138 years to the day after the firm Friedr. Bayer et comp. was entered in the commercial register, we took what was one of the most serious decisions ever made by our company in line with our Responsible Care philosophy. On Tuesday, August 7, 2001, we decided to withdraw our cholesterol-lowering drug Lipobay®/Baycol® from the market. The following day we announced this decision to the public throughout the world and informed doctors and pharmacists. We were fully aware that this would have an exceptionally serious impact on our share price, but, in the interests of the safety and health of the six million or so patients taking Lipobay®/Baycol® worldwide, we saw no alternative but to take the product off the market.
Cerivastatin, the active ingredient in Lipobay®, belongs to a class of substances called statins, which are known for their outstanding cholesterol-lowering effect. An excessive cholesterol level in the blood is regarded as one of the major risk factors for cardiovascular diseases, above all arteriosclerosis, which can lead to heart attacks or strokes.

No anomalous findings during registration
When we launched our cholesterol-lowering drug in 1997, the medical world was already aware of the fact that in rare cases, when taken in combination with other statins, it can lead to a potentially life-threatening side effect, a muscle weakness known as rhabdomyolysis. During the clinical testing of cerivastatin, which involved some 50 studies with around 2,500 patients, no anomalous findings in connection with this side effect were observed. It was not until the study program was extended, after the product had been licensed and after the information from over 15,000 patients had been evaluated, that a small number of cases of rhabdomyolysis came to light.

The risk of this muscle weakness increases when statins are used in combination with gemfibrozil, another cholesterol-lowering product. Particularly in the United States, this drug is frequently prescribed as a generic product. Statistics indicate that when cerivastatin is used concomitantly with gemfibrozil, cases of rhabdomyolysis seem to occur more frequently than when gemfibrozil is taken in combination with other statins.

When the product was originally launched, we included warnings in package leaflets and physicians' prescribing information about the increased risk of side effects when cerivastatin is used in combination with gemfibrozil. Later, we even included a contraindication in the pack inserts and sent letters to doctors drawing their attention to this. Despite all these safety precautions, which had been agreed to by the relevant health authorities, we continued to receive reports of muscle weakness among patients who were being prescribed both drugs at the same time. According to market research data, some 1.5 percent of the patients being treated with cerivastatin in the United States were also taking gemfibrozil. Of the 31 fatalities reported by the Food and Drug Administration (FDA), the American health authority, 40 percent are attributable, according to the FDA, to concomitant therapy with gemfibrozil.

A further reason for the market withdrawal was the fact that the maximum dosage of 0.8 milligrams was being used contrary to instructions as the starting dose to initiate therapy. This is why, in our prescribing recommendations, we explicitly stated that therapy should be initiated with a low dosage and that this should be increased only gradually during the course of the treatment. Unfortunately, some doctors did not observe this important recommendation.

We considered the misuse of the product to be an additional risk for patients. Every physician is obliged to submit spontaneous reports of any adverse effects of drugs to the health authorities. However, these reports are of limited conclusiveness, a fact that is repeatedly emphasized by the health authorities themselves. It is very difficult indeed to prove a true causal relationship between taking a medication and an adverse effect. Frequently, there is a lack of information, for example about other drugs being taken by the patient. Moreover, according to expert opinion, it is exceedingly difficult to distinguish between a fatality that occurs as a result of an existing or accompanying illness and one which can be attributed directly to the side effect of the prescribed products. The fact is that patients treated with statins tend to be older and suffering from serious accompanying illnesses, particularly cardiovascular disorders with a high morbidity and mortality rate.

Thorough and comprehensive information policy
In all potential cases, Bayer carefully and thoroughly followed up on the spontaneous reports from physicians and issued detailed information. In accordance with European law, all relevant information was submitted to the MCA (Medicines Control Agency), acting on behalf of the reference member state, which in this case was the United Kingdom. This agency passed on all information necessary for the inclusion of a contraindication in the prescribing information to the relevant authorities of other member states, including the German Federal Institute for Drugs and Medical Devices (BfArM). Since we were nevertheless unable to exclude the possibility that some doctors would continue their previous prescribing habits, despite these urgent warnings, and because there are also therapeutic alternatives, we decided to take the product off the market voluntarily.

Pharma

BfArM

The preclinical development of cerivastatin began in 1989. The subsequent clinical trial involved around 50 studies with approx. 2,500 patients. The drug was submitted for regulatory approval in 1996. The research and development cost for cerivastatin amounted to approximately € 300 million.