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BMJ. 2007 August 25; 335(7616): 363.
PMCID: PMC1952527

Australian drugs regulator cancels registration of COX 2 inhibitor

The Australian drug regulator has cancelled the registration of Novartis's osteoarthritis drug Prexige (lumiracoxib), a cyclo-oxygenase-2 (COX 2) inhibitor, after eight cases of serious liver side effects, including two deaths, with another two patients needing liver transplants.

The Therapeutic Goods Administration approved the 200 mg and 400 mg a day doses for the treatment of osteoarthritis in July 2004 based on the clinical trial data available at the time. Although the drug was on sale from November 2005, it was only after the 200 mg dose was added to the government subsidised Pharmaceutical Benefits Scheme in August 2006 that sales jumped. At that time the National Prescribing Service, an independent reviewer of drug performance, cautioned that the long term safety of lumiracoxib was unknown and that paracetamol should be used as preferred treatment.

Novartis Australia's corporate affairs director, Rebecca Fisher-Pollard, said that the drug was registered in Australia at the higher dose because the clinical trial data on a 100 mg dose was only completed later. Other governments took a more cautious approach to the drug. The US Food and Drug Administration has rejected Novartis's application for lumiracoxib, pending further studies. Canada has warned patients against taking a dose greater than 100 mg “as this does not provide any additional benefit in efficacy and may increase the potential safety risks associated with the NSAIDs [non-steroidal anti-inflammatory drugs] class.”

In June 2007, four months after the first case of liver failure was reported, Novartis Australia gained registration for the 100 mg dose, and the administration insisted that should be the dose limit for osteoarthritis. Novartis UK describes 100 mg as “the recommended dose worldwide for treatment of osteoarthritis.” However, before the company could complete the phase-in of the 100 mg dose in Australia, reports of six liver damage cases between 27 June and 9 August prompted the administration to cancel the registration. In five of the eight reported cases patients were taking the 200 mg dose, one patient had taken 400 mg a day for three months and then 200 mg a day, one patient had taken 200-400 mg a day, and the remaining patient was taking an as yet unknown dose. The administration now says that even the 100 mg dose of lumiracoxib “is unsafe.”

The drug is licensed for use in the United Kingdom at a 100 mg a day dose. In a statement, Novartis UK says that the 100 mg dose of lumiracoxib “has a positive benefit-risk profile in the treatment of appropriate patients, especially those at risk of serious gastrointestinal side effects.”

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) said that it was aware that liver reactions are known to occur with lumiracoxib and other products in this class but that most cases of serious liver reactions with lumiracoxib were at doses greater than that licensed in the UK and European Union.

“We are not aware of any fatal cases of liver toxicity in the EU,” said the spokesperson. “The MHRA and other European regulatory authorities are currently reviewing the evidence in relation to liver reactions with lumiracoxib at a European level and will communicate the outcome of that review in September. In the mean time, patients who feel unwell on treatment with lumiracoxib or who are concerned should speak to their doctor or pharmacist,” she said.

David Henry, professor of clinical pharmacology at the University of Newcastle, in Australia, disagrees: “If you get liver damage at twice the typical dosage it is not acceptable . . . So I think if the 200 mg is risky, and the company seems to have accepted that, that margin is too narrow for a drug used in this setting. The company should do the right thing and pull the product off the market globally or regulatory agencies in other countries should take action against it.”

Ms Fisher-Pollard said that the company would review seeking re-registration of the 100 mg dose.


Articles from The BMJ are provided here courtesy of BMJ Publishing Group