Celecoxib

Celecoxib

Systematic (IUPAC) name
4-[5-(4-methylphenyl)-3-(trifluoromethyl) pyrazol-1-yl]benzenesulfonamide
Identifiers
CAS number	169590-42-5
ATC code	L01XX33 M01AH01
PubChem	CID 2662
DrugBank	APRD00373
ChemSpider	2562
Chemical data
Formula	C17H14F3N3O2S
Mol. mass	381.373 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	40%
Protein binding	97% (mainly to serum albumin)
Metabolism	Hepatic (mainly CYP2C9)
Half-life	~11 h
Excretion	Renal 27%, faecal 57%
Therapeutic considerations
Pregnancy cat.	B3(AU) C(US)
Legal status	℞ Prescription only
Routes	Oral
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Celecoxib (INN) (pronounced /sɛlɨˈkɒksɪb/) is a sulfa 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. It is known under the brand name Celebrex or Celebra for arthritis and Onsenal for polyps. Celecoxib is available by prescription in capsule form.

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 rectal polyps in patients with familial adenomatous polyposis. It was originally intended to relieve pain while minimizing the gastrointestinal adverse effects usually seen with conventional NSAIDs. In practice, 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 addition, the pain relief offered by celecoxib is similar to that offered by paracetamol (acetaminophen).^[1]

Fabricated efficacy studies

On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that 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 being exaggerated. Dr. Reuben was also a former paid spokesperson for Pfizer. The retracted studies were not submitted to either the FDA or the European Union's regulatory agencies prior to the drug's approval. 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." ^[2][3]

Availability

Pfizer sells celecoxib under the brand name Celebrex. Celecoxib is not currently available as a generic in the United States, because the intellectual property is still controlled by Pfizer. However, in other countries, including India and the Philippines, it is legally available as a generic under the brand names Cobix and Celcoxx.

XL Laboratories sells celecoxib under the brand name Selecap in Vietnam and the Philippines.

Pharmacology

Celecoxib is a highly selective COX-2 inhibitor and primarily inhibits this isoform of cyclooxygenase (and thus causes inhibition of prostaglandin production), whereas nonselective NSAIDs (like asprin and ibuprofen) inhibit both COX-1 and COX-2. Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1.^[4] It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site.^[5] 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 non-selective NSAIDs.

Celecoxib inhibits COX-2 without affecting COX-1. COX-1 is involved in synthesis of prostaglandins and thromboxane, but COX-2 is only involved in the synthesis of prostaglandin. Therefore, inhibition of COX-2 inhibits only prostaglandin synthesis without affecting thromboxane and thus has no effect on platelet aggregation or blood clotting.

Dosing

The usual adult dose of celecoxib is 100 to 200 mg once or twice a day. The lowest effective dose should be used.

Adverse effects

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).

Special precaution

Patients with prior history of ulcer disease or GI bleeding. Moderate to severe hepatic impairment, GI toxicity can occur with or without warning symptoms in patients treated with NSAIDs

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.

Risk of heart attack and stroke

There has been much concern about the possibility of increased risk for heart attack and stroke in users of NSAID drugs, particularly COX-2 selective NSAIDs such as celecoxib, since the withdrawal of the COX-2 inhibitor rofecoxib (Vioxx) in 2004. Like all NSAIDs on the U.S. market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association warned that celecoxib should be used "as a last resort on patients who have heart disease or a risk of developing it", and suggested that paracetamol (acetaminophen), or certain older NSAIDs, such as naproxen, may be safer choices for chronic pain relief in these patients.^[6]

The cardiovascular risks of celecoxib are controversial, with apparently contradictory data produced from different clinical trials. In December 2004, "APC", the first of two trials of celecoxib for colon cancer prevention, found that long-term (33 months) use of high-dose Celebrex (400 and 800 mg daily) demonstrated an increased cardiovascular risk compared with placebo.^[7] A similar trial, named PreSAP, did not demonstrate an increased risk.^[8] Still, the APC trial, combined with the recent Vioxx findings, suggested that there might be serious cardiovascular risks specific to the COX-2 inhibitors. On the other hand, a large Alzheimer's prevention trial, called ADAPT, was terminated early after preliminary data suggested that the nonselective NSAID naproxen, but not celecoxib, was associated with increased cardiovascular risk.^[9] In 2005, a study published in the Annals of Internal Medicine found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug.^[10] Other COX-2 selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib.^[11] In April 2005, after an extensive review of data, the FDA concluded that it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs".^[12] 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 non-selective NSAIDs or placebos.^[13]

Two studies on the cardiovascular risks of celecoxib and other NSAIDs were meta-analyses, published in 2006. The first of these, published in the British Medical Journal, looked at the incidence of cardiovascular events in all previous randomized controlled trials of COX-2 inhibitors, as well as some trials of other NSAIDs. The authors concluded that a significant increased risk did exist for celecoxib, as well as some other selective and nonselective NSAIDS. However, the increased cardiovascular risk in celecoxib was noted only at daily doses of 400 mg or greater.^[14] A second meta-analysis published in the Journal of the American Medical Association, which included observational rather than randomized studies (mostly at lower doses) did not find an increased cardiovascular risk of celecoxib vs placebo.^[15]

To establish more conclusively the true cardiovascular risk profile of celecoxib, Pfizer has agreed to fund a large, randomized trial specifically designed for that purpose. The trial, centered at the Cleveland Clinic, has a planned enrollment of 20,000 high-risk patients. Celecoxib will be compared with the non-selective NSAIDS naproxen and ibuprofen.^[16] 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 2013. Ultimately, this trial will help answer the question as to whether Celebrex has a riskier cardiovascular profile compared with naproxen or ibuprofen.

History

Celecoxib was developed by G. D. Searle & Company and 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 (Vioxx) from the market in September 2004, Celebrex 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 Vioxx, and Pfizer announced a moratorium on direct-to-consumer advertising of Celebrex soon afterwards. After a significant drop, sales of Celebrex have recovered, and reached $2 billion in 2006.^[6] Pfizer resumed advertising Celebrex in magazines in 2006,^[17] and resumed television advertising in April 2007 with an unorthodox, 2½ 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.^[18] Pfizer has 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 late 2007, Pfizer released another U.S. television ad for Celebrex, which also discussed celecoxib's adverse effects in comparison with those of other anti-inflammatory drugs.

Dr. Simmons of Brigham Young University, who discovered the COX-2 enzyme, is suing Pfizer to be credited with discovery of the technique in 1989 that eventually led to the drug, and for $1 billion USD, (The company has made about $30 billion from the drug as of 2006). ^[19]

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.^[7] Results show a 33 to 45% polyp recurrence reduction in people taking 400–800 mg 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,^[20][21][22] has demonstrated cardioprotective effects and is significantly cheaper, but there have been no head-to-head clinical trials comparing the two drugs.

Research into cancer treatment

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 ongoing to determine whether celecoxib might be useful for this latter condition.^[23] However, during molecular studies in the laboratory, it became apparent that celecoxib could interact with other intracellular components besides its most famous target, cyclooxygenase 2 (COX-2). The discovery of these additional targets has generated much controversy, and the initial assumption that celecoxib reduces tumor growth primarily via the inhibition of COX-2 became contentious.^[24]

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 that 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 don’t even contain COX-2.^[25]

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.^[26] Some of these analogs retained COX-2 inhibitory activity, whereas many others didn't. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, it turned out that the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing that inhibition of COX-2 was not required for the anticancer effects.^[26][27] One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually turned out to display stronger anticancer activity than celecoxib itself.^[28]

Research into adhesion prevention

Celocoxib may prevent intra-abdominal adhesion formation. Adhesions are a common complication of surgery, especially abdominal surgery, and major cause of bowel obstruction and infertility. Publishing in 2005, researchers in Boston noticed a "dramatic" reduction in post-surgical adhesions in mice taking the drug celecoxib.^[29] Multi-institutional trials in adult human patients are planned.^[30] The initially suggested course of treatment is a mere 7–10 days following surgery.^[31]

See also

• COX-2 selective inhibitor
• Cyclooxygenase 2 inhibitors: drug discovery and development

References

Sources

• Malhotra S, Shafiq N, Pandhi P (2004). "COX-2 inhibitors: a CLASS act or Just VIGORously promoted". Medscape General Medicine 6 (1): 6. PMID 15208519. PMC 1140734. http://www.medscape.com/viewarticle/47342. 
• Silverstein FE, Faich G, Goldstein JL, et al. (September 2000). "Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study". Journal of the American Medical Association 284 (10): 1247–55. doi:10.1001/jama.284.10.1247. PMID 10979111. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=10979111. 
• Solomon SD, McMurray JJ, Pfeffer MA, et al. (March 2005). "Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention". New England Journal of Medicine 352 (11): 1071–80. doi:10.1056/NEJMoa050405. PMID 15713944. 
• ^[5]

Notes

External links

• Celebrex website run by Pfizer
• FDA Alert for Practitioners on Celebrex (celecoxib), published December 17, 2004
• FDA Alert for Healthcare Professionals published July 4, 2005
• Largest systematic review of adverse renal and arrhythmia risk of Celecoxib and other COX-2 inhibitors, in JAMA 2006
• U.S. National Library of Medicine: Drug Information Portal - Celecoxib