The de-registration of the drug Prexige (lumiracoxib) following several cases of severe liver damage is another nail in the coffin of a class of anti-inflammatory drugs known as cyclo-oxygenase 2(Cox-2) inhibitors.

These drugs were first marketed in 2000 with the promise that they caused less damage to the stomach than older anti-inflammatory drugs such as Naprosyn and Brufen. But this advantage came at a cost. The Cox-2 inhibitors were found to cause thrombosis leading to heart attack and stroke and one product, Vioxx, was withdrawn from sale in late 2004.

Faced with a new threat to the liver the Therapeutic Goods Administration (TGA) appears to have acted swiftly by withdrawing the license for Prexige. The product has no efficacy advantage over competitors; it is symptom relieving rather than life extending, so patients can substitute it safely.

But is this the full story? According to the TGA website the Australian Drug Evaluation Committee recommended registration of two strengths of Prexige (200mg and 400mg) in April 2004, although the TGA appears to have licensed a lower (100 mg) strength later. Only the 200mg tablet was listed on the Pharmaceutical Benefits Scheme for treatment of osteoarthritis and the current Australian product information recommends this dose for osteoarthritis.

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By contrast, the current Canadian product information states:

The recommended dose of Prexige is 100mg once daily. The dose should not be increased as this does not provide any additional benefit in efficacy and may increase the potential safety risks associated with NSAIDs.

The Canadian document reports data from clinical trials showing a significantly lower rate of liver damage with a dose of 100mg daily than with 200mg or more. These data are not included in the current Australian product information.

Novartis has recently asked pharmacists to hand out leaflets advising patients to ask their doctor to switch them from the 200mg to 100mg strength of Prexige, without offering any explanation.

Yet, as this UK press release alerting the medical industry of the withdrawal of Prexige shows, the recommended dose globally is 100mg:

UK Standby Statement: Withdrawal of Prexige® (lumiracoxib)

Novartis is complying with a decision by the Australian Therapeutic Goods Administration (TGA) to withdraw Prexige® (lumiracoxib), a selective COX-2 inhibitor, where it is used for the treatment of osteoarthritis (OA) and acute pain, from the Australian market with immediate effect.

This action was taken because of TGA concerns about the liver safety profile of lumiracoxib. A number of cases of liver failure have been reported in Australian patients, mostly following treatment with higher doses of lumiracoxib. Liver failure is a known rare but serious side effect of all COX-2 inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs).

The 100 mg dose of lumiracoxib, which is the recommended dose worldwide for treatment of osteoarthritis, has not been associated with an unexpected incidence of liver-related side effects for an osteoarthritis population treated with NSAIDs.

Novartis is informing appropriate health authorities worldwide and is communicating with healthcare professionals and patients in Australia about the decision.

Novartis is collaborating with the TGA, however we continue to believe that the way in which lumiracoxib is used in the UK has a positive benefit/risk profile in the treatment of appropriate patients, especially those at risk of serious gastrointestinal side effects.

The clinical trial database for lumiracoxib comprises approximately 40,000 patients, making it one of the largest bodies of evidence for any drug in its class. This includes the TARGET study involving more than 18,000 patients, which showed that lumiracoxib significantly reduced serious gastrointestinal events without compromising cardiovascular safety compared to the NSAIDs naproxen and ibuprofen.

Since lumiracoxib was first launched in July 2005, it is estimated that over seven million prescriptions have been issued worldwide. Lumiracoxib 100 mg once-daily is approved for use in patients with osteoarthritis in more than 50 countries, including the European Union, Canada and Latin America.

Novartis supports the recommendation of health authorities that anti-inflammatory treatments should be used in appropriate patients at the lowest possible dose for the shortest possible duration.

Patients taking lumiracoxib who have any concerns about their medication should consult their healthcare provider.

So, for how long have Novartis and the TGA been aware of a dose-related liver toxicity? Why did Australia apparently lag behind other countries in continuing to use the higher (200mg) strength of Prexige. And why were patients recently asked to switch to the 100mg dose?