoxib. Rockville, MD: 2001 Feb 1. From the FDA website (). Accessed 2004 Oct 25.
110. Food and Drug Administration. CLASS Advisory Committee briefing document. Rockville, MD: 2001 Feb 7. From the FDA website (). Accessed 2004 Oct 25.
111. Pfizer. Comparative studies with Vioxx (rofecoxib) in cardiovascular safety. New York, NY; 2004 Aug.
112. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med. 2004: 351:1709-11.
113. Ott E, Nussmeier NA, Duke P C et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003; 125:1481-92. [IDIS 501834] [PubMed 12830070]
114. Pfizer. The overall cardiovascular safety profile: Bextra. New York, NY; 2004 Nov 1.
115. White WB, Strand V, Roberts R et al. Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther. 2004; 11:244-50. [PubMed 15266215]
116. Bombardier C, Laine L, Reicin et al. Compariosn of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343:1520-8. [IDIS 456596] [PubMed 11087881]
117. Anon. What about Celebrex? Med Lett Drugs Ther. 2004; 46:87-8.
118. Juni P, Nartey L, Reichenbach S et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004; 364:2021-9. [IDIS 534414] [PubMed 15582059]
119. White WB, Raich G, Borer JS et al. Cardiovascular events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol. 2003; 92:411-8. [IDIS 503537] [PubMed 12914871]
120. Pfizer. Pfizer provides information to healthcare professionals about its Cox-2 medicine Bextra (valdecoxib). New York, NY: 2004 Oct 15. Press release.
121. Reviewers’ comments (personal observations) on COX-2 inhibitors and issue of potential cardiovascular risk.
122. Ray WA, Stein CM, Daugherty JR et al. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet. 2002; 360:1071-3. [IDIS 487865] [PubMed 12383990]
123. Graham DJ, Campen D, Hui R et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005; 365:475-81. [IDIS 527993] [PubMed 15705456]
124. Bing RJ. Cyclooxygenase-2 inhibitors: is there an association with coronary or renal events? Current Atherosclerosis Rep. 2003; 5:114-7.
125. White WB, Faich G, Whelton A et al. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol. 2002; 89:425-30. [IDIS 478176] [PubMed 11835924]
126. Pfizer, New York, NY. Personal communication on COX-2 inhibitors and issue of potential cardiovascular risk.
127. Kimmel SE, Berlin JA, Reilly M et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med. 2005; 142:157-64. [IDIS 528366] [PubMed 15684203]
128. Finckh A, Aronson MD. Cardiovascular risks of cyclooxygenase-2 inhibitors: where we stand now. Ann Intern Med. 2005; 142:212-4. [IDIS 528369] [PubMed 15684210]
129. Burklow J, Ralbovsky D. NIH Halts use of COX-2 inhibitor in large cancer prevention trial. NIH News. 2004 Dec 17.
130. US Food and Drug Administration. FDA statement on the halting of a clinical trial of the Cox-2 inhibitor Celebrex. Press release. Rockville, MD; 2004 Dec 17.
131. Pfizer. Pfizer statement on new information regarding cardiovascular safety of Celebrex. Press release. New York, NY; 2004 Dec 17.
132. Dougados M, Behier JM, Jolchine I et al. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum. 2001; 44:180-5. [PubMed 11212158]
133. Food and Drug Administration. Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6.
134. Lévesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med. 2005; 142:481-9. [PubMed 15809459]
135. Solomon SD, McMurray JJV, Pfeffer MA et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005; 352:1071-80. [IDIS 529762] [PubMed 15713944]
136. Anon. Use of non-steroidal anti-inflammatory drugs suspended in large Alzheimer’s disease prevention trial. NIH News. 2004 Dec 20.
137. Nussmeier NA, Whelton AA, Brown MT et al. Complications of the COX-2 inhibitors paracoxib and valdecoxib after cardiac surgery. N Engl J Med. 2005; 352:1081-91. [IDIS 529763] [PubMed 15713945]
138. Shaya FT, Blume SW, Blanchette CM et al. Selective cyclooxygenase-2 inhibition and cardiovascular effects: an observational study of a Medicaid population. Arch Intern Med. 2005; 165:181-6. [IDIS 528610] [PubMed 15668364]
139. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ. 2005; 330:1366-72. [PubMed 15947398]
140. Johnson SP, Larsson H, Tarone RE et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-controlled study. Arch Intern Med. 2005; 165:978-84. [IDIS 533589] [PubMed 15883235]
141. Farkouh ME, Kirshner H, Harrington RA et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet. 2004; 364:675-84. [IDIS 519765] [PubMed 15325832]
142. Cush JJ. The safety of COX-2 inhibitors: deliberations from the February 16-18, 2005, FDA meeting. From the American College of Rheumatology website (). Accessed 2005 Oct 12.
143. Bennett JS, Daugherty A, Herrington D et al. The use of nonsteroidal anti-inflammatory drugs (NSAIDs); a Science Advisory from the American Heart Association. Circulation. 2005; 111:1713-16. [IDIS 538428] [PubMed 15781731]
144. La Grenade L, Lee L, Weaver J et al. Comparison of reporting of Stevens-Johnson syndrome and toxic epidermal necrosis in association with selective COX-2 inhibitors. Drug Saf. 2005; 28:917-24. [PubMed 16180941]
145. Shaya FT, Samant N, Skolasky R et al. Modeling risk of gastrointestinal events among Medicaid NSAID users using propensity scores. Expert Rev Pharmacoeconomics Outcomes Res. 2005; 5:625-32.
146. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006; 296; 1633-44. [PubMed 16968831]
147. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006; 332; 1302-5. [PubMed 16740558]
148. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense. JAMA. 2006; 296:1653-6. [PubMed 16968830]
149. Bertagnolli MM, Eagle CJ, Zauber A et al., for the APC study investigators. Celecoxib for the prevention of sporadic colorectal adenomas. N Eng J Med. 2006; 355:873-84. [PubMed 16943400]
150. Arber N, Eagle CJ, Spicak J, et al., for the PreSAP trial investigators. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006; 355; 885-95. [PubMed 16943401]
151. Chou R, Helfand M, Peterson K et al. Comparative effectiveness and safety of analgesics for osteoarthritis. Comparative effectiveness review no. 4. (Prepared by the Oregon evidence-based practice center under contract no. 290-02-0024.) . Rockville, MD: Agency for Healthcare Research and Quality. 2006 Sep. Available at: .
152. Solomon SD, Pfeffer MA, McMurray JJV, et al., for the APC and PreSAP trial investigators. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation. 2006; 114: 1028-35. [PubMed 16943394]
153. Merck & Co. Clinoril (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.
154. Boulos P, Dougados M, MacLeod SM et al. Pharmacological treatment of ankylosing spondylitis. A systematic review. Drugs. 2005; 65:2111-27. [PubMed 16225367]
155. Zochling Z, van der Heijde D, Braun J et al. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis. 2006; 65:423-32. [PubMed 16126792]
156. Zochling Z, van der Heijde D, Burgos-Vargas R et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis. 2006; 65:442-52. [PubMed 16126791]
157. Gislason GH, Jacobsen S, Rasmussen JN et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation. 2006; 113:2906-13. [PubMed 16785336]
158. Andersohn F, Suissa A, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction. Circulation. 2006; 113:1950-57. [PubMed 16618816]
159. Giannini EH, Ruperto N, Ravelli A et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997; 40:1202-9. [PubMed 9214419]
160. Ilowite NT. Current treatment of juvenile rheumatoid arthritis. Pediatrics. 2002; 109:109-115. [IDIS 477889] [PubMed 11773549]