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  "notes": "The slide uses a historical precedent (Seldane/terfenadine recall) to frame the severity of a current drug's (pitolisant) safety profile, highlighting specific death and exposure statistics.",
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      "text": "Only two Seldane-related deaths by early 1990's despite 100 million people having taken the drug, per letter published in New England Journal of Medicine in 1993",
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      "text": "Given the anomalous number of adverse event reports associated with pitolisant – visible quickly after US launch a mere couple of years ago – the evidence demonstrates that its cardiotoxicity is exponentially greater than Seldane’s.",
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      "text": "One study reviewed cases of torsades de pointes, the severe ventricular arrhythmia associated with terfenadine intake, reported to the FDA. Of the 25 reported cases, two patients died and the others required hospitalization. The researchers found that it is the parent drug terfenadine, not its major metabolite, that blocks potassium channels, causing substantial prolongation of the QT interval. A prolonged QT interval is associated with torsades de pointes. Erythromycin and ketoconazole inhibit metabolism of terfenadine, leading to elevated concentration of the drug, which in turn is associated with prolongation of the QT interval.",
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      "text": "the FDA had only “received about 40 reports of serious heart rhythm irregularities, evidently caused by Seldane, that led to eight deaths.” — FDA",
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      "text": "Source: https://www.jwatch.org/jd199305010000002/1993/05/01/cardiac-toxicity-terfenadine",
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      "text": "After the Seldane/terfenadine debacle, the FDA is highly sensitized to QT risk, as are drugmakers who screen and eliminate development programs with any QT issue. While a number of older drugs have hERG/QT liability, it is extremely rare to see a new drug come to market with pitolisant's flagrant cardiotoxicity and QT profile. It is critical to note that the absolute number of confirmed cases of QT prolongation and fatalities from Seldane was astonishingly small relative to its use. By 1990, five years after introduction, 100 million people had taken Seldane with only two reported deaths. By 1997 when it was recalled - 12 years after launch - the FDA had only \"received about 40 reports of serious heart rhythm irregularities, evidently caused by Seldane, that led to eight deaths.\" Given the anomalous number of adverse event reports associated with pitolisant – visible quickly after US launch a mere couple of years ago – the evidence demonstrates that its cardiotoxicity is exponentially greater than Seldane's.",
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