GlaxoSmithKline and Schering-Plough have been hit by a US Food and Drug Administration (FDA)-mandated label change for their long-acting beta2 adrenergic agonist drugs which could have a dramatic impact on their use in asthma.

In a Public Health Advisory released November 18, the FDA asked for label changes to GSK’s big selling combination asthma drug Advair Diskus (salmeterol plus fluticasone) and Serevent Diskus (salmeterol), as well as Schering-Plough’s Foradil Aerolizer (formoterol; sold by Novartis in Europe), that effectively reserve them for second-line use.

These LABAs are generally used in the morning to provide a background protection against asthma attacks, with any breakthrough symptoms tackled with a short acting beta agonist, such as salbutamol. But the FDA maintains that use of these products means that when breakthrough attacks do occur, they tend to be more severe.

The decision rests on data from the SMART study, never published but presented to an FDA advisory committee meeting in 2003, which found an increased risk of asthma death amongst patients taking GSK's salmeterol. This has already led to Serevent and Advair having ‘black box’ warnings added to their labeling to warn of the potential for severe breakthrough asthma attacks.

“LABAs should not be the first medicine used to treat asthma [and] should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low-or-medium dose corticosteroids,” said the FDA advisory.

This relegation of LABA-based therapy to second- or third-line use – depending on the severity of asthma – could have a dramatic impact on the sales of these products, according to analysts. Advair, marketed as Seretide outside the USA, is GSK’s biggest selling drug; it brought in £737 million to the company’s coffers in the third quarter of this year, or around 15% of GSK’s total product turnover, while Serevent added another £79 million.

For Schering-Plough the potential impact is less significant, as Foradil lay outside the company’s top 15 products by sales revenue in the third quarter.

GSK was swift to offer a rebuttal to the FDA advisory, claiming that the FDA’s action is inconsistent with asthma treatment guidelines laid out by the US National Institutes of Health and other expert bodies and could ‘put many patients at risk of uncontrolled asthma’.

The UK-headquartered company also said that the decision runs counter to the findings of an FDA advisory committee meeting held in July 2005 which concluded that Advair and Serevent were safe when used as labeled and should stay on the market. However, the panel did conclude that a black box warning should also be added to Foradil.

“These proposed labeling changes would reserve the most effective asthma treatment — the combination of inhaled corticosteroids and long-acting beta agonists — until after a patient has failed on other treatment options and therefore may be at risk for severe outcomes, such as exacerbations and potentially death,” said GSK in a statement.

Last month, the Canadian health authorities published a similar warning about the salmeterol and formoterol after reviewing the SMART data and issued advice on how the drugs should be used in practice.

Formoterol, along with the corticosteroid budesonide also forms a constituent of AstraZeneca’s combination asthma treatment Symbicort which is not sold in the USA but remains a major product for AstraZeneca worldwide. The product brought in ex-US revenues of $240 million in the third quarter of this year.

- Meanwhile, the FDA has updated labeling for GSK’s HIV protease inhibitor Lexiva (fosamprenavir calcium) to indicate that simultaneous administration of Lexiva in combination with AstraZeneca’s gastrointestinal drug Nexium (esomeprazole) does not result in lowering of blood levels for the HIV drug.

Among HIV-positive patients, heartburn, gastroesophageal reflux disease and ulcers are common disorders. Drug interactions that result in lower blood levels may increase the risk for virologic failure in patients treated with HIV protease inhibitors, said GSK.