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  "notes": "The slide highlights the safety margin between the recommended dose (40mg) and the doses where QTc prolongation was observed (120-240mg), while noting specific patient populations at higher risk.",
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      "text": "At the recommended doses, pitolisant does not prolong the QT interval. However, patients with moderate liver impairment, moderate and severe kidney impairment, and patients taking medications that affect the metabolism of pitolisant may have higher blood concentrations of pitolisant and a higher risk of QT interval prolongation.",
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      "text": "“A concentration-dependent QTc prolongation over a dose range of 40 to 240 mg was detected in this QT assessment. At steady state concentrations with the 40 mg dose, the expected mean (90% CI) increase in QTc is 4.2 (3.2 to 5.2) msec [...] The highest dose tested (240 mg) provides a 1.8-fold exposure margin over the high clinical exposure scenario and the expected mean increase is 15.5 (12.0 o 18.9) msec.”",
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      "text": "The Sponsor evaluated the effect of pitolisant on the QT interval in two studies (Studies P09-11 and P14-05) [...] Study P09-11 was a total QT (TQT) study that evaluated doses up to 120 mg (single dose). Study P14-05 was a single ascending dose (SAD) study that evaluated doses up to 240 mg. The TQT study did not find a clinically significant QTc prolonging effect with the recommended pitolisant dose of 40 mg once daily, though a dose of 120 mg was associated with QTc prolongation of approximately 10 milliseconds (msec).",
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      "text": "Although the FDA exhibited keen awareness of the risk of QTc prolongation beyond a certain dose, it was persuaded that plasma levels at the labeled 40 mg dose are safe while doses from 120 to 240 mg – tested in the two cardiac safety studies (P09-11 and P14-05) – resulted in Qtc prolongation, hence indicating a safety margin. The FDA noted that 107 mg was associated with a QT prolongation of 10 msec, the typical threshold beyond which a drug is considered cardiotoxic enough to prevent approval; and that 240 mg resulted in prolongation of 12-19 msec – “Most patients who receive pitolisant are unlikely to reach exposures seen with the 106.8 mg dose, as the highest recommended dose is 35.6 mg once daily.” The agency also noted the risk of higher blood concentration of pitolisant in patients with moderate liver or kidney issues, or poor CYP3D6 metabolizers.",
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      "text": "Most patients who receive pitolisant are unlikely to reach exposures seen with the 106.8 mg dose, as the highest recommended dose is 35.6 mg once daily. — FDA CDER Clinical Review, Dec 2018",
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