QTc Interval in Infants Receiving Cisapride

Systematic review: cardiovascular safety profile of 5‐HT4 agonists developed for gastrointestinal disorders

“…65 Other studies suggested that it was not QT prolongation per se, but rather, the increase in dispersion of repolarisation that usually accompanies QT prolongation, which provides the arrhythmogenic substrate. 66 Although some studies suggested that cisapride had a low arrhythmogenic potential among neonates regardless of gestational age, 67 others drew attention to the low levels of CYP 3A4 in the neonatal liver 68 and the consequent effects on cisapride metabolism. Indeed, a pharmacokinetic study in premature infants demonstrated increased serum concentrations of cisapride and parallel prolongations of the QT interval.…”

Untitled

“…Adverse cardiac events (serious ventricular arrhythmias, QTc interval prolongation, syncope and sudden death) have been reported in adult patients treated with cisapride, especially with the concomitant ingestion of antifungal medicines (fluconazole, miconazole) and macrolides (clarithromycin). A study from the United States of America has reported that 15 (30%) of 50 infants receiving cisapride developed QTc interval prolongation three days after starting to take the medicine, and in the majority the QTc interval had normalized by day 14 of cisapride therapy (25). This study suggested that documenting a prolongation of the QTc interval, three days following initiation of cisapride administration, would identify infants at risk for adverse cardiac events.…”

“…They are also described in the ICH Guideline E2E pharmacovigilance planning (25). However, by analogy to the assessment of effectiveness and benefit of medicine treatment for orphan diseases, less conventional approaches might be required and be acceptable to evaluate potential medicine toxicity and to identify ADRs when there are few patients available to analyse.…”

“…The European Medicines Agency (EMEA) and the FDA develop the policies for risk management strategies (proposed pharmacovigilance measures and if necessary risk minimization) to be applied in the future to the management of medicines throughout their life-cycle. Additionally, in 2004, the International Conference on Harmonisation (ICH) published a guideline Pharmacovigilance planning (25) that addressed the issue of the type of studies required for the marketing of a new medicine. The safety specification addresses the populations potentially at risk (where the product is likely to be used) such as children, and outstanding safety questions which warrant further investigation to further the understanding of the benefit-risk profile during the post-approval period.…”

Cisapride: What can we learn from the rise and fall of a prokinetic?

“…107 Other studies suggested that it was not QT prolongation per se but rather the increase in dispersion of repolarization, which usually accompanies QT prolongation, that provides the arrhythmogenic substrate. 108 Though some studies suggested that cisapride had a low arrhythmogenic potential among neonates regardless of gestational age, 109 others drew attention to the low levels of CYP3A4 in the neonatal liver 110 and the consequent effects of this on cisapride metabolism. The clinical implications of the latter were confirmed in a pharmacokinetic study in premature infants that demonstrated increased serum concentrations of cisapride and parallel prolongations of the QT interval in premature infants.…”