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Erschienen in:
01.04.2000 | Adis Drug Evaluation
Celecoxib
A Review of its Use in Osteoarthritis, Rheumatoid Arthritis and Acute Pain
Erschienen in: Drugs | Ausgabe 4/2000
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Abstract
Celecoxib is a cyclo-oxygenase (COX) inhibitor that exhibits relative in vitro and ex vivo selectivity for COX-2 over COX-1.
Results of randomised double-blind multicentre studies indicate that celecoxib is superior to placebo and has similar efficacy as conventional nonsteroidal anti-inflammatory drugs (NSAIDs) in improving the signs and symptoms of osteoarthritis and rheumatoid arthritis. Analgesic efficacy and improvements in functional status are apparent within 2 weeks of starting therapy and are maintained throughout treatment. Available data suggest that celecoxib has analgesic efficacy in patients with postsurgical dental pain, although this is yet to be confirmed.
In patients with osteoarthritis of the knee, celecoxib 100 and 200mg and naproxen 500mg twice daily were similarly efficacious and superior to placebo. Once and twice daily celecoxib dosage regimens provided comparable efficacy. Improvements in physical function paralleled those in pain relief. Celecoxib also has efficacy in treating the signs and symptoms of osteoarthritis of the hip. The effects of celecoxib were not diminished in elderly patients with osteoarthritis of the hip or knee.
All dosages of celecoxib (100 to 400mg twice daily) and naproxen 500mg twice daily produced significant anti-inflammatory and analgesic effects in patients with active rheumatoid arthritis. In patients with stable rheumatoid arthritis, celecoxib 200mg twice daily showed sustained symptomatic improvements similar to those of twice daily slow-release diclofenac 75mg over a 24-week period.
Celecoxib was well tolerated in clinical trials. Upper gastrointestinal complications occurred in significantly fewer patients treated with twice daily celecoxib 25 to 400mg than in those receiving comparator NSAIDs. There was no evidence of a dose relationship in endoscopic ulcer development and incidences in celecoxib and placebo recipients were lower than in those receiving twice daily naproxen 500mg or ibuprofen 800mg 3 times daily.
Conclusions: Celecoxib is the first COX-2 specific inhibitor approved for use in osteoarthritis and rheumatoid arthritis. Celecoxib produces significant improvements in pain and inflammation and these effects are maintained during treatment for up 24 weeks in clinical trials. Studies indicate that celecoxib has similar efficacy to conventional NSAIDs in relieving pain and improving functional status, but is associated with a lower incidence of upper gastrointestinal ulceration and complications. This promising gastrointestinal safety profile, together with sustained symptomatic relief, places celecoxib as a useful alternative for the treatment of osteoarthritis and rheumatoid arthritis, particularly in patients at high risk of developing gastrointestinal events. Although data are encouraging, its place in acute pain states remains to be established.
Pharmacodynamic Properties
Celecoxib is a cyclo-oxygenase (COX) inhibitor that exhibits clinically meaningful relative (375-fold) selectivity for COX-2 over COX-1. In human whole blood assays, celecoxib suppressed lipopolysaccharide (LPS)-stimulated prosta-glandin (PG)E2 formation but had no effect on serum thromboxane (Tx)B2 levels at therapeutic doses.
Administration of celecoxib produced analgesic and anti-inflammatory effects similar to those of comparator nonsteroidal anti-inflammatory drugs (NSAIDs) in rodent models of arthritis and pain.
Celecoxib produced less gastrointestinal (GI) damage than comparator NSAIDs in a single dose study in rats with gastric damage, and after repeated administration in dogs and human volunteers with endoscopically normal GI mucosa.
Single and multiple administration of celecoxib at supratherapeutic dosages (up to 1200mg) had no effect on collagen- and arachidonate-induced platelet aggregation or bleeding time in humans.
In elderly volunteers, twice daily celecoxib 400mg appeared to have little effect on renal haemodynamic function although reductions in PGE2, 6-keto-PGF1α and sodium excretion (transient decrease of 30%) were similar to those of naproxen 500mg.
Pharmacokinetic Properties
After oral administration of a single 200mg dose, a mean maximum plasma celecoxib concentration (Cmax) of 705 μg/L was reached after 2.8 hours. Cmax and the area under the plasma concentration-time curve increased linearly over the therapeutic dose range of 100 to 200mg. Steady state plasma levels were reached within 5 days in multiple dose studies.
Celecoxib is 97% bound to plasma proteins and has an apparent volume of distribution at steady-state of approximately 400L. The drug undergoes extensive hepatic metabolism via cytochrome P450 (CYP)2C9, forming inactive metabolites. Approximately 27% of the administered dose is eliminated in the urine and 58% in the faeces. A mean effective half-life of 11.2 hours has been reported.
Therapeutic Efficacy
Celecoxib 50, 100 and 200mg twice daily and 200mg once daily significantly improved the signs and symptoms of osteoarthritis of the knee compared with placebo. There were no apparent differences in efficacy between once and twice daily dosage regimens. The onset of symptomatic relief occurred within 24 to 48 hours of starting treatment and analgesic efficacy and functional improvements were sustained during treatment for 6 or 12 weeks. Twice daily celecoxib 100 and 200mg had efficacy similar to that of naproxen 500mg, administered twice daily.
Preliminary reports of a double-blind study indicate that celecoxib is also effective in treating the signs and symptoms of osteoarthritis of the hip.
Double-blind studies have compared the efficacy of celecoxib 100 to 400mg with that of naproxen 500mg or slow-release diclofenac 75mg, administered twice daily, in patients with rheumatoid arthritis. All drugs significantly improved pain, the number of swollen joints and the duration of morning stiffness compared with placebo. The effects of twice daily celecoxib 200mg were maintained for 24 weeks in patients with stable rheumatoid arthritis and were similar to those of slow-release diclofenac 75mg twice daily.
In abstract reports, the analgesic efficacy of a single dose of celecoxib 100 to 400mg was superior to placebo but similar to that of aspirin 650mg in patients with moderate to severe pain after third molar extraction. However, celecoxib 200mg was less effective than ibuprofen 400mg. Celecoxib 200mg produced greater pain relief than hydrocodone 10mg/paracetamol (acetaminophen) 1000mg in a 5-day postorthopaedic surgery analgesia study.
Upper Gastrointestinal Safety
The annualised incidence of upper GI complications, in the presence of a confirmed upper GI mucosal lesion, was 8-fold lower in patients receiving celecoxib 25 to 400mg twice daily (0.20%) than those receiving comparator NSAIDs (1.68%).
Endoscopic ulcer rates in patients receiving twice daily celecoxib 50 to 400mg in 12- and 24-week studies were not significantly different from that in placebo groups. Comparator NSAID treatment was associated with a 2.5-to 4-fold higher incidence of gastroduodenal ulceration than celecoxib treatment.
Tolerability
Celecoxib was generally well tolerated during clinical trials and adverse events were not dose-related. The potential for cross-allergenicity with sulfonamide-containing drugs was similar among celecoxib, nonsulfonamide-containing NSAIDs and placebo groups.
The incidence of renal adverse events with celecoxib was similar to that of comparator NSAIDs but significantly higher than with placebo (4.4, 4.1 and 2.5%, respectively). The cumulative incidence of upper GI adverse events (abdominal pain, dyspepsia and nausea) in a pooled analysis of 12-week studies was lower with placebo (8.5%) and celecoxib 50 to 400mg twice daily (6.0 to 8.1%) than with naproxen 500mg twice daily (12.0%).
Dosage and Administration
The recommended oral dosage of celecoxib in patients with osteoarthritis is 200 mg/day, administered in 1 or 2 doses. In adults with rheumatoid arthritis, the recommended dosage is 100 to 200mg twice daily. Dosages should be reduced by approximately 50% in patients with moderate hepatic impairment.
Celecoxib should not be used during the third trimester of pregnancy or in patients with a history of allergic-type reactions after administration of other NSAIDs or sulfonamides. Treatment should proceed with caution in patients with a history of ulcer disease or GI complications, and in those with fluid retention, hypertension or heart failure.
Postmarketing surveillance has identified a small number of episodes of elevated prothrombin times in patients receiving concomitant celecoxib and warfarin. Anticoagulant efficacy should be monitored in patients receiving concomitant celecoxib and anticoagulants because of the increased risk of bleeding complications.