June 15, 1998-Roche withdraws Posicor on drug interaction issue
Roche has voluntarily withdrawn its T-type calcium channel blocker Posicor (mibefradil) from the market after deciding that the drug interactions encountered with the product have made it too difficult to label with confidence. Posicor, the only drug of its type on the market, was first launched in the middle of last year and is currently available in 38 countries.
The decision has been taken following a preliminary analysis of the three-year MACH 1 study which has evaluated Posicor as a treatment for congestive heart failure. The drug was originally approved for the treatment of hypertension and angina pectoris. An analysis of preliminary results from MACH 1 revealed that the drug performed no differently to placebo when added to standard therapy in this patient population but, more significantly, the study yielded further information on drug interactions which prompted the decision to withdraw. This is another setback for Roche, which announced last month that US registration of its new antiobesity drug Xenical (orlistat) could be delayed until next year. Shares in the company dropped on the announcement but recovered later on in the day as the markets absorbed the news.
At the end of last year, Roche sent a letter to physicians describing a series of side effects seen when Posicor was used in combination with other agents, including several members of the statin class of lipid-lowering drugs (Marketletter December 15, 1997). Combined use of the agents was associated with an increased incidence of rhabdomyolysis, a clinical condition of variable severity which at its worst can be life-threatening, causing renal failure and multi-organ dysfunction. It is a recognized but uncommon side effect with statins.
Furthermore, there were also reports of excessive heart rate lowering (bradycardia) when Posicor was combined with beta blockers. Both these effects are addressed in the drug interaction information on the labeling for Posicor. A spokesman for Roche said that the preliminary MACH 1 analysis revealed that the drug interaction issue was far more complex than originally thought. The clinical effects associated with the drug interactions - while they cannot be linked definitively with Posicor - occurred with a higher frequency than anticipated. Some deaths were seen, but the spokesman stressed that these were seen in hypertensive patients who already have an elevated risk of a negative outcome and not a single case can be attributed to the drug. He added that he did not think it likely that any lawsuits would follow the decision.
Posicor inhibits one of the cytochrome p450 enzymes (2d6) which is involved in the metabolism of a wide range of drugs, including psychoactive drugs such as tricyclic antidepressants, codeine and dextromethorphan, in addition to beta blockers and statins. "In principle, drug interactions can be addressed by appropriate labeling," commented Roche in a statement. "However, with respect to Posicor. . .the complexity of such a prescribing information would make it too difficult to implement." The primary problem is that the interactions occur with some classes of drugs which are often used in patients with cardiovascular disease, so it would be hard to guarantee that patients would not receive them concomitantly. At its launch, analysts had predicted that sales of Posicor might reach 500 million - 800 million Swiss francs ($ 340 million-$ 540 million) a year, but the emergence of the drug interaction issue shortly thereafter dampened the uptake of the drug.
Limited Financial Impact?
The company played down the disappointment, saying that Posicor was forecast to represent only 0.5%-1% of total group sales this year, rising to 1.5%-2% in 1999. In the near-term, positive benefits will accrue as costs of sales and marketing are reduced, so the net effect on the bottom line should be minimal, and perhaps even positive, said the spokesman. The costs of development, estimated at between 500 million and 1 billion francs, have already been written off over the last few years. Roche also said that its pipeline should be more than adequate to make up the shortfall experienced by Posicor's demise. The company said it expects to file at least eight New Drug Applications in 1999, and in the long term these will counteract any impact of the withdrawal.
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