Celecoxib
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Celecoxib
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| Systematic (IUPAC) name | |
| 4-[5-(4-methylphenyl)-3-(trifluoromethyl) pyrazol-1-yl]benzenesulfonamide |
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| Identifiers | |
| CAS number | |
| ATC code | L01 M01AH01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C17H14F3N3O2S |
| Mol. mass | 381.373 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 40% |
| Protein binding | 97% (mainly to serum albumin) |
| Metabolism | Hepatic (mainly CYP2C9) |
| Half life | ~11 hours |
| Excretion | Renal 27%, faecal 57% |
| Therapeutic considerations | |
| Pregnancy cat. |
B3 (Au) |
| Legal status |
℞ Prescription only |
| Routes | Oral |
Celecoxib (INN) (IPA: [sɛlɛˈkɒksɪb]) is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis. It is marketed by Pfizer under the brand name Celebrex. In some countries, it is branded Celebra. Celecoxib is available by prescription in capsule form.
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[edit] Indications
Celecoxib is licensed for use in osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce the number of colon and rectum polyps in patients with familial adenomatous polyposis. It was originally intended to relieve pain while minimising the gastrointestinal adverse effects usually seen with conventional NSAIDs. In practise, its primary indication is in patients who need regular and long term pain relief: there is probably no advantage to using celecoxib for short term or acute pain relief over conventional NSAIDs. In particular, the pain relief offered by celecoxib is only marginally superior to that offered by paracetamol.[1]
[edit] Pharmacology
Celecoxib is a highly selective COX-2 inhibitor and primarily inhibits this isoform of cyclooxygenase (inhibition of prostaglandin production), whereas traditional NSAIDs inhibit both COX-1 and COX-2. Celecoxib is approximately 7.6 times more selective for COX-2 inhibition over COX-1. In theory, this specificity 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 non-selective NSAIDs.
[edit] Dosing
The usual adult dose of celcoxib is 100 to 200mg once or twice a day. The lowest effective dose should be used.
[edit] Adverse effects
Celebrex, like all the other NSAIDs on the market, carries a boxed warning for cardiovascular and gastrointestinal risk. However, the medicine appears to carry more cardiovascular risk than other NSAIDS, such as Tylenol or Aleve. In February 2007, the American Heart Association has warned that it should be used "as a last resort on patients who have heart disease or a risk of developing it". [2]
[edit] Gastrointestinal ADRs
In theory the COX-2 selectivity should result in a significantly lower incidence of gastrointestinal ulceration than traditional NSAIDs. The main body of evidence touted to support this theory were the preliminary (6 month) results of the Celecoxib Long-term Arthritis Safety Study (CLASS) as published in 2000, which demonstrated a significant reduction in the combination of symptomatic ulcers plus ulcer complications in those taking celecoxib versus ibuprofen or diclofenac, provided they were not on aspirin (Silverstein et al, 2000). However, this was not significant at 12 months (full study length). It should be noted that this study used a very high dose of Celebrex, 800mg daily (400mg twice a day).
[edit] Allergy
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 patients with severe allergies to other NSAIDs.
[edit] History
Celecoxib was developed by G. D. Searle & Company and co-promoted by Monsanto (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia, which was then 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 (Vioxx) from the market in September 2004, Celebrex enjoyed a robust increase in sales. Then, in December 2004, one of two colon cancer prevention trials, named APC, found that long-term (33 months) of high-dose Celebrex (400 and 800mg daily) demonstrated an increased cardiovascular risk compared with placebo.[3] The other trial, named PreSAP, did not demonstrate an increased risk.[4] Still, the APC trial, combined with the Vioxx study, led to speculation that there is a cardiovascular risk for only the COX-2 drugs. However, a large Alzheimers prevention trial, called ADAPT, found that over-the-counter Aleve (naproxen) demonstrated an increased cardiovascular risk compared to placebo, whereas high-dose Celebrex (400mg daily) did not.[5]
Class Effect includes all NSAIDs, not just COX-2: In April 2005, after an extensive review of data and a 3-day Advisory Committee Meeting, the FDA concluded in its official memorandum: "we believe that it is reasonable to conclude that there is a 'class effect' for increased CV risk for all NSAIDs."[6] The FDA then mandated that all 18 prescription NSAIDs, including naproxen, ibuprofen, celebrex, diclofenac, etc, carry a boxed warning for cardiovascular risk. The FDA also published an NSAID medication guide for the public, which is available for free public download.[7] One interesting note for Celebrex is that no study has demonstrated an increased risk for heart attack or stroke when used at the approved dose for osteoarthritis: 200mg a day. A large observational study by David Graham of the Office of Drug Safety/FDA,[8] and a recent meta-analysis published in JAMA,[9] did not find an increased cardiovascular risk of Celebrex vs placebo. Neither of these studies were sponsored by a pharmaceutical company.
Still, it would be ideal if there could be a large, randomized trial that is specifically designed to measure cardiovascular events, as opposed to measuring colon cancer or Alzheimers disease. Pfizer has agreed to fund such a study, which will be directed by the Cleveland Clinic.[10] In this study that plans to enroll 20,000 high-risk patients, Celebrex will be compared to traditional anti-inflammatories (naproxen and ibuprofen), primarily to evaluate cardiovascular risk. Since all patients have arthritis, ethical considerations make it difficult to have a placebo group. This trial has just begun enrollment according to the Clinical Trials database, and is not scheduled to be completed until 2010. Ultimately, this trial will help answer the question as to whether Celebrex has a safer, riskier, or equal cardiovascular profile compared to naproxen or ibuprofen. Until then, the FDA guidelines remain the same: any NSAID, be it a non-selective NSAID such as naproxen or ibuprofen, as well as the COX-2 selective NSAID Celebrex, may increase cardiovascular risk.
[edit] Research into cancer prevention
The role that celecoxib might have in reducing the rates of certain cancers has been the subject of many studies. However, given the side effects of anti-COX-2 on rates of heart disease, there is no current medical recommendation to use this drug for cancer reduction.
- Colorectal cancer risk is clearly reduced in people regularly taking a NSAID like aspirin or celecoxib. In addition, some epidemiological studies, and most preclinical studies pointed out that specific COX-2 inhibitors like celecoxib are more potent and less toxic than "older" NSAIDs. Twelve carcinogenesis studies support that celecoxib is strikingly potent to prevent intestinal cancer in rats or mice (data available on the Chemoprevention Database). Small-scale clinical trials in very high risk people (belonging to FAP families) also indicate that celecoxib can prevent polyp growth. Hence large-scale randomized clinical trials were undertaken and results published by N.Arber and M.Bertagnolli in the New England Journal of Medicine, August 2006[1] Results show a 33 to 45% polyp recurrence reduction in people taking 0.4-0.8 g celecoxib each day. However, serious cardiovascular events were significantly more frequent in the celecoxib treated groups (see above, cardiovascular toxicity). Aspirin shows a similar (and possibly larger) protective effect,[11][12][13] has demonstrated cardioprotective effects and is significantly cheaper, but there have been no head-to-head clinical trials comparing the two drugs.
[edit] References
- Malhotra S, Shafiq N, Pandhi P (2004). COX-2 inhibitors: a CLASS act or Just VIGORously promoted. MedGenMed 6 (1), 6. PMID 15208519
- Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al (2000). Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 284 (10), 1247-55. PMID 10979111
- Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et al (2005). Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352 (11), 1071-80. PMID 15713944
[edit] Footnotes
- ^ Yelland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM (2007). "Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials". Rheumatology 46: 135–40. PMID 16777855.
- ^ CNBC.com (Feb 26, 2007). Pfizer's Celebrex Should Be 'Last Resort,' Heart Group Says. CNBC.com.
- ^ Bertagnolli M, Eagle C, Zauber A, Redston M, Solomon S, Kim K, Tang J, Rosenstein R, Wittes J, Corle D, Hess T, Woloj G, Boisserie F, Anderson W, Viner J, Bagheri D, Burn J, Chung D, Dewar T, Foley T, Hoffman N, Macrae F, Pruitt R, Saltzman J, Salzberg B, Sylwestrowicz T, Gordon G, Hawk E (2006). "Celecoxib for the prevention of sporadic colorectal adenomas.". N Engl J Med 355 (9): 873-84. PMID 16943400.
- ^ Arber N, Eagle C, Spicak J, Rácz I, Dite P, Hajer J, Zavoral M, Lechuga M, Gerletti P, Tang J, Rosenstein R, Macdonald K, Bhadra P, Fowler R, Wittes J, Zauber A, Solomon S, Levin B (2006). "Celecoxib for the prevention of colorectal adenomatous polyps.". N Engl J Med 355 (9): 885-95. PMID 16943401.
- ^ ADAPT Research Group. Public Library of Science (PloS) Clinical Trials 2006;e33:1-10.
- ^ Jenkins JK, Seligman PJ. (April 6, 2005). Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk [decision memorandum] (PDF). FDA Center for Drug Evaluation and Research.
- ^ Medication Guide for Non-steroidal Anti-inflammatory Drugs (NSAIDs). FDA (June 15, 2005).
- ^ Graham D, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray W (2005). "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 365 (9458): 475-81. PMID 15705456.
- ^ McGettigan P, Henry D (2006). "Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2.". JAMA 296 (13): 1633-44. PMID 16968831.
- ^ PRECISION : Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen. ClinicalTrials.gov. National Library of Medicine (December 7, 2006).
- ^ Baron JA, Cole BF, Sandler RS, et al. (2003). "A randomized trial of aspirin to prevent colorectal adenomas". N Engl J Med 348: 891–899. PMID 12621133.
- ^ Sandler RS, Halabi S, Baron JA, et al. (2003). "A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer". N Engl J Med 348: 883–90. PMID 12621132.
- ^ Bosetti C, Talamini R, Franceschi S, Negri E, Garavello W, La Vecchia C (2003). "Aspirin use and cancers of the upper aerodigestive tract". Brit J Cancer 88: 672-674. DOI:10.1038/sj.bjc.6600820.
[edit] External links
- Celebrex website run by Pfizer
- FDA Alert for Practitioners on Celebrex (celecoxib), published 17 December 2004
- Largest systematic review of adverse renal and arrhythmia risk of Celecoxib and other COX-2 inhibitors, in JAMA 2006
Salicylates: Aspirin (Acetylsalicylic Acid), Diflunisal, Ethenzamide
Arylalkanoic acids: Diclofenac, Indometacin, Sulindac
2-Arylpropionic acids (profens): Carprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Tiaprofenic acid
N-Arylanthranilic acids (fenamic acids): Mefenamic acid
Pyrazolidine derivatives: Phenylbutazone
Coxibs: Celecoxib, Etoricoxib, Parecoxib, Rofecoxib, Valdecoxib
Sulphonanilides: Nimesulide
Topically used products: Diclofenac, Flurbiprofen, Ibuprofen, Indometacin, Ketoprofen, Naproxen, Piroxicam
