Lumiracoxib (Prexige) has been urgently withdrawn by the Australian Government Therapeutic Goods Administration (TGA) because of serious liver adverse effects. The TGA advises that all people taking lumiracoxib should stop immediately and contact their doctor. Health professionals should read the TGA's urgent advice regarding management for more information.
- Lumiracoxib is an alternative to other NSAIDs for managing pain in osteoarthritis. Paracetamol remains first line.
- Lumiracoxib is a COX-2 selective NSAID. Some trials of COX-2 selective NSAIDs have found an increase in the risk of cardiovascular events compared with placebo or with naproxen. Evidence for the long-term cardiovascular safety of lumiracoxib is limited.
- Lumiracoxib is contraindicated in patients with established cardiovascular disease and should be prescribed with caution for patients with significant cardiovascular risk factors.
- Lumiracoxib causes fewer serious ulcer complications than naproxen or ibuprofen, but should be used with caution in people with gastrointestinal risk factors.
- Use lumiracoxib for the shortest possible time. Try intermittent use for symptomatic relief of exacerbations or before painful activities.
- As with all NSAIDs, use lumiracoxib with caution in people with renal dysfunction, heart failure, oedema and hypertension. Lumiracoxib is contraindicated in severe renal dysfunction.
Lumiracoxib 200 mg tablets are PBS listed for symptomatic treatment of osteoarthritis.
Reason for PBS listing
Lumiracoxib was recommended for listing by the Pharmaceutical Benefits Advisory Committee (PBAC) on a cost-minimisation basis compared with celecoxib.1,2 The PBAC agreed that lumiracoxib 200 mg was shown to be as effective as celecoxib 200 mg in treating the symptoms of osteoarthritis.
The PBAC was concerned about making another COX-2 selective NSAID widely available, in light of concerns about cardiovascular risks associated with this group of drugs.1 It considered that caution in prescribing lumiracoxib was warranted, given the uncertainty regarding risk versus benefit for COX-2 selective NSAIDs.1
Place in therapy
Lumiracoxib is a COX-2 selective NSAID. Several COX-2 selective NSAIDs have been shown to increase the risk of cardiovascular events compared with placebo and naproxen. Evidence about the cardiovascular safety of lumiracoxib is limited. Avoid lumiracoxib in patients at high cardiovascular risk. When symptoms cannot be managed with non-drug therapy and paracetamol alone, lumiracoxib is as effective as other NSAIDs in reducing symptoms of osteoarthritis and has a similar adverse-effect profile. As with other COX-2 selective NSAIDs, lumiracoxib is likely to be most useful for individuals at increased risk of gastrointestinal complications, although the possibility of ulcer complications remains high in these patients.
Paracetamol is first-line drug therapy for most patients with osteoarthritis
Paracetamol is effective in osteoarthritis and has a superior safety profile to that of NSAIDs.3 Ensure that the dose is adequate (up to 4 g/day). Toxicity at therapeutic doses is extremely rare; paracetamol should be avoided if risk factors for hepatotoxicity are present (see NPS News 28: Minimising the risks of using analgesics for musculoskeletal pain).
Lumiracoxib is an alternative to other NSAIDs for symptomatic treatment of osteoarthritis
Prescribe lumiracoxib for patients in whom a favourable balance between benefit and harm is expected. The efficacy of lumiracoxib is similar to that of other NSAIDs4–6, while risk of adverse events depends on individual renal, cardiovascular and gastrointestinal risk factors (see Box 1). In patients without gastrointestinal risk factors, the difference in adverse effects between lumiracoxib and conventional NSAIDs is small. Response to different NSAIDs varies, so lumiracoxib may also be useful for people who are intolerant of or have not responded to other NSAIDs.
Use lumiracoxib for the shortest possible time and periodically evaluate the need for ongoing therapy.7 Adding an intermittent NSAID (e.g. for symptomatic relief of exacerbations or before painful activities) to regular paracetamol may produce additive benefit and limit the dose of NSAID required.3
Box 1: Risk factors for gastrointestinal adverse events18
- Age ≥ 65 years
- History of ulcer
- Concomitant use of anticoagulants or corticosteroids
- Presence of serious comorbidity
- Use of NSAIDs with higher gastrointestinal risk
- Prolonged use of high NSAID doses (which includes the combination of aspirin and another NSAID or of 2 non-aspirin NSAIDs)
COX-2 selective NSAIDs may elevate cardiovascular risk
Lumiracoxib is a COX-2 selective NSAID, and COX-2 selective NSAIDs may increase the risk of serious cardiovascular events relative to placebo or to naproxen. There was an increased rate of cardiovascular events in long-term placebo-controlled trials of rofecoxib (Vioxx) and celecoxib (Celebrex), as well as in a trial of parecoxib combined with valdecoxib for postoperative pain after coronary artery bypass surgery.8–10 Although there is a biologically plausible mechanism linking the inhibition of the COX-2 enzyme with an increase in thrombotic events11, there is not enough evidence from clinical use to draw such conclusions about COX-2 selective NSAIDs as a group. Other trials of COX-2 selective NSAIDs have not had the power to detect important changes in cardiovascular risk.
Evidence for the long-term cardiovascular safety of all NSAIDs is limited. Therefore all NSAIDs should be used with greater caution in people with cardiovascular risk factors.
For further discussion (excluding the evidence on lumiracoxib) see the NPS RADAR review Elevated cardiovascular risk with NSAIDs?
Evidence about the cardiovascular safety of lumiracoxib is limited
The best available comparison of lumiracoxib with conventional NSAIDs in osteoarthritis is the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET).12–14 TARGET investigated the incidence of upper gastrointestinal ulcer complications as its primary endpoint, as well as the incidence of cardiovascular events such as death, myocardial infarction and stroke.
The trial consisted of two distinct substudies, each involving about 9000 people for 1 year. One substudy compared lumiracoxib with ibuprofen, the other with naproxen; about one-quarter of TARGET participants were receiving low-dose aspirin.
The results of TARGET are inconclusive regarding cardiovascular risk associated with lumiracoxib, as the total number of cardiovascular events in the study was small, resulting in low statistical power. TARGET found no statistically significant differences in the incidence of myocardial infarction, stroke or cardiovascular death between lumiracoxib and either ibuprofen or naproxen. The wide confidence intervals (CIs) indicate that a clinically significant increase in cardiovascular risk has not been ruled out: the relative risk of a cardiovascular event with lumiracoxib compared with naproxen was 1.46 (95% CI 0.89 to 2.37), while the relative risk for lumiracoxib in the ibuprofen substudy was 0.76 (95% CI 0.41 to 1.40).13
The degree of cardiovascular risk associated with using lumiracoxib for longer than 12 months is unknown; rofecoxib toxicity only emerged after 18 months in the APPROVe trial.9 In a meta-analysis of lumiracoxib clinical trials at all daily doses tested, covering a total exposure to lumiracoxib of about 2000 patient–years, the relative risk of cardiovascular events with lumiracoxib compared with placebo was 1.08 (95% CI 0.41 to 2.86). 15 Again, the CI does not rule out a clinically significant increase in risk and the trials were of short duration, with mean exposure of about 3 months.
Lumiracoxib is not recommended for people at high cardiovascular risk
Lumiracoxib is contraindicated in patients with established ischaemic heart disease (including patients who have recently undergone coronary artery bypass graft surgery), peripheral arterial disease and/or cerebrovascular disease.7
Avoid all NSAIDs in people with high background cardiovascular risk. With a high starting point (e.g. absolute 5-year risk of cardiovascular events of 15% or higher), any increase is of particular concern. If an NSAID must be used, prescribe intermittent or short-term therapy to reduce the potential risk, and monitor and manage cardiovascular risk factors. The product information indicates that lumiracoxib should be prescribed with caution for patients with significant cardiovascular risk factors (including diabetes, hypertension, hypercholesterolaemia, congestive heart failure [NYHA II–IV] or smoking).7 Estimate overall cardiovascular risk using a tool such as the New Zealand Guideline Group's Cardiovascular Risk Calculator when assessing the balance of benefits and harms for lumiracoxib.
Low-dose aspirin removes lumiracoxib's gastrointestinal safety advantage
Patients at increased cardiovascular risk should be considered for low-dose aspirin therapy (see Prescribing Practice Review 24: Using antithrombotics). In patients receiving aspirin, lumiracoxib will rarely be the preferred NSAID. When combined with aspirin, lumiracoxib has no gastrointestinal safety advantage over conventional NSAIDs (see Lumiracoxib caused fewer serious ulcer complications than naproxen or ibuprofen in TARGET). Combining any NSAID with aspirin should be done with caution, as the risk of gastrointestinal adverse effects is increased. There is also little evidence that aspirin removes any increased cardiovascular risk associated with NSAIDs.
Lumiracoxib caused fewer serious ulcer complications than naproxen or ibuprofen in TARGET
In TARGET, lumiracoxib caused significantly fewer gastrointestinal perforations, obstructions and bleeds than either naproxen or ibuprofen in patients who did not take aspirin (relative risk 0.21, 95% CI 0.12 to 0.37). As participants in TARGET receiving naproxen or ibuprofen experienced gastrointestinal complications at a rate of about 1% per patient–year, the absolute reduction in risk with lumiracoxib was small: about 120 patients needed to receive lumiracoxib for 1 year rather than ibuprofen or naproxen to avoid one perforation, obstruction or bleed.14 For patients taking low-dose aspirin, there was no significant reduction in risk (relative risk 0.79, 95% CI 0.40 to 1.55); similarly, the combination of low-dose aspirin and celecoxib was no lower risk than aspirin combined with ibuprofen or diclofenac in the CLASS trial.16
Lumiracoxib is not recommended for patients with active peptic ulceration, gastrointestinal bleeding or inflammatory bowel disease.7 Patients with a history of gastrointestinal perforations, obstructions or bleeding in the previous 12 months were excluded from TARGET, but for comparison, studies of celecoxib in patients with a previous bleeding ulcer showed a 5% incidence of ulcer recurrence over a 6-month period, despite prior Helicobacter pylori elimination.17
When possible, all NSAIDs should be avoided in patients at increased gastrointestinal risk (see Box 1 for risk factors), but if the benefits of using an NSAID outweigh the possible harm of causing ulcer complications, lumiracoxib may be preferable to conventional NSAIDs. This is because the absolute reduction in gastrointestinal complications with lumiracoxib compared with conventional NSAIDs is likely to be considerably greater in high-risk patients than in low-risk patients.
Lumiracoxib has a similar range of adverse effects to those of other COX-2 selective and conventional NSAIDs. Patients taking lumiracoxib have experienced oedema and renal and hepatic adverse effects at a similar rate to those in patients taking conventional NSAIDs. Lumiracoxib caused fewer gastrointestinal complications (perforations, obstructions and bleeds) than conventional NSAIDs in a 1-year clinical trial14, but should be used with caution in patients with risk factors for gastrointestinal bleeding. Lumiracoxib may increase the risk of cardiovascular death, myocardial infarction or stroke.
Report suspected adverse reactions to the Adverse Drug Reactions Advisory Committee (ADRAC) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the Therapeutic Goods Administration website.
Lumiracoxib elevates liver enzyme concentrations in some patients
As with other NSAIDs, about 1.4% of patients experienced threefold or greater elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with lumiracoxib 200 mg once daily7; lumiracoxib 400 mg daily was associated with more frequent elevations and, rarely, cases of hepatitis.5 Monitor patients who have had an abnormal liver test or who have other signs of liver dysfunction. Discontinue lumiracoxib if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash).7
As with all NSAIDs, lumiracoxib may cause renal impairment and oedema
Typical NSAID-related adverse effects such as elevated serum creatinine concentration and oedema have been observed in patients receiving lumiracoxib7; elevated creatinine concentrations were observed in 3.5% of patients in clinical trials using lumiracoxib 200 mg/day and 400 mg/day.7
Lumiracoxib is contraindicated for people with renal impairment with estimated creatinine clearance < 30 mL/min (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2). The elderly and patients with heart failure, existing mild to moderate renal dysfunction, or dehydration or those taking diuretics and ACE inhibitors concomitantly (i.e. the 'triple whammy') are at risk of renal toxicity. Monitor renal function in these patients.
Avoid lumiracoxib, or use only with close monitoring, in patients with fluid retention, hypertension, left ventricular dysfunction or heart failure; discontinue lumiracoxib if there is clinical evidence of deterioration due to oedema.
Lumiracoxib may potentiate the effects of warfarin
Monitor patients using warfarin, after initiating or altering lumiracoxib treatment. Studies in healthy volunteers showed a mean increase in prothrombin times of about 15% when lumiracoxib was coadministered with warfarin.7,19
The recommended dose of lumiracoxib for osteoarthritis is 200 mg once daily. Do not exceed this dose.7
Avoid coadministering lumiracoxib with another NSAID, as using multiple NSAIDs is associated with an increased risk of gastrointestinal complications.18 Patients who require low-dose aspirin for cardiovascular prevention should receive it; avoid lumiracoxib in these patients if possible (see Place in therapy).
Information for patients
Suggest or provide the Prexige consumer medicine information (CMI) leaflet when prescribing lumiracoxib.
- to avoid aspirin and over-the-counter painkillers containing NSAIDs: diclofenac (Voltaren Rapid, Diclac); ibuprofen (Nurofen, Tri-Profen, Herron Blue, Advil, Actiprofen, Compufen, Bugesic, Panafen, Rafen); mefenamic acid (Ponstan); or naproxen (Naprogesic, Alleve, Nurolasts); topical NSAIDs and salicylates may be used as the level of systemic exposure is very low\
- to use paracetamol for minor complaints such as headache and fever
- to try intermittent use as needed during exacerbations or before painful activities.
Discuss the possible adverse effects of lumiracoxib and advise patients to seek prompt medical attention if they experience symptoms suggesting possible gastrointestinal, cardiovascular or renal adverse effects, such as:
- black stools or dark, coffee-coloured vomit
- swollen ankles or feet
- chest pain, irregular heart beat, collapse or fainting.
- Pharmaceutical Benefits Branch. Lumiracoxib public summary document. http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbac-psd-lumiracoxib-nov05 (accessed 15 March 2006).
- Department of Health and Aging. November 2005 PBAC outcomes: positive recommendations. http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbacrec-pbacrecnov05-positive (accessed 23 June 2006).
- Australian Medicines Handbook, 2006.
- Fleischmann R, Sheldon E, Maldonado-Cocco J, et al. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a prospective randomized 13-week study versus placebo and celecoxib. Clin Rheumatol 2006;25:42–53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16132165
- Medicines and healthcare products regulatory agency. UK public assessment report for Prexige 100mg tablets (Lumiracoxib) PL 00101/0677. http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con2022707.pdf (accessed 3 January 2006).
- Tannenbaum H, Berenbaum F, Reginster JY, et al. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib. Ann Rheum Dis 2004;63:1419–26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15020310
- Prexige product information. 29 October 2005.
- Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071–80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15713944
- Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092–102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15713943
- Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352:1081–91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15713945
- Grosser T, Fries S, Fitzgerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006;116:4–15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16395396
- Therapeutic arthritis research and gastrointestinal event trial of lumiracoxib — study design and patient demographics. Aliment Pharmacol Ther 2004;20:51–63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15225171
- 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: randomised controlled trial. Lancet 2004;364:675–84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15325832
- 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: randomised controlled trial. Lancet 2004;364:665–74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15325831
- Matchaba P, Gitton X, Krammer G, et al. Cardiovascular safety of lumiracoxib: A meta-analysis of all randomized controlled trials ≥1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis. Clin Ther 2005;27:1196–214. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16199245
- 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;284:1247–55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10979111
- Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104–10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12501222
- Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340:1888–99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10369853
- Novartis Pharmaceuticals UK Ltd. Prexige summary of product characteristics. 2 December 2005. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=17149 (accessed 23 June 2006).