Abstract
Aims
A post-marketing surveillance study using the technique of Prescription Event Monitoring was undertaken to monitor the safety of celecoxib, a cyclo-oxygenase (COX)-2 inhibitor, as prescribed in primary care in England.
Methods
Patients were identified from dispensed British National Health Service prescription data supplied in confidence by the Prescription Pricing Authority for celecoxib between May and December 2000. Simple questionnaires were sent to the prescribing general practitioner at least 6 months after the date of the first dispensed prescription for each individual patient. Event incidence densities (IDs) [the number of 1st reports per 1000 patient-months of exposure (pme)] were calculated. ID differences for events reported in month 1 (ID1) and months 2–6 (ID2) were examined for temporal changes in event rate. Information on suspected adverse drug reactions (ADRs), reasons for stopping treatment, outcome of pregnancies and cause of death were also requested. Data were gathered on potential gastrointestinal (GI) risk factors [recent use of other non-steroidal anti-inflammatory drugs (NSAIDs), past history of upper GI disorders and concomitant gastro-irritant agents or anti-ulcer drugs]. Crude IDs per 1000 pme and ID ratios were calculated according to potential risk factors, and age (≥65 years, ≤64 years).
Results
The cohort comprised of 17,458 patients [median age 62 years (IQR 51,73); 68.3% female]. The most common specified indication was osteoarthritis (28.1%, n=4905). Not effective was the event with the highest ID1 (139.9 per 1000 pme). The clinical events with the highest ID1 were dyspepsia (25.4 per 1000 pme) followed by abdominal pain (10.6). These were also given frequently as reasons for stopping (551 and 174 of 9126 reports). Of 436 events in 325 patients (1.9% of total cohort) that were reported as ADRs, the most frequent were events within the alimentary system (186 reports). Uncommon events reported during treatment (not necessarily as ADRs) included allergy (0.10%, n=17), anaphylaxis (0.01%, n=2), angioneurotic oedema (0.02%, n=3) and bronchospasm (0.05%, n=9). There were 103 reports of events associated with thromboembolism and 111 reports of serious GI events [90 GI bleeds (upper and lower); 21 peptic ulcers] received during treatment or within 1 month of stopping. A past history of dyspeptic/other upper GI conditions and use of concomitant gastro-protective drugs were each associated with a significantly increased risk of dyspepsia and abdominal pain.
Conclusions
Frequently reported adverse events were those GI events commonly associated with treatment with other NSAIDS. Stratification by identified risk factors suggested that channelling of high-risk patients is likely. Serious upper and lower GI events, and thromboembolic events did occur during this study, although the incidence was low (<1%). Doctors should continue to prescribe NSAIDs, including COX-2-specific inhibitors, with caution.
Similar content being viewed by others
Notes
Unspecified—no event term currently exists within DSRU dictionary
References
Anonymous (2000) Summary of product characteristics: Celebrex (celecoxib). Searle/Pfizer
FitzGerald GA, Patrono C (2001) The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 345:433–442
Kam PC, See AU (2000) Cyclo-oxygenase isoenzymes: physiological and pharmacological role. Anaesthesia 55:442–449
Ehrich EW, Dallob A, De L, I, Van Hecken A, Riendeau D, Yuan W et al (1999) Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 65:336–347
Williams GW, Hubbard RC, Yu SS, Zhao W, Geis GS (2001) Comparison of once-daily and twice-daily administration of celecoxib for the treatment of osteoarthritis of the knee. Clin Ther 23:213–227
Bensen WG, Fiechtner JJ, McMillen JI, Zhao WW, Yu SS, Woods EM et al (1999) Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 74:1095–1105
Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC et al (1999) Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 282:1921–1928
Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H et al (1999) Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 354:2106–2011
Shakir SA (2002) PEM in the UK. In: Mann RD, Andrews E (eds) Pharmacovigilance, 1st edn. John Wiley and Sons Ltd., Chichester, pp 333–344
Mann RD (1998) Prescription-event monitoring—recent progress and future horizons. Br J Clin Pharmacol 46:195–201
Legemaate J (1994) The CIOMS guidelines for biomedical research involving human subjects. Eur J Health Law 1:161–165
Royal College of Physicians of London (1996) Guidelines on the practice of ethical committees in medical research involving human subjects. Royal College of Physicians of London, London
Anonymous (2000) Multi-centre research ethics committees guidance notes. Examples of enquiries and surveys in the public interest where no reference to a Research Ethics Committee is necessary. Web address:http://www.corec.org.uk/wordDocs/Guidenotes.doc. Report no. appendix C
Layton D, Riley J, Wilton LW, Shakir S (2002) Safety profile of rofecoxib as used in general practice in England: results of a prescription-event monitoring study. Br J Clin Pharmacol 55:166–174
Shakir SAW (2004) Causality and correlation in pharmacovigilance. In: Talbot J, Waller PC (eds) Stephens’ detection of new adverse drug reactions, 5th edn. John Wiley and Sons Ltd., Chichester, pp 329–343
Stephens MD (1987) The diagnosis of adverse medical events associated with drug treatment. Adverse Drug React Acute Poisoning Rev 6:1–35
Campbell M, Daly L, Machin D (2000) Special topics. In: Altman D, Machin D, Bryant T, Gardner MJ (eds) Statistics with confidence, 2nd edn. BMJ Books, Bristol
Strom B (1994) Sample size considerations for pharmacoepidemiology studies. In: Strom B (ed) Pharmacoepidemiology, 2nd edn. John Wiley and Sons, Chichester
Machin D, Campbell M, Fayers P et al (1997) Sample size tables for clinical studies. Table 7.1. Blackwell Science Ltd., Oxford
Machin D, Campbell M, Fayers P et al (1997) Sample size tables for clinical studies. Table 7.2. Blackwell Science Ltd., Oxford
Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ (1999) Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther 21:1653–1663
Heeley E, Riley J, Layton D, Wilton LV, Shakir SA (2001) Prescription-event monitoring and reporting of adverse drug reactions. Lancet 358:1872–1873
Meyboom RH, Egberts AC, Edwards IR, Hekster YA, de Koning FH, Gribnau FW (1997) Principles of signal detection in pharmacovigilance. Drug Saf 16:355–365
McAvoy BR, Kaner EF (1996) General practice postal surveys: a questionnaire too far? BMJ 313:732–733
Templeton L, Deehan A, Taylor C, Drummond C, Strang J (1997) Surveying general practitioners: does a low response rate matter? Br J Gen Pract 47:91–94
Deehan A, Templeton L, Taylor C, Drummond C, Strang J (1997) The effect of cash and other financial inducements on the response rate of general practitioners in a national postal study. Br J Gen Pract 47:87–90
Key C, Layton D, Shakir SA (2002) Results of a postal survey of the reasons for non-response by doctors in a prescription event monitoring study of drug safety. Pharmacoepidemiol Drug Saf 11:143–148
Wensing M, Mainz J, Kramme O, Jung HP, Ribacke M (1999) Effect of mailed reminders on the response rate in surveys among patients in general practice. J Clin Epidemiol 52:585–587
Stephens MD (2004) Introduction. In: Stephens MD (ed) Stephens’ detection of new adverse drug reactions, 5th edn. John Wiley and Sons Ltd., Chichester, pp 1–90
Simon LS, Strand V (1997) Clinical response to nonsteroidal antiinflammatory drugs. Arthritis Rheum 40:1940–1943
Tive L (2000) Celecoxib clinical profile. Rheumatology (Oxford) 39[Suppl 2]:21–28
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. Celecoxib long-term arthritis safety study. JAMA 284:1247–1255
McCarthy DM (1999) Comparative toxicity of nonsteroidal anti-inflammatory drugs. Am J Med 107:37S–46S
Juni P, Rutjes AW, Dieppe PA (2002) Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 324:1287–1288
Geis GS (2002) Are selective COX 2 inhibitors superior to traditional NSAIDs? Pharmacia’s response to editorial. BMJ 325:161
Hansen JM, Hallas J, Lauritsen JM, Bytzer P (1996) Non-steroidal anti-inflammatory drugs and ulcer complications: a risk factor analysis for clinical decision-making. Scand J Gastroenterol 31:126–130
Wolfe MM, Lichtenstein DR, Singh G (1999) Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340:1888–1899
Laine L (2001) Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 120:594–606
Anonymous (2003) Serious gastrointestinal effects with celecoxib and rofecoxib. Australian adverse drug reactions advisory committee (ed) Australian Adverse Drug Reactions Bulletin 22:15
Garcia Rodriguez LA (1997) Nonsteroidal antiinflammatory drugs, ulcers and risk: a collaborative meta-analysis. Semin Arthritis Rheum 26[Suppl 1]:16–20
Deeks JJ, Smith LA, Bradley MD (2002) Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ 325:619
Mamdani M, Rochon PA, Juurlink DN, Kopp A, Anderson GM, Naglie G et al (2002) Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 325:624
Martin RM, Biswas P, Mann RD (2000) The incidence of adverse events and risk factors for upper gastrointestinal disorders associated with meloxicam use amongst 19,087 patients in general practice in England: cohort study. Br J Clin Pharmacol 50:35–42
Wolfe F, Flowers N, Burke TA, Arguelles LM, Pettitt D (2002) Increase in lifetime adverse drug reactions, service utilization, and disease severity among patients who will start COX-2 specific inhibitors: quantitative assessment of channeling bias and confounding by indication in 6689 patients with rheumatoid arthritis and osteoarthritis. J Rheumatol 29:1015–1022
Layton D, Hughes K, Harris S, Shakir SA (2003) Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed celecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology (Oxford) 42:1332–1341
Layton D, Heeley E, Hughes K, Shakir SA (2003) Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring data. Rheumatology (Oxford) 42:622–631
Layton D, Hughes K, Harris S, Shakir SA (2003) Comparison of the incidence rates of thromboembolic events reported for patients prescribed celecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology (Oxford) 42:1354–1365
Layton D, Heeley E, Hughes K, Shakir SA (2003) Comparison of the incidence rates of thromboembolic events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology (Oxford) 42:1342–1353
Kaufmann HJ, Taubin HL (1987) Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 107:513–516
Lipsky PE, Brooks P, Crofford LJ, DuBois R, Graham D, Simon LS et al (2000) Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease. Arch Intern Med 160:913–920
Lipsky PE, Abramson SB, Breedveld FC, Brook P, Burmester R, Buttgereit F et al (2000) Analysis of the effect of COX-2 specific inhibitors and recommendations for their use in clinical practice. J Rheumatol 27:1338–1340
Wallace JL (1999) Distribution and expression of cyclooxygenase (COX) isoenzymes, their physiological roles, and the categorization of nonsteroidal anti- inflammatory drugs (NSAIDs). Am J Med 107:11S–16S
Anonymouse (2001) Food and Drug Administration advisory committee. Cardiovascular safety review of rofecoxib.http://www fda gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio pdf 2001. Cited 8 September 2001
Freston JW (1999) Rationalizing cyclooxygenase (COX) inhibition for maximal efficacy and minimal adverse events. Am J Med 107:78S–88S
Crofford LJ, Oates JC, McCune WJ, Gupta S, Kaplan MJ, Catella-Lawson F et al (2000) Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors. A report of four cases. Arthritis Rheum 43:1891–1896
Cleland LG, James MJ, Stamp LK, Penglis PS (2001) COX-2 inhibition and thrombotic tendency: a need for surveillance. Med J Aust 175:214–2147
Clark DW, Layton D, Shakir SAW (2004) Do some inhibitors of cyclooxygenase-2 (COX-2) increase the risk of thromboembolic events? Linking pharmacology with pharmacoepidemiology. Drug Saf (in press)
Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS (2000) Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 40:124–132
White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM et al (2002) Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 89:425–430
White WB, Faich G, Borer JS, Makuch RW (2003) Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 92:411–418
Ray W, Stein C, Daugherty J, Hall K, Arbogast P, Griffin M (2002) COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 360:1071
Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G et al (2003) Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 163:481–486
Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B et al (2001) Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 345:1809–1817
Whelton A, Fort JG, Puma JA, Normandin D, Bello AE, Verburg KM (2001) Cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 8:85–95
Whelton A, Maurath CJ, Verburg KM, Geis GS (2000) Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am J Ther 7:159–175
Alkhuja S, Menkel RA, Alwarshetty M, Ibrahimbacha AM (2002) Celecoxib-induced nonoliguric acute renal failure. Ann Pharmacother 36:52–54
Crofford LJ, Lipsky PE, Brooks P, Abramson SB, Simon LS, van de Putte LB (2000) Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum 43:4–13
Schellenberg RR, Isserow SH (2001) Anaphylactoid reaction to a cyclooxygenase-2 inhibitor in a patient who had a reaction to a cyclooxygenase-1 inhibitor. N Engl J Med 345:1856
Dahlen B, Szczeklik A, Murray JJ (2001) Celecoxib in patients with asthma and aspirin intolerance. The celecoxib in aspirin-intolerant asthma study group. N Engl J Med 344:142
Gyllfors P, Bochenek G, Overholt J, Drupka D, Kumlin M, Sheller J et al (2003) Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2-selective analgetic drug celecoxib. J Allergy Clin Immunol 111:1116–1121
Tredger JM, Stoll S (2002) Cytochromes P450—their impact on drug treatment. Hospital Pharmacist 9:167–173
O’Beirne JP, Cairns SR (2001) Drug points: cholestatic hepatitis in association with celecoxib. BMJ 323:23
Alegria P, Lebre L, Chagas C (2002) Celecoxib-induced cholestatic hepatotoxicity in a patient with cirrhosis. Ann Intern Med 137:75
Carrillo-Jimenez R, Nurnberger M (2000) Celecoxib-induced acute pancreatitis and hepatitis: a case report. Arch Intern Med 160:553–554
Garcia Rodriguez LA, Perez GS, Walker AM, Lueck L (1992) The role of non-steroidal anti-inflammatory drugs in acute liver injury. BMJ 305:865–868
Arellano FM, Zhao SZ, Reynolds MW (2002) Case of cholestatic hepatitis with celecoxib did not fulfil international criteria. BMJ 324:789
Knowles S, Shapiro L, Shear NH (2001) Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of ‘sulfa’ allergy. Drug Saf 24:239–247
Wiholm BE (2001) Identification of sulfonamide-like adverse drug reactions to celecoxib in the World Health Organization database. Curr Med Res Opin 17:210–216
Mohammed S, Croom DW (1999) Gastropathy due to celecoxib, a cyclooxygenase-2 inhibitor. N Engl J Med 340:2005–2006
Schneider F, Meziani F, Chartier C, Alt M, Jaeger A (2002) Fatal allergic vasculitis associated with celecoxib. Lancet 359:852–853
Kelkar PS, Butterfield JH, Teaford HG (2001) Urticaria and angioedema from cyclooxygenase-2 inhibitors. J Rheumatol 28:2553–2554
Gill S, Hermolin R (2001) Case report of a Stevens-Johnson type reaction to celecoxib. Can J Hosp Pharm 54:146
Grob M, Pichler WJ, Wuthrich B (2002) Anaphylaxis to celecoxib. Allergy 57:264–265
Ernst EJ, Egge JA (2002) Celecoxib-induced erythema multiforme with glyburide cross-reactivity. Pharmacotherapy 22:637–640
Mehandru S, Smith RL, Sidhu GS, Cassai N, Aranda CP (2002) Migratory pulmonary infiltrates in a patient with rheumatoid arthritis. Thorax 57:465–467
CARM (2002) Acute psychiatric events with COX-2 inhibitors
Anonymous (2003) Acute neuropsychiatric events with celecoxib and rofecoxib. Australian adverse drug reactions advisory commitee (ed) Australian Adverse Drug Reactions Bulletin 22:3
Lund BC, Neiman RF (2001) Visual disturbance associated with celecoxib. Pharmacotherapy 21:114–115
Coulter DM, Clark DW, Savage RL (2003) Celecoxib, rofecoxib, and acute temporary visual impairment. BMJ 327:1214–1215
Anonymous (2003) Meeting of the committee for proprietary medicinal products (CPMP). Press release. Doc Ref: EMEA/CPMP/5732/03. Web address:http://www.emea.eu.int/htms/hotpress/h573203.htm. The European Agency for the Evaluation of Medicinal Products (EMEA) 21 November 2003. Cited 25 November 2003
Anonymous (2001) National institute of clinical excellence. guidance on use of cyclo-oxygenase (COX II) selective inhibitors celecoxib, rofecoxib, meloxicam and etodoloac for osteoarthritis and rheumatoid arthritis. Report No. Technology Appraisal No.27. Department of Health, London
Acknowledgments
We would like to record our keen appreciation of the co-operation of the general practitioners and numerous other colleagues who have helped in this investigation. We would also like to thank for their important participation: The Prescription Pricing Authority, The Health Authorities of England and The Office for National Statistics. The Drug Safety Research Unit is an independent charity (no. 327206), which works in association with the University of Portsmouth. It receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. The Unit has received such funds from the manufacturer of celecoxib. S.A.S. has received lecture fees and support to attend scientific conferences from Pfizer.
Author information
Authors and Affiliations
Corresponding author
Additional information
Conflict of interest. The Drug Safety Research Unit is an independent charity (No. 327206), which works in association with the University of Portsmouth. It receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. The Unit has received such funds from the manufacturer of celecoxib. SAS has received lecture fees and support to attend scientific conferences from Pfizer.
Rights and permissions
About this article
Cite this article
Layton, D., Wilton, L.V. & Shakir, S.A.W. Safety profile of celecoxib as used in general practice in England: results of a prescription-event monitoring study. Eur J Clin Pharmacol 60, 489–501 (2004). https://doi.org/10.1007/s00228-004-0788-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-004-0788-2