Ondansetron 8mg/4ml solution for injection pre-filled syringes

Ondansetron is a highly specific and selective serotonin 5-HT₃ receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors [FDA Label], [A1160][A1161]. The serotonin 5-HT₃ receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema [FDA Label], [A1160][A1161]. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents, suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract [FDA Label], [A1160][A1161]. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT₃ receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting [FDA Label], [A1160][A1161].

Moreover, the effect of ondansetron on the QTc interval was evaluated in a double-blind, randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women [F3181, F3184]. Ondansetron was tested at single doses of 8 mg and 32 mg infused intravenously over 15 minutes [F3181, F3184]. At the highest tested dose of 32 mg, prolongation of the Fridericia-corrected QTc interval (QT/RR0.33=QTcF) was observed from 15 min to 4 h after the start of the 15 min infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 19.6 (21.5) msec at 20 min [F3181, F3184]. At the lower tested dose of 8 mg, QTc prolongation was observed from 15 min to 1 h after the start of the 15-minute infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 5.8 (7.8) msec at 15 min [F3181, F3184]. The magnitude of QTc prolongation with ondansetron is expected to be greater if the infusion rate is faster than 15 minutes [F3181, F3184]. The 32 mg intravenous dose of ondansetron must not be administered [F3181, F3184]. No treatment-related effects on the QRS duration or the PR interval were observed at either the 8 or 32 mg dose [F3181, F3184].

An ECG assessment study has not been performed for orally administered ondansetron [F3181, F3184]. On the basis of pharmacokinetic-pharmacodynamic modelling, an 8 mg oral dose of ondansetron is predicted to cause a mean QTcF increase of 0.7 ms (90% CI -2.1, 3.3) at steady-state, assuming a mean maximal plasma concentration of 24.7 ng/mL (95% CI 21.1, 29.0) [F3181, F3184]. The magnitude of QTc prolongation at the recommended 5 mg/m2 dose in pediatrics has not been studied, but pharmacokinetic-pharmacodynamic modeling predicts a mean increase of 6.6 ms (90% CI 2.8, 10.7) at maximal plasma concentrations [F3181, F3184].

In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time F3178. Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects F3178. Ondansetron has no effect on plasma prolactin concentrations F3178.