Prescribing guidance for AstraZeneca's 'superstatin' Crestor has been changed across the European Union as a precaution against dangerous side-effects associated with high doses of the drug.

The European Commission's pharmacovigilance committee requested AstraZeneca change Crestor's labelling following a review of the product's first year of European post-marketing safety data.

The 40mg dose should now only be used under specialist supervision and avoided completely in the minority of patients deemed to be at a high risk of muscle wasting and toxicity (myopathy/rhabdomyolysis).

In addition to the restrictions of Crestor's 40mg dose, all patients will now have to start on the lowest possible dose of 10mg and then wait for four weeks before it is increased, if necessary, to a 20mg dose.

Doubts about the safety of the drug have dogged AZ since before its launch and the company will be looking to draw a line under uncertainties with the new prescribing guidance.

Following the changes AZ was asked to write to healthcare professionals across Europe to inform them of the changes, having last month already warned doctors in the UK and the Netherlands about the drug's dosage regime following the side-effect reports.

The European regulators' action was prompted by safety data analysis of the drug's monitoring by the MHRA and CSM. Their findings suggest that, although Crestor's highest dose benefits a small percentage of patients, it could be associated with a higher rate of side-effects, including rhabdomyolysis.

The potentially fatal kidney condition can result from the muscle wasting condition myopathy, sometimes seen in patients taking statins. In 2001 the same condition prompted Bayer to withdraw Lipobay/Baycol after the statin was linked to 31 deaths in the US.

The CSM has so far received six reports of suspected non-fatal rhabdomyolysis associated with Crestor. Five of these patients were receiving the maximum recommended dose of 40mg and one patient was receiving 80mg.

AZ said that four of the patients had received higher than the recommended starting dose and most of them had other risk factors for rhabdomyolysis.

Keen to emphasise the similarity of Crestor's safety profile to other statins, AZ said that, although doctors should exercise "appropriate caution" when increasing a patient's dose to 40mg, the drug's benefits "make it an important, clinically useful and effective medicine".

Only 4% of Crestor patients in Europe currently receive the 40mg dose, a small number of whom have predisposing factors for myopathy/rhabdomyolysis. In the UK, some 110,000 patients had been prescribed Crestor by March 2004, with about 4,000 to 4,500 of them receiving the 40mg dose.

Last year Crestor enjoyed the best ever launch of a new product in the UK and the drug is predicted to reach peak annual sales of $4 billion; it has been increasing its market share at the expense of Pfizer's Lipitor, the $9.3 billion market leader.

It suffered a sales blip earlier this year after a report by US consumer watchdog Public Citizen petitioned for Crestor's removal from the market, highlighting worldwide rhabdomyolysis cases, which caused a 3% drop in weekly product sales. But sales recovered the following week and AZ issued a detailed response to Public Citizen's campaign.

Although any serious doubts about the product's safety would have devastating consequences for AZ, the company's share price fell only 15p to £25.94 on the latest news, investors  taking the view that the warning would not seriously affect sales.

James Culverwell, analyst at Merrill Lynch, told the Financial Times the new prescribing rules would have "minimal impact" on Crestor's sales prospects.

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AstraZeneca issues Crestor safety warning 

Thursday , May 20, 2004

pharmafocus@pharmafile.co.uk