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Trial Confirms Overall Benefits of Prexige (Lumiracoxib) Over NSAIDs in Combined Gastrointestinal and Cardiovascular Safety: Presented at UEGW

PRAGUE, CZECH REPUBLIC -- September 29, 2004 -- Recent data presented during United European Gastroenterology Week (UEGW) in Prague, from the largest GI safety outcomes trial ever conducted in osteoarthritis (OA), confirm that in a representative OA population Prexige® (lumiracoxib) shows a class-leading combined gastrointestinal (GI) and cardiovascular (CV) safety profile when compared with nonsteroidal anti-inflammatory drugs (NSAIDs) in an outcomes study1. The data represent the key findings from the landmark TARGET study (Therapeutic Arthritis Research & Gastrointestinal Event Trial of lumiracoxib).

Serious GI events are the most frequent side effects in patients treated with NSAIDs and are estimated to lead to 7,6004 deaths annually in the U.S. alone. "There was a 79% reduction in the incidence of GI ulcer complications (the primary endpoint) when patients not taking aspirin were given lumiracoxib, compared to non-selective NSAIDs (ibuprofen and naproxen). A reduction of this magnitude has not been demonstrated with any other COX-2 inhibitor in an outcomes study", said Chris Hawkey, Professor of Gastroenterology and Co-director of the Institute of Clinical Research, University of Nottingham (UK) and Chairman of the GI committee during the TARGET trial. "Whilst one must be cautious about the possible reasons, the evidence of such GI benefit is more clear cut for lumiracoxib than other COX-2 inhibitors and this should influence prescribing choice when a selective COX-2 inhibitor is needed."

Class-leading GI safety
Prexige is the most selective COX-2 inhibitor clinically developed to date3 and the only one to demonstrate such a high reduction in risk of ulcer complications in people living with OA, when compared with NSAIDs1.

Prexige significantly reduced the rate of upper GI ulcer complications for the overall study population (patients taking and not taking low dose aspirin) by 66% (p<0.0001), and by 79% (p<0.0001) for patients not taking low dose aspirin, compared to the two NSAIDs. In the aspirin subgroup a numerical reduction of 21% was seen compared to the NSAIDs1.

These results are unprecedented when comparing them with previous selective COX-2 inhibitor safety outcomes trials1,5,6. The large size of the trial (>18,000 patients), maintenance of high levels of patient retention rate over one year, comparison with more than one NSAID and the endpoint of clinically meaningful ulcer complications all contributed to a study specifically designed to provide authoritative answers regarding the GI safety of Prexige7.

No compromise on CV safety when compared to NSAIDs
This class-leading GI safety of Prexige was achieved without compromising CV safety when compared to NSAIDs2. No significant difference was seen between Prexige and ibuprofen or naproxen in the incidence of MIs, stroke, coronary heart disease or any of the CV endpoints2. "These results are reassuring, since 12% of the patients in the TARGET clinical trial were at high CV risk, 24% were taking low dose aspirin, 45% had hypertension, 20% had dyslipidaemia and 8% were diabetics. This meant the study reflected the 'real-life' situation", said Professor Hawkey, speaking at the UEGW Congress.

In addition mean changes in systolic and diastolic blood pressure from baseline in patients taking Prexige were significantly smaller (p=0.0001) than for those taking NSAIDs (systolic +0.4 mmHg vs. +2.1 mmHg respectively; diastolic -0.1 mmHg vs +0.5 mmHg respectively)1,2. Data have shown that even small increases in blood pressure can lead to increased CV risk8. This is illustrated by the fact that increases in systolic blood pressure of 1-5mm Hg in patients with OA were associated with 7,000 - 35,000 additional ischemic heart disease and stroke events in the US each year alone8.

Serious GI or CV events are more frequent side effects in patients treated with NSAIDs and
COX-2 selective inhibitors than serious hepatic events, as confirmed in TARGET with a more than ten times higher frequency of serious GI and CV events than hepatic events. In TARGET, there was no significant difference in serious hepatic events leading to jaundice between Prexige and the NSAID groups1. Of the approximately 9,000 patients using twice the maximum dose of Prexige for use in OA, six cases of jaundice were observed [0.07%], while two cases in the group using ibuprofen [0.05%] and one with naproxen [0.02%] at therapeutic doses with approximately 4,500 patients in each group1. After discontinuation of therapy, all effects resolved fully1. Less serious and transient hepatic enzyme elevations were recorded more often with Prexige compared to NSAIDs [2.6% versus 0.6% respectively]1, but were less frequent than seen with the most widely prescribed NSAID diclofenac [4%]9.

Recently completed studies with Prexige 100 mg daily in OA have shown hepatic enzyme elevations to be comparable to placebo at 13 weeks [0.25% 3xULN] (data on file).

Proven efficacy
Prexige has proven efficacy in an extensive clinical trial program. Prexige has demonstrated rapid onset in acute pain with 400mg once daily (od)10, efficacy in OA with 100mg od11-13 and 200mg od14-16 as well as efficacy with 200 mg od in RA17,18. Prexige has demonstrated similar efficacy to celecoxib 200mg od in OA14-16, naproxen 500 mg bid in RA17,18 and also provided superior pain relief to rofecoxib 50mg over the first 8 hours for acute pain following dental surgery (pooled data)10.

Novartis has filed applications for regulatory approval throughout the world based on data from more than 40 pre-clinical and clinical studies in OA, rheumatoid arthritis, acute pain and primary dysmenorrhea involving more than 13,000 adult patients around the world (not including TARGET). Prexige has been approved in 17 countries to date, including the United Kingdom, Australia and several countries in Latin America, including Argentina, Brazil and Mexico. Novartis has shared the TARGET data with health authorities, including the MHRA in the UK, and has recently initiated the Mutual Recognition Procedure (MRP) process in Europe.


References:
1. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: a randomised controlled trial. Lancet 2004; 364(9435):665-674.
2. Farkouh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: a randomised controlled trial. Lancet 2004; 364(9435):675-684.
3. Warner T and Mitchell J. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 2004 May;18(7):790-804.
4. Fries JF. NSAID Gastropathy: The Second Most Deadly Rheumatic Disease? Epidemiology And Risk Appraisal. Jnl of Rheumatology. 1991;18:6-10.
5. Silverstein FE, Faich G, Goldstein JL, et al. 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. 2000 Sep 13;284(10):1247-55.
6. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23;343(21):1520-8.
7. Hawkey CJ, Farkouh M, Gitton X, et al. Therapeutic Arthritis Research and Gastrointestinal Event Trial of lumiracoxib - study design and patient demographics. Aliment Pharmacol Ther 2004;20(1):51-63.
8. Singh G, Miller JD, Huse DM, et al. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol 2003;30:714-9.
9. Diclofenac US package insert
10. Kellstein D, Ott D, Jayawardene S, et al. Analgesic efficacy of a single dose of lumiracoxib compared with rofecoxib, celecoxib and placebo in the treatment of postoperative dental pain. Int J Clin Pract 2004;58(3):244-250.
11. Schnitzer T, Beier J, Geusens P, et al. Efficacy and safety of 4 doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: a 4-week multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Care Res 2004;51(4):549-557.
12. Benevolenskaya L, Tüzün S, Hagin E, et al. Lumiracoxib is effective in relieving symptoms of knee or hip osteoarthritis after 4 weeks of treatment: results from a randomized, placebo-controlled trial. Ann Rheum Dis 2003;62(Suppl. I):270 (Abstract FRI0246).
13. Novartis data on file.
14. Tannenbaum H, Berenbaum F, Reginster J-Yet al. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13-week, randomized, double-blind study versus placebo and celecoxib. Ann Rheum Dis Published Online First February 27 2004. doi: 10.1136/ard.2003.015974.
15. Fleischmann R, Sheldon E, Maldonado Cocco J, et al. A prospective randomized 13-week study evaluating the efficacy of lumiracoxib in patients with osteoarthritis of the knee. Ann Rheum Dis. 2003a;62(Suppl.1):266(Abstract FRI0233)
16. Schell E, Boucher L, Tamasi L et al. Long-term efficacy and tolerability of lumiracoxib in osteoarthritis of the knee. Ann Rheum Dis. 2003;62(Suppl.1):264(Abstract FRI0224)
17. Pavelka K, Nayiager S, Kivitz A, et al. Efficacy and tolerability of lumiracoxib in the treatment of rheumatoid arthritis: A 13-week, randomized, double-blind study. Ann Rheum Dis 2004;63(Suppl. I):280 (Abstract FRI0107).
18. Geusens P, Alten R, Rovensky J, et al. Efficacy, safety and tolerability of lumiracoxib in patients with rheumatoid arthritis: Results of a randomized double-blind study. Arthritis Rheum 2003;48(Suppl. 9):242 (Abstract 544).


SOURCE: Novartis AG

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