The Pharmaceutical Journal Vol 267 No 7161 p222
18 August 2001

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Cerivastatin withdrawal: the impacts

Clare Bellingham examines the implications of Bayer’s withdrawal of cerivastatin last week

The withdrawal of cerivastatin (Lipobay) came as a surprise despite the earlier withdrawal of the highest dose preparation in July. Lower strength preparations had been used in the United Kingdom for four years without any obvious safety problems.

Cerivastatin’s withdrawal has led to questions over whether or not the adverse reactions are a class effect for all statins or whether the problem is specific to cerivastatin. Muscle toxicity is a well-known side effect with all statins but Bayer said in a statement last week that the effects of co-prescription with gemfibrozil are more pronounced with cerivastatin than with other statins. However, data on adverse events reported via the Yellow Card scheme reveal that rhabdomyolysis is not limited to cerivastatin (see Table). The Medicines Control Agency cautions that it may be invalid to compare the number of adverse events for one statin with the number for another because the level of event reporting can be influenced by different factors such as level of usage and media coverage of issues associated with a drug.

The United States Food and Drug Administration says that cerivastatin was withdrawn following 31 deaths in the US caused by rhabdomyolysis associated with cerivastatin use. Concomitant use of gemfibrozil was present in 12 of these cases. Bayer is aware of 52 deaths worldwide which have been linked with rhabdomyolysis and cerivastatin treatment. None has occurred in the UK.

Dr Alan Rees, senior member, British Hyperlipidaemia Association and consultant physician, University Hospital of Wales, said: “The occurrence of rhabdomyolysis appears to be a particular problem when cerivastatin is used in combination with gemfibrozil. In the US, gemfibrozil is used much more than it is in the UK, where the preferred fibrates are bezafibrate and fenofibrate.” Another difference between the US and UK is that the normal starting dose for patients in the US was 400µg, compared with 100µg in the UK. The lowest dose available in the US was 200µg, which was used mainly for renal patients.

Although the statins share the same basic structure there are variations in their side chains, said Dr Rees. “This leads to different pharmacokinetic properties, such as differences in lipophilicity and potency,” he said. It is not known whether these structural differences result in different side effect profiles.

The safety of all statins is now under review at a European Union level. The review, to be conducted by member states and the European Committee for Proprietary Medicinal Products’s pharmacovigilance working party, will specifically examine the adverse effects encountered with cerivastatin and whether or not this is a problem with other statins. A spokesman for the European Medicines Evaluation Authority thought the working party would make its first assessment in the autumn.

Changing to other statins

Until the results of the review are known, patients taking cerivastatin need to change to another drug. A spokesman for the MCA said: “Patients who are currently being treated with cerivastatin and are feeling well need not be concerned. Their doctor will review their treatment in due course. Anyone being treated with cerivastatin who is concerned or unwell, particularly with fever or muscle pain, should see their doctor.” The MCA sent a letter to health professionals last week recommending that patients receiving the combination of cerivastatin and gemfibrozil should be changed to an alternative regimen. Patients receiving cerivastatin should be changed to alternative treatment when their next prescription is due.

Manufacturers of other statins have been keen to stress the safety of their particular drug compared with cerivastatin. Novartis, manufacturer of fluvastatin (Lescol), has developed a practice-based management programme to help identify patients on cerivastatin and assist with a change to fluvastatin.

Pfizer, manufacturer of atorvastatin (Lipitor), stresses that the long-term benefits of using statins need to be weighed against the incidence of side effects. “It is important to carry on monitoring cholesterol and aim for the national service framework targets,” a spokesman said. The NSF for Coronary Heart Disease, published in March 2000, recommended reducing cholesterol levels to below 5mmol/L. The Government has been criticised by GPs recently for failing to allow flexibility in the NSF targets following the publication of a study in The Lancet (2001;358:351) that raised questions over the safety of aggressive lipid lowering in the elderly.

AstraZeneca is planning to launch a new statin, rosuvastatin (Crestor), next year. A spokeswoman said that it did not expect any delays in regulatory approval and that it is still working towards the same launch date, although she was unable to be more specific about when this would be.

Dr Rees commented that one of the problems with choosing between the statins is that a class effect has been assumed and long-term outcome data are not available for some of the newer statins. “Long-term safety data are only available for simvastatin and pravastatin,” he said. When newer statins were launched, it had been unethical to carry out placebo-controlled trials because of the data available on the statins that were already available. “It was a mistake to change people en bloc from simvastatin and pravastatin to cheaper statins for commercial reasons. Long-term safety and outcome data are confined to these two drugs,” he said.

Business implications

The withdrawal of cerivastatin is certain to have major economic implications for Bayer. The company’s half-year report, issued at the end of last week, stated: “In view of the financial burden and loss of earnings for Bayer’s health care segment resulting from the withdrawal of its cholesterol-lowering drug, as well as the continuing weakness of the world economy, it is now assumed that earnings for the full year will fall substantially short of previous estimates.”

At a press conference on 13 August, Dr Manfred Schneider, chairman of Bayer’s board of management, denied that Bayer was fundamentally unstable and in need of rescue. He pointed to the fact that Bayer is a diversified company with business interests in agriculture and chemicals as well as health care. “Nevertheless, we will be thoroughly reviewing our strategy for pharmaceuticals,” he said, leading to speculation that this part of the company might be sold. While analysts believe that cerivastatin is unlikely to be relaunched, Dr Schneider said that it was too early to say whether it would be possible to market the active ingredient again.

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Clare Bellingham is on the staff of The Pharmaceutical Journal