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JANSSEN LIDOFLAZINE ADDITIONAL CLINICAL DATA IS NEEDED TO SHOW ADVANTAGE OVER OTHER ANTI-ANGINAL AGENTS, FDA CARDIO-RENAL DRUGS ADVISORY CMTE. CONCLUDES

Executive Summary

Janssen's lidoflazine calcium channel blocker requires additional studies to establish that distinctive pharmacologic properties result in clinical advantages over other anti-anginal agents, FDA's Cardio-Renal Drugs Advisory Cmte. recommended at its March 27 meeting. The cmte. unanimouly agreed not to recommend approval of lidoflazine because it can cause sudden death related to torsade de pointes and because there is no clinical evidence that it has any advantage over other approved drugs. Cmte. member Bertram Pitt, MD, University of Michigan School of Medicine, commented: "I think everyone would agree that the pharmacology [of the drug] is exciting . . . One should go out and study that drug and prove that [it] indeed has clinical properties . . . But I think without the data one could be misled, even misled from inferences of preclinical data in other calcium blockers, as we translate this into clinical trials." Janssen presented experimental pharmacologic data which it said distinguished lidoflazine from commonly used calcium channel blockers. Janssen representative Marcel Borger, DSc, presented a film of various cell cultures treated with one of several calcium channel blockers, including lidoflazine, verapamil, diltiazem, and nifedipine. Veratrine was added to the cultures to induce a contraction. According to Borger's film, lidoflazine inhibited the increased contraction rate while the other calcium channel blockers did not. Cmte. consultant Stephen Epstein, MD, Natl. Institutes of Health, maintained that lidoflazine is a new type of drug. "It is not a calcium channel blocker. It is not a beta blocker. It is not a nitrate. It is totally unique from the drugs that we have available to us now. It is a calcium entry drug, a calcium entry blocker different from all the other calcium channel blockers." Epstein asserted that "one could at least infer from that there's good possibility that, therefore, this drug will be active in patients who are not responsive to the more traditional categories of drugs." He said even though the drug "hasn't been shown to be effective in patients, I think the odds are there's a good chance it will work" and therefore it should be available "as a second line or third line drug." With regard to the occurence of death in lidoflazine patients, Joel Morganroth, MD, Hahnemann University, said the issue surfaced in 1977 with publication of a study by Kennelly. In that study, Morganroth said, "lidoflazine was used in a formal trial in Europe for atrial fibrillation with the intent of taking patients who were converted from atrial fibrillation to normal kinds of rhythm and determining whether lidoflazine was as good as, or worse, or better, than quinidine in terms of maintaining those patients in normal kinds of rhythm." There were four deaths among lidoflazine patients. Morganroth maintained that two of the deaths were "very likely to be proarrhythmic deaths," while two were not. Morganroth stated that in the entire lidoflazine database there were 742 patients in 23 studies that were either treated for conversion or maintenance. He said there were 13 deaths among 742 patients, an incidence rate of about 2%. "In all of these patients I would arbitrarily assume proarrhythmic deaths," Morganroth said. However, "if you look at the patients who were just treated in conversion, rather than just maintenance, that is, if you remove the Kenelly maintenance study" the number of patients drops to 629 among which there were a total of nine deaths in four studies. Morganroth concluded that one could then claim an incidence of about 1.5%. He further maintained that the incidence would drop to .5% if one took into account only proarrhythmic deaths, of which he said there were three. Morganroth concluded that lidoflazine "can cause torsade related sudden death as proarrhythmic response, especially in patients with atrial fibrillation, cardiac heart failure, severe bradycardia and hypokalemia." He asserted that lidoflazine "may not be any more of a risk than other" calcium channel blockers. For example, he stated that "there is a clear case of torsade with nifedipine in the literature." In prepared questions to the cmte., FDA's Cardio-Renal Div. noted that two previous advisory cmtes. "were comfortable with the conclusion that lidoflazine is an effective anti-anginal agent." Noting that the major issue of concern, at present, is arrhythmogenicity, FDA asked the cmte. to "determine the frequency of arrhythmogenicity as an adverse event." Cmte. reviewer Elsa-Grace Giardina, MD, Columbia College of Physicians and Surgeons, said the frequency "depends on what study you are looking at. It looks as though . . . arrhythmias range from about 0-20%." She said she wished "there had been a prospective study in a population where we might truly determine the significance, the frequency of arrhythmias on lidoflazine, as an effort we've made with bepridil in angina patients with arrhythmias."
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