CELECOXIB

SUMMARY SHEET

PDF VERSION OF SUMMARY SHEET AVAILABLE

TRADE NAME: Celebrex®

A COX-2 specific NSAID for the treatment of osteoarthritis & rheumatoid arthritis

 

Licensed Indication:

Symptomatic relief in the treatment of osteoarthritis or rheumatoid arthritis.

 

Background information

Osteoarthritis (OA) is a heterogenous group of overlapping pathological conditions causing damage to the articular cartilage and leading to clinically & radiographically recognised impairment of the joints and disability of the patient.1

OA is common. The estimated prevalence of severe radiographic disease is 2%, 30% and 68% for women aged <45, 45-64 and over 65 years and 3%, 24.5% and 58% respectively in men.1,2

Rheumatoid arthritis (RA) affects approximately 1-2% of adults in the UK.3 It is a chronic disabling condition. The clinical hallmark of RA is persistent synovial inflammation of peripheral joints which results in some degree of irreversible joint damage in the majority of patients. In addition many other tissues may be affected. In severe disease life expectancy may be reduced by up to 10 years.3-5

 

Current treatment options

In OA, treatment is symptomatic and individualised to patients needs. Non-steroidal anti-inflammatory drugs (NSAIDs) are only used if non-pharmacological therapy and paracetamol fail to provide adequate symptom relief.1 Other treatment options include intra-articular injections of corticosteroids or hyaluronan, topical analgesics and finally surgery.1

In RA, conventional pharmacological management falls into 2 broad categories – disease modifying therapy and symptomatic relief. Disease modifying anti-rheumatic drugs (DMARDs) are now used aggressively early in the disease process before erosions develop. They are used to suppress the disease and prevent further progression and joint damage. NSAIDs represent the mainstay of symptomatic treatment in RA. They are taken by most patients either alone or in combination with analgesics, or DMARDs.3,6

 

COX-2

All NSAIDs act on the cyclo-oxygenase (COX) enzyme to inhibit prostaglandin synthesis. This enzyme exists in at least two isoforms; COX-1 and COX-2. The COX-1 enzyme maintains a normal gastric mucosa, whilst COX-2 is seen at sites of inflammation, the brain and colon cancer cells. Conventional NSAIDs are non-selective COX-inhibitors. Celecoxib acts primarily on COX-2.7

 

Dosage and administration

Celecoxib is administered orally. In OA the recommended dose is 200mg daily; given either as a single daily dose or in two divided doses. A dose of 200mg twice daily may be used if needed.

In RA the licensed dose is 100-200mg twice a day.

In black patients and those > 65 years of age, the lowest dose of 200mg per day should be used initially.

Other dosage restrictions are listed in the Summary of Product Characteristics (SPC).8

 

Clinical Efficacy

A total of 22 phase II/III clinical efficacy studies have evaluated the use of celecoxib. Eight evaluated use in OA, 4 in RA and 2 trials enrolled patients with OA or RA. These trials were all double-blind, randomised, controlled studies conducted over 2-24 weeks, 9 of which compared celecoxib to conventional NSAIDs (naproxen, diclofenac and ibuprofen). In total 7,238 patients with OA and 3,672 with RA were enrolled in these trials; 6321 received celecoxib; 2744 a NSAID and 1845 placebo. Abstract reports and fully published papers are only available for 6 of these trials.9-16 Data for all trials are provided in the FDA-New Drug Application.17

In the OA trials, the primary endpoints evaluated were patients and physicians global assessments, patients assessment of arthritis pain by visual analogue scale and the Western Ontario and McMaster Universities (WOMAC) OA index*. Celecoxib ³ 100mg bd demonstrated significant efficacy compared to placebo and comparable efficacy to naproxen 500mg bd in all the primary and secondary endpoints.9-12,17

In the RA trials, the primary endpoints evaluated were patients and physicians global assessments, number of tender or painful joints, number of swollen joints and the American College of Rheumatology 20% responder index (ACR20)*. Overall celecoxib ³ 100mg bd demonstrated improved efficacy compared to placebo, and comparable efficacy to naproxen 500mg bd or diclofenac SR 75mg bd.12-15, 17 A long term, open label study, which is yet to be published, suggests - that continued efficacy is seen over 1 – 2 years.17

 

Adverse Effects

Over 8000 patients have been exposed to celecoxib in the arthritis clinical trial programme. The majority of patients received treatment for less than 1 year. The most common adverse events seen were fluid retention, dyspepsia, abdominal pain, flatulence, diarrhoea, dizziness, insomnia, sinusitis, pharyngitis, rhinitis, upper respiratory tract infection and rash. Across the trials, skin rashes were the most common reason for withdrawal.17

Gastrointestinal adverse events have been evaluated in detail. Six clinical trials conducted endoscopies. At the wide range of doses studied (50-400mg bd) celecoxib treatment was consistently associated with a significantly lower incidence of endoscopic gastro-duodenal ulcers than naproxen 500mg bd (6-9% vs 19-26%, p < 0.05) and ibuprofen 800mg tds (9% vs 28%, p < 0.05). Inconsistent results were seen compared to diclofenac.12,14,15,18

Endoscopic ulcers represent a surrogate marker. In the arthritis clinical trial programme 21 clinically significant upper gastrointestinal events were recorded. Due to the small number of events seen, no valid conclusions can be drawn.17,19 Post-launch experience in the USA confirms that whilst celecoxib might be associated with reduced gastrointestinal side effects, it is not without risk for these events.20

Other adverse events seen with celecoxib include renal events similar to those seen with conventional NSAIDs; cardiovascular events, e.g. hypertension and clinically significant oedema.17 Celecoxib does not appear to have any effect on platelet function and bleeding time.17 However, serious bleeding events have occurred in patients on concurrent warfarin therapy. Careful monitoring of these patients is therefore required. Other potential drug interactions are listed in the SPC.

 

Costs

At current prices, one year’s treatments costs:

Celecoxib may be associated with reduced gastrointestinal adverse events. It has been estimated that for low-risk patients 500 patients would need to be treated with a COX-2 specific NSAID to avoid one NSAID induced ulcer complication. The additional cost to avoid such an event using celecoxib is £187,000. For high risk patients, 40 patients would need to be treated to avoid one NSAID induced ulcer complication. The additional cost to avoid such an event is £14,960. Data on use in high-risk patients are limited.21

 

Summary

Celecoxib is the second COX-2 specific inhibitor to be launched in the UK. It is licensed for the symptomatic treatment of both OA and RA. Over 14 clinical efficacy trials have been undertaken with celecoxib in patients with OA or RA. In the short term comparative trials, celecoxib demonstrated improved efficacy to placebo and comparable efficacy to naproxen and diclofenac.

The adverse event profile of celecoxib appeared more like that of the comparator NSAIDs studied than placebo. Celecoxib was however associated with a reduced incidence of endoscopic gastroduodenal ulcers compared to naproxen and high dose ibuprofen. The clinical significance of this not yet known. The published results of a long-term prospective trial are awaited.

*The WOMAC index & ACR20 responder index were secondary endpoints in some trials.

 

References

  1. Creamer P, Hochberg M. Osteoarthritis. Lancet 1997;350:503-9.
  2. Cicuttini F, Spector TD. Osteoarthritis. Medicine 1998;26:68-71.
  3. Anon. Modifying disease in rheumatoid arthritis. DTB 1998;36:3-6.
  4. Buckley C. Treatment of rheumatoid arthritis. BMJ 1997;315:236-8.
  5. Vandenbroucke JP, Hazevoet HM, Cats. Survival and cause of death in rheumatoid arthritis: a 25 year prospective follow-up. J Rheumatol 1984;11:158-61.
  6. Brooks P. Rheumatology. BMJ 1998;316:1810-2.
  7. Hawkey CJ. COX-2 inhibitors. Lancet 1999;353:307-14.
  8. Anon. Celebrex. Summary of Product Characteristic. Searle & Pfizer, May 2000
  9. Hubbard RC et al. SC-58635 (celecoxib), a novel COX-2 selective inhibitor, is effective as a treatment for osteoarthritis(OA) in a short-term pilot study. Arthritis Rheum 1996; 39:S226 Abstract 1188.
  10. Hubbard RC et al. A pilot study of the efficacy of SC-58635, a novel COX-2-selective inhibitor, in treating osteoarthritis. 19th ILAR Congress of Rheumatology Singapore 8th-13th June 1997 1997;46 (Abstract).
  11. Bensen W et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: A randomized controlled trial. Mayo Clin Proc 1999;74:1095-105.
  12. Simon LS 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.
  13. Hubbard RC, Koepp R, Yu SS, Talwalker S, Geis GS. Pilot efficacy of SC-58635, a COX-2-selective inhibitor, in rheumatoid arthritis 1997. Arthritis Rheum 1997;40:s51 Abstract 125.
  14. Simon LS, et al. Anti-inflammatory and Upper Gastrointestinal Effects of Celecoxib in Rheumatoid Arthritis. JAMA 1999;282:1921-8.
  15. Emery P et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999;354:2106-11.
  16. Hubbard RC et al. A highly selective inhibitor of COX-2, is an effective analgesic in an acute post-surgical pain model. J Invest Med 1996;44:293A.
  17. Anon. Celecoxib. FDA-NDA 1998;20-998:1-225.
  18. Lanza FL et al. A pilot endoscopic study of the gastroduodenal effects of SC-58635, a novel COX-2 selective inhibitor. Gastroenterology 1997;112:A194.
  19. Goldstein JL et al. Celecoxib is associated with a significantly lower incidence of clinically significant upper gastrointestinal (UGI) events in osteoarthritis (OA) and rheumatoid arthritis (RA) patients as compared to NSAIDs. Gastroenterology 1999;116:Abstract G0758.
  20. Singh G, Ramey DR, Triadafilopoulos G. Early experience with selective COX-2 inhibitors: safety profile in over 340,000 patient years of use. Arthritis Rheum 1999;42:Abstract 1352.
  21. Peterson WL, Cryer B. COX-1-sparing NSAIDs - is the enthusiasm justified. JAMA 2000;282:1961-3.
Date: April 2000

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© MTRAC, Department of Medicines Management