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Objective: Ondansetron, a 5HT3 receptor antagonist, is commonly used in emergency departments to treat nausea and vomiting. In 2011, the Food and Drug Administration (FDA) issued a warning that this medicine may cause QT prolongation, potentially leading to deadly arrhythmias. The objective of this study was to characterize the QT interval prolongation associated with ondansetron use in the Emergency Department., Methods: This was a prospective, observational cohort study of adult patients who presented to the emergency department during a one-year period and were treated with intravenous ondansetron. We investigated the QT prolongation associated with dosages. ECGs were obtained before the medication and 5, 15, and 30 minutes after IV drug administration. Every QT measurement was recorded and compared to the zero point. The severity of drug-induced QT prolongation was determined according to the recommendations of the International Conference on Compliance (ICH). QTc prolongation was categorized as 'negligible' (<5 ms), 'significant' (>20 ms), 'potential concern' (>30 ms), or 'definitely worrying' (>60 ms)., Results: Of the 435 patients enrolled in the study, 60% (261 patients) were female and the mean age was 39 (±18). The QT prolongation peaked at the fifth minute and remained consistent at the fifteenth and thirty-first minutes. The maximum prolongation of the mean QT duration occured at the fifth minute (7.9 ± 18.1 ms). No patient revealed any problems with cardiac conduction. The prolonged QT interval was not related to the dose of ondansetron, but QT measurements were higher in the 30th minute in patients treated with 8 mg of ondansetron. The effect of ondansetron administration on QT prolongation was found to be above the 'negligible' but below the 'significant' value, according to the ICH recommendations., Discussion: In this study, QT prolongation due to ondansetron administration was below the 'important' value according to the recommendations of the ICH. No cases of cardiac arrhythmia were reported in any of the partients. Thus, routine ECG monitoring in patients given ondansetron due to the risk of QTc prolongation does not seem cost-effective when evaluated together with additional factors such as its negative impact on emergency patient flow, waste of personnel and time, and increase in healthcare costs. In the absence of a known risk of cardiac arrhythmia, IV administration of 4 mg and 8 mg of ondansetron doses no risk of QT prolongation in the emergency population., Competing Interests: Declaration of competing interest HYM, MA, EÖİ report no conflicting interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies. Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker). The liver safety of AD04 has never been evaluated in subjects with AUD. The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD., Methods: Liver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling. ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24. Adverse cardiac events, general well-being, and study completion were also assessed., Results: Low-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin. While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04. Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment., Conclusions: Low-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort. Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD., Competing Interests: Declaration of competing interest All authors are paid consultants of Adial Pharmaceuticals Inc. Bankole Johnson is an officer of Adial Pharmaceuticals Inc., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of competing interest Dr. Swift has received grant funding from the US National Institutes of Health and the Department of Veterans Affairs.

Background: The safety of triple antiemetic therapy consisting of ondansetron, haloperidol, and a steroid, to surgical patients is unknown., Objective: To determine the incidence of torsade de pointes (TdP) or death following perioperative administration of triple antiemetic therapy., Methods: A retrospective cohort study identified 19,874 patients who received 22,202 doses of triple antiemetics during the 2.5-year time frame from March 4, 2020 to September 7, 2022 for surgical nausea prophylaxis or treatment of nausea. These patients above were cross-matched with an electrocardiogram and adverse outcome database; this identified 226 patients with documentation of a QTc > 450 ms, all ventricular tachycardias including TdP within 48 hours of receiving triple antiemetic therapy, or death within 7 days of receiving ondansetron., Results: There were 3 patients who had documented VT (n = 3), but there were no documented incidents of TdP (n = 0). There were 9 codes called on patients within 48 hours of medication administration, and none of them were due to ventricular arrythmias (n = 0). A total of 11 patients died within 7 days of triple antiemetic therapy. Ten of the 11 deaths were determined to not be from the triple antiemetic. One patient died at home within 24 hours of the procedure of an unknown cause (n = 1)., Conclusions and Relevance: No episodes of TdP were identified in patients receiving triple antiemetic therapy perioperatively, though the cause of death in 1 patient could not be determined. This suggest that low-dose triple antiemetic therapy is low risk for the development of TdP., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Ondansetron is an antiemetic drug (AED) used to prevent and treat nausea and vomiting. The summary of product characteristics reports a rare risk of transient blindness primarily during IV injections, notably with the concomitant use of chemotherapeutic agents. We aimed to refine the characterization of ondansetron-induced blindness., Research Design and Methods: We performed a descriptive and a case/non-case analysis using VigiBase®. Cases were defined as reports of adverse drug reactions (ADRs) related to blindness: amaurosis, amaurosis fugax, blindness. Non-cases were all other recorded reactions. Reporting risk of blindness-related ADRs was assessed using a disproportionality analysis and expressed as Reporting Odds Ratios (ROR)., Results: 138,315 ADRs were reported with AEDs, including 136 blindness-related ADRs, among them 44 (32.4%) with ondansetron. For ondansetron users, blindness-related ADRs occurred mainly on the first day. Out of the 25 patients with known outcomes, 18 (72.0%) were recovering or had recovered, 7 (28.0%) patients had not recovered There were no statistical differences in the number of cases for IV or oral users and for users or not of chemotherapeutic agents. Compared with other AEDs, ondansetron was associated with an increase in the reporting risk of blindness-related ADRs (ROR = 4.00 [2.79-5.72], p  < 0.001)., Conclusions: Rarely blindness can occur following intravenous or oral administration of ondansetron.

Background: Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking., Objectives: To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS., Methods: We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR., Results: Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02)., Conclusions: Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: Prevention of postoperative nausea and vomiting (PONV) is important to achieve DREAM (drinking, eating, mobilization). Ondansetron inhibits PONV, but its effects on postoperative food intake have not been investigated. This study aimed to examine associations between ondansetron and PONV incidence, and postoperative food intake., Methods: This retrospective study included adult patients (n = 632) who underwent laparoscopic gynecological surgery at Kyushu University Hospital between January 2017 and June 2023. Outcomes were PONV on the day of surgery, PONV up to the day after surgery, and food intake, which was assessed for breakfast and lunch on the day after surgery. Odds ratios (ORs) for PONV incidence and postoperative no-food intake were calculated between those with and without ondansetron during surgery. Multivariable-adjusted analysis was performed using possible confounding factors for PONV. Synergistic effects of combining ondansetron with dexamethasone or total intravenous anesthesia (TIVA) were assessed., Results: Multivariable-adjusted ORs for PONV on the day of surgery and up to the day after surgery were 0.56 (95% confidence interval, 0.32-0.99, p = 0.04) and 0.52 (0.30-0.93, p = 0.03), respectively, in the ondansetron group (n = 84) compared with the non-ondansetron group (n = 548). In contrast, multivariable-adjusted ORs for no-food intake of breakfast and lunch the day after surgery in the ondansetron group compared with the non-ondansetron group were not significant. Analysis of synergistic effects on PONV showed no significant interaction between ondansetron and dexamethasone or ondansetron and TIVA combinations., Conclusion: Ondansetron administration during surgery was significantly associated with decreased PONV risk but was not associated with food intake the day after surgery., (© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in vivo and in vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal calcitonin gene-related peptide (CGRP) release in vitro hemiskull preparations. Mechanical allodynia was tested by von Frey filaments. CGRP concentrations in trigeminovascular structures and in vitro superfusates and c-Fos levels in the brainstem were determined by enzyme-linked immunosorbent assay. Meningeal mast cells were evaluated with toluidine blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in vitro, whereas the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated nociceptive reactions by further enhancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migraine-like conditions., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Competing Interests: The author declares no conflict of interest.

Background: Limited data are available regarding efficacious antiemetic regimens to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). In patients aged 60 years or older, allogeneic HSCT is associated with improved survival, but tolerability of the transplant is a significant barrier. Fludarabine and melphalan (Flu-Mel) is a frequently utilized multi-day reduced intensity conditioning regimen for allogeneic HSCT. However, the optimal CINV prevention regimen is unknown., Objective: The purpose of this study was to evaluate the efficacy of a novel CINV prophylaxis regimen prior to allogeneic HSCT with Flu-Mel compared to a historical control group., Study Design: This was a retrospective, single-center, cohort review of 123 patients who received a Flu-Mel preparative regimen prior to allogeneic HSCT from January 1, 2019, to September 30, 2022. Fifty-nine patients received high dose ondansetron (HDO) for CINV prevention, while sixty-four patients received a combination of palonosetron, fosaprepitant, and olanzapine (PFO). The primary outcome was average number of rescue antiemetic doses administered per day. A key secondary outcome was time to first rescue antiemetic., Results: The median number of antiemetic doses used per day was significantly lower in patients who received PFO compared to HDO (1.94 doses [0.31-3.60] vs 3.31 doses [1.61-4.92]; p = 0.002). In addition, use of PFO significantly prolonged the median time to first rescue antiemetic compared to HDO (41.3 h [24.3-122.7] vs 26.2 h [14.7-48.1]; p = 0.016)., Conclusion: The combination of palonosetron, fosaprepitant, and olanzapine is an effective antiemetic regimen for patients receiving a Flu-Mel-based preparative regimen., Competing Interests: Declaration of Competing Interest No authors have any potential conflicts to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Postoperative nausea or vomiting occurs in up to 40% in patients with multiple risk factors, despite prophylaxis. Olanzapine is an antipsychotic drug that is used to prevent nausea and vomiting in palliative care and to treat chemotherapy-induced nausea and vomiting. This study aimed to examine whether pre-operative olanzapine, as a prophylactic anti-emetic added to intra-operative dexamethasone, ondansetron and total intravenous anaesthesia, reduced the incidence of postoperative nausea or vomiting. We performed a multiply-blinded randomised controlled trial in patients aged 18-60 years with cancer at high risk of postoperative nausea or vomiting (three or four risk factors according to the Apfel criteria) plus a previous history of chemotherapy-induced nausea and vomiting. Patients were allocated at random to receive 10 mg olanzapine or placebo orally 1 h before surgery in addition to a two-drug regimen (dexamethasone and ondansetron) and propofol anaesthesia to prevent postoperative nausea or vomiting. The primary outcome was the incidence of postoperative nausea or vomiting in the first 24 h after surgery. In total, 100 patients were enrolled; 47 in the olanzapine group and 49 in the control group completed the study. The baseline characteristics of the groups were similar. The incidence of postoperative nausea or vomiting in the first 24 h after surgery was lower in the olanzapine group (12/47, 26%) than in the control group (31/49, 63%) (p = 0.008, RR 0.40 (95%CI 0.21-0.79)). Adding pre-operative oral olanzapine to intra-operative dexamethasone and ondansetron was highly effective in reducing the risk of postoperative nausea or vomiting in the first 24 hours after surgery in patients with a previous history of chemotherapy-induced nausea and vomiting and at least three Apfel risk factors for postoperative nausea or vomiting., (© 2023 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Background: Consensus guidelines recommend the use of multiple antiemetics as prophylaxis in patients at high risk of postoperative nausea and vomiting (PONV), but the evidence regarding combining acupuncture and antiemetics as a multimodal approach was of very low quality., Objective: This study aimed to assess the effect of combinations of acupuncture with ondansetron versus ondansetron alone for PONV prophylaxis in women at a high risk., Methods: This parallel, randomised controlled trial was conducted in a tertiary hospital in China. Patients who had three or four PONV risk factors on the Apfel simplified risk score, undergoing elective laparoscopic gynaecological surgery for benign pathology, were recruited. Patients in the combination group received two sessions of acupuncture treatment and 8 mg intravenous ondansetron, whereas those in the ondansetron group received ondansetron alone. The primary outcome was the incidence of PONV within 24 h postoperatively. Secondary outcomes included the incidence of postoperative nausea, postoperative vomiting, adverse events etc. RESULTS: Between January and July 2021, a total of 212 women were recruited, 91 patients in the combination group and 93 patients in the ondansetron group were included in the modified intention-to-treat analysis. In the first 24 h postoperatively, 44.0% of the patients in the combination group and 60.2% of the patients in the ondansetron group experienced nausea, vomiting, or both (difference, -16.3% [95% CI, -30.5 to -2.0]; risk ratio, 0.73 [95% CI, 0.55-0.97]; p = 0.03). However, the results of the secondary outcomes showed that compared to ondansetron alone, acupuncture together with ondansetron was only effective in reducing nausea but did not have a significant impact on vomiting. The incidence of adverse events was similar between the groups., Conclusion: Acupuncture combined with ondansetron as a multimodal prophylaxis approach is more effective than ondansetron alone in preventing postoperative nausea in high-risk patients., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Malignant melanoma is a highly metastatic tumour, resistant to treatment. Serotonin type-3 (5-HT 3 ) receptor antagonists, such as tropisetron and ondansetron, are well-tolerated antiemetic drugs commonly used to prevent nausea caused by chemotherapy or radiotherapy. We investigated the anticancer effects of these drugs on melanoma cancer cell lines WM-266-4 and B16F10 with or without paclitaxel. We constructed IC 50 curves and performed Chou-Talalay analysis, using data obtained with the MTT assay. Flow cytometry and fluorescent microscopy were used to examine characteristics of the cell cycle, cell death and cytoskeleton changes. Protein levels and activation were analysed by western blotting and molecular docking studies carried out. Data were analysed by one way ANOVA and post hoc testing. Ondansetron and tropisetron showed selective concentration-dependent cytotoxicity in melanoma cell lines WM-266-4 and B16F10. The effect in combination with paclitaxel was synergistic. The drugs did not cause cell cycle arrest but did promote characteristics of classical apoptosis, including accumulation of subG1 DNA, cleaved caspase-3, mitochondrial membrane permeability and phosphatidylserine exposure. As well, the cytosolic calcium level in the melanoma cells was enhanced, phosphorylated ERK1/2 induced and NF-κB inhibited. Finally, the formation of microtubules was shown to be impaired in melanoma cells treated with ondansetron or tropisetron. Docking studies were used to predict that these drugs could bind to the colchicine binding site on the tubulin molecule. Antiemetic drugs, already given in combination with chemotherapy, may enhance the cytotoxic effect of chemotherapy, following successful delivery to the tumour site., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Anesthesiologists' contribution to perioperative healthcare disparities remains unclear because patient and surgeon preferences can influence care choices. Postoperative nausea and vomiting is a patient- centered outcome measure and a main driver of unplanned admissions. Antiemetic administration is under the sole domain of anesthesiologists. In a U.S. sample, Medicaid insured versus commercially insured patients and those with lower versus higher median income had reduced antiemetic administration, but not all risk factors were controlled for. This study examined whether a patient's race is associated with perioperative antiemetic administration and hypothesized that Black versus White race is associated with reduced receipt of antiemetics., Methods: An analysis was performed of 2004 to 2018 Multicenter Perioperative Outcomes Group data. The primary outcome of interest was administration of either ondansetron or dexamethasone; secondary outcomes were administration of each drug individually or both drugs together. The confounder-adjusted analysis included relevant patient demographics (Apfel postoperative nausea and vomiting risk factors: sex, smoking history, postoperative nausea and vomiting or motion sickness history, and postoperative opioid use; as well as age) and included institutions as random effects., Results: The Multicenter Perioperative Outcomes Group data contained 5.1 million anesthetic cases from 39 institutions located in the United States and The Netherlands. Multivariable regression demonstrates that Black patients were less likely to receive antiemetic administration with either ondansetron or dexamethasone than White patients (290,208 of 496,456 [58.5%] vs. 2.24 million of 3.49 million [64.1%]; adjusted odds ratio, 0.82; 95% CI, 0.81 to 0.82; P < 0.001). Black as compared to White patients were less likely to receive any dexamethasone (140,642 of 496,456 [28.3%] vs. 1.29 million of 3.49 million [37.0%]; adjusted odds ratio, 0.78; 95% CI, 0.77 to 0.78; P < 0.001), any ondansetron (262,086 of 496,456 [52.8%] vs. 1.96 million of 3.49 million [56.1%]; adjusted odds ratio, 0.84; 95% CI, 0.84 to 0.85; P < 0.001), and dexamethasone and ondansetron together (112,520 of 496,456 [22.7%] vs. 1.0 million of 3.49 million [28.9%]; adjusted odds ratio, 0.78; 95% CI, 0.77 to 0.79; P < 0.001)., Conclusions: In a perioperative registry data set, Black versus White patient race was associated with less antiemetic administration, after controlling for all accepted postoperative nausea and vomiting risk factors., (Copyright © 2023, the American Society of Anesthesiologists. All Rights Reserved.)

Ondansetron is a widely administered medication for nausea and vomiting of pregnancy. Further examination of its teratogenic capacity is necessary. This study examines the association between ondansetron treatment during pregnancy and birth defects and adverse obstetric outcomes. Patient data were extracted from Clalit Health Services, Israel. A propensity-score analysis was performed matching those exposed to ondansetron with those who were not. Findings identified 774 women exposed to ondansetron, matched 1:1 with unexposed control patients. No significant differences were found between the groups for: cleft palate, cardiovascular congenital abnormalities, spina bifida occulta, preterm delivery, or small for gestational age. Ondansetron may be a useful and safe alternative as treatment for women who suffer from hyperemesis gravidarum and do not respond to other antiemetic drugs. Notwithstanding, additional prospectively designed research is needed to establish the safety of ondansetron treatment during pregnancy.

Background/aims: We compared the efficacy of the granisetron transdermal system (GTS) with that of ondansetron for controlling chemotherapy-induced nausea and vomiting (CINV) in patients treated with highly emetogenic chemotherapy (HEC)., Methods: We randomized a total of 389 patients to groups treated by GTS and ondansetron before HEC. The primary endpoint was the percentage of patients achieving complete response (CR; no retching/vomiting/rescue medication) of CINV from the time of chemotherapy initiation to 24 hours after the last administration of chemotherapy (prespecified non-inferiority margin of 15%). Quality of life (QoL) was also assessed using the Functional Living Index-Emesis (FLIE)., Results: The per protocol analysis included 152 (47.80%) and 166 patients (52.20%) in the GTS and ondansetron groups, respectively. In the full analysis set, the most common diagnosis, regimen, and period of chemotherapy were lung cancer (149 patients, 40.27%), cisplatin-based regimen (297 patients, 80.27%), and 1 day chemotherapy (221 patients, 59.73%). The CR rates were 86.84% and 90.36% in the GTS and ondansetron groups, respectively; the treatment difference was -3.52% (95% confidence interval, -10.52 to 3.48) and met the primary endpoint, indicating that GTS was not inferior to ondansetron. Patient satisfaction, assessed on the FLIE, showed significantly higher scores in the GTS group compared to the ondansetron group (mean ± standard deviation, 1,547.38 ± 306.00 and 1,494.07 ± 312.05 mm, respectively; p = 0.0449)., Conclusion: GTS provided effective, safe, and well-tolerated control of CINV and improved the QoL in HEC.

Background: There have been recent reports of increased QT interval after head trauma in concussed athletes and adult patients. Ondansetron, which is widely used in treatment of nausea and vomiting symptoms in head injuries, was issued a safety warning from the U.S. Food and Drug Administration regarding QT prolongation and risk of fatal dysrhythmias., Objective: The purpose of this study was to evaluate the safety of ondansetron regarding QT prolongation for patients experiencing nausea or vomiting after head trauma., Methods: Patients aged 1-20 years presenting to a pediatric emergency department with head trauma and who required a dose of ondansetron for nausea or vomiting were enrolled in the study. Patients received a baseline 12-lead electrocardiogram (ECG) prior to administration of either oral or IV ondansetron. A second post-ondansetron 12-lead ECG was performed after administration of ondansetron. All ECGs were reviewed and the QTc calculated manually by a board-certified pediatric cardiologist., Results: Forty-two patients met enrollment criteria. Five patients received IV ondansetron and 37 received oral ondansetron. Mean QTc pre ondansetron was 387.5 ms and mean QTc post ondansetron was 400.9 ms (p = 0.120). We found no statistically significant difference in other ECG parameters pre and post ondansetron., Conclusions: Ondansetron is safe in regard to QTc prolongation in patients with head trauma. Based on this research, ondansetron should continue to be used for the treatment of nausea and vomiting in emergency department patients who present with head injury., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: We evaluated the characteristics and sought risk factors for hospitalization in children who return to the emergency department within 7 days of discharge after oral or intravenous ondansetron treatment for vomiting. The secondary aim was to determine whether the diagnosis of any serious condition had been delayed as the result of discharge after ondansetron treatment., Methods: This retrospective analysis of the medical records of children who had been treated for vomiting with ondansetron in a tertiary care pediatric emergency department and revisited the emergency department within 7 days was performed between 2017 and 2019. We compared demographic and clinical features as well as management between hospitalized and discharged patients, focusing upon potentially delayed diagnoses of serious conditions., Results: Fifty of the 89 ondansetron-treated children (56.2%) who revisited the emergency department were discharged home after their second emergency department visit and the remaining 39 (43.8%) were hospitalized. No parameter of the management of the first visit was predictive of the outcome of the revisit. Five revisit patients (5.6%) were newly diagnosed with a serious condition, with intussusception and ovarian torsion being the most substantial time-sensitive delays (the other diagnoses were pneumonia and aseptic meningitis)., Conclusions: Physicians assessing patients who had been treated with ondansetron as supportive care for vomiting at an earlier visit to the pediatric emergency department should consider alternative diagnoses despite initial clinical improvement. No definitive risk factor for readmission was identified, but a high level of alertness to a possible meningeal or acute abdominal source is imperative., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Although ondansetron was considered to prevent post-anesthesia shivering during cesarean section, its efficiency remained controversial. Our review was conducted to estimate the efficiency and safety of ondansetron in preventing post-anesthesia shivering during cesarean section., Methods: The literature were searched from their inception to October 2020 without restriction of language. All randomized controlled trials investigating the efficacy of ondansetron versus placebo in preventing shivering during cesarean section under neuraxial anesthesia were included. The meta-analysis was conducted using Stata software., Results: Eleven randomized controlled studies with a total of 748 individuals were finally included in our meta-analysis. Our results manifested that intravenous ondansetron compared with intravenous placebo significantly reduced the incidence of post-anesthesia shivering (PAS) (RR 0.53, 95% CI 0.14-0.68). Subgroup analysis according to doses of ondansetron indicated that the efficacy of 4 mg doses of ondansetron (RR 0.37, 95% CI 0.21-0.64) is equivalent to that of 8 mg doses of ondansetron (RR 0.61, 95% CI 0.47-0.81) in preventing PAS. In addition, the intravenous ondansetron led to a lower incidence of hypotension than intravenous placebo (OR 0.47, 95% CI 0.32-0.70). We could not demonstrate differences in the incidence of bradycardia between intravenous ondansetron and intravenous placebo., Conclusion: Our results found that intravenous ondansetron was effective in preventing shivering during cesarean section under neuraxial anesthesia, and had an advantage in reducing the incidence of hypotension compared with intravenous placebo., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Postoperative nausea and vomiting occur in about 20-30% of women; however, some reports have estimated the rate at 70% in at-risk individuals. Gynecological and obstetrical operations are among the most frequent types of surgeries to be associated with nausea and vomiting postoperatively. Ondansetron and dexamethasone have been compared in a variety of studies for postoperative prophylaxis., Aim of the Study: This study was conducted in order to compare the efficacy and safety of dexamethasone and ondansetron, alone or in combination, for prevention of postoperative nausea and vomiting in a sample of Iraqi women undergoing gynecological surgeries., Patients and Methods: The study was conducted in Al-Diwaniyah Province, a region belonging to the Mid-Euphrates sector of Iraq, at the Child and Maternity Teaching Hospital. The study started in June 2021 and the work with the research was accomplished in September 2022. The study included a total of 100 women undergoing different gynecological surgeries such as ovarian cystectomy, oophorectomy, ectopic pregnancy, total abdominal hysterectomy, and myomectomy. All participants involved in the study were categorized randomly into four groups, namely, dexamethasone, ondansetron, combined, and placebo groups., Results: The rates of nausea in the different groups were analyzed. The rates of nausea in dexamethasone, ondansetron, and combined groups revealed a significant decrease compared with that of placebo group (P < 0.05), and the rate was significantly lower in combined group when compared with dexamethasone and ondansetron groups (P < 0.05). The rate of nausea in combined group was significantly lower than that of dexamethasone and ondansetron groups. The rate of vomiting in combined group was significantly lower than that of placebo group and less than that of the dexamethasone group (P < 0.05)., Conclusion: Based on our study and previous reports, both dexamethasone and ondansetron are efficient and safe in preventing nausea and vomiting in gynecological operations; however, combination of both provides the best results., Competing Interests: No conflict of interest was declared by the author.

Background: In this trial, we evaluated the safety and efficacy of olanzapine in children receiving highly emetogenic chemotherapy., Materials and Methods: In this study, patients aged 3 to 18 years were randomly assigned to either the olanzapine group or the placebo group. All patients received intravenous ondansetron and dexamethasone 30 minutes before highly emetogenic chemotherapy, followed by oral ondansetron for 48 hours. Participants in the olanzapine group received olanzapine once daily on days 1 and 2, while those in the control group received a placebo in the same dosage and schedule. The primary objective was: (a) to compare the complete control rates of vomiting in the delayed phase and (b) to compare the complete control rates of vomiting in acute and overall phases. The secondary objective was to evaluate the safety of olanzapine and the need for rescue medications., Results: A total of 128 patients were randomly assigned either to the olanzapine group (n=63) or the control group (n=65). Complete control of vomiting between olanzapine and placebo group was 73% versus 48% ( P =0.005) in the delayed phase, 60% versus 54% ( P =0.46) in the acute phase, and 48% versus 34% ( P =0.117) in the overall phase, respectively. Grades 1 and 2 sedation was greater in the olanzapine group (46% vs. 14%; P <0.001). A significantly higher proportion of patients in the placebo group required rescue medications for vomiting compared with in the olanzapine group ( P =0.025)., Conclusions: Olanzapine significantly improved complete control of vomiting in the delayed phase. A considerably lesser proportion of patients in the olanzapine group needed rescue medications., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ondansetron is a preferred anti-emetic in critical care to treat nausea and vomiting, and has historically been considered a largely safe option. A recent pharmacoepidemiology study reported that ondansetron may be associated with an increased risk for acute kidney injury (AKI). Methods: We interrogated the High-Density Intensive Care (HiDenIC-15) database containing intensive care data for 13 hospitals across Western Pennsylvania between Oct 2008-Dec 2014. AKI was defined using the Kidney Disease, Improving Global Outcomes 2012 guidelines. Ondansetron use was considered as receiving any form of ondansetron within 24 h of admission. The subsequent 48 h (hours 25-72 after admission) were analyzed for outcomes. Primary outcome was development of AKI; secondary outcomes included 90-day mortality and time to AKI. Propensity-matched, multivariate logistic regression was applied for both outcomes. Comparator groups were metoclopramide and prochlorperazine using the same exposure criteria. Results: AKI occurred in 965 (5.6%), 12 (3.0%), and 61 (6.5%) patients receiving ondansetron, prochlorperazine, and metoclopramide, respectively. In the adjusted analysis, no anti-emetic was associated with a significant change in the odds of developing AKI. Ondansetron was associated with a 5.48% decrease (CI -6.17--4.79) in death within 90 days of ICU-admission, which was independent of AKI status; an effect not seen with other anti-emetics. Anti-emetic usage was not associated with a change in the time to first AKI. Conclusion: Anti-emetic usage did not alter AKI risk. Ondansetron was associated with a significant decrease in 90-day mortality that was not seen by other anti-emetics, which requires further exploration.

Background: There is sparse research reporting effective interventions for preventing nausea and emesis caused by concurrent chemoradiotherapy (CCRT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC)., Methods: Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concomitant cisplatin 100 mg/m 2 (33 mg/m 2 /days [d]1-3) every 3 weeks for two cycles. All patients were given oral aprepitant 125 mg once on d1, then 80 mg once on d2-5; ondansetron 8 mg once on d1; and dexamethasone 12 mg once on d1, then 8 mg on d2-5. The primary endpoint was complete response (CR). Pursuant to δ = 0.2 and α = 0.05, the expected CR rate was 80%., Results: A total of 43 patients with LA-HNSCC were enrolled. The median age was 53 years, and 86.0% were male. All patients received radiotherapy and 86.0% of patients completed both cycles as planned. The overall CR rate was 86.0% (95% confidence interval [CI]: 72.1-94.7). The CR rates for cycles 1 and 2 were 88.4% (95% CI: 74.9-96.1) and 89.2% (95% CI: 74.6-97.0). The complete protection rate in the overall phase was 72.1% (95% CI: 56.3-84.7). The emesis-free and nausea-free responses in the overall phase were 88.4% (95% CI: 74.9-96.1) and 60.5% (95% CI: 44.4-75.0), respectively. The adverse events related to antiemetics were constipation (65.1%) and hiccups (16.3%), but both were grade 1-2. There was no grade 4 or 5 treatment-related toxicity with antiemetic usage., Conclusion: The addition of aprepitant into ondansetron and dexamethasone provided effective protection from nausea and emesis in patients with LA-HNSCC receiving radiotherapy and concomitant high-dose cisplatin chemotherapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. We developed a generic physiologically-based pharmacokinetic lactation model for small molecule drugs and applied this model to predict ondansetron transfer into breast milk and characterize infant exposure. Drug-specific model inputs were parameterized using data from the literature. Population-specific inputs were derived from a previously conducted systematic literature review of anatomic and physiologic changes in postpartum women. Model predictions were evaluated using ondansetron plasma and breast milk concentration data collected prospectively from 78 women in the Commonly Used Drugs During Lactation and infant Exposure (CUDDLE) study. The final model predicted breast milk and plasma exposures following a single 4 mg dose of intravenous ondansetron in 1,000 simulated women who were 2 days postpartum. Model predictions showed good agreement with observed data. Breast milk median prediction error (MPE) was 18.4% and median absolute prediction error (MAPE) was 53.0%. Plasma MPE was 32.5% and MAPE was 43.2%. The model-predicted daily and relative infant doses were 0.005 mg/kg/day and 3.0%, respectively. This model adequately predicted ondansetron passage into breast milk. The calculated low relative infant dose indicates that mothers receiving ondansetron can safely breastfeed. The model building blocks and population database are open-source and can be adapted to other drugs., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug-metabolizing enzyme (CYP2D6), transporter (ABCB1), or receptor (5-HT3) were associated with ondansetron failure., Methods: DNA was extracted from blood and used to genotype: ABCB1 (3435C > T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T > C and rs45460698 (delAAG/dupAAG)), and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs)., Results: One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p = 0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (age > 12 (OR 1.12, p = 0.0012) and higher BMI (OR 1.13, p = 0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p = 0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p = 0.0426)., Conclusion: Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Study Objective: The primary objective of this retrospective safety study was to determine the incidence of torsades de pointes (TdP) or death following perioperative administration of low-dose, 4 mg, ondansetron for postoperative nausea and vomiting., Design and Setting: This is a single-center retrospective clinical trial., Patients: The authors identified 32,737 patients who received 37,589 doses of ondansetron during a 2-year time frame between March 2009 and February 2011 for surgical nausea prophylaxis or treatment of nausea., Measurements and Main Results: Patients were cross-matched with an electrocardiogram and adverse outcome database; this identified 4759 patients with documentation of a QTc >450 milliseconds (ms), all ventricular tachycardias including TdP within 48 hours of receiving ondansetron, or death within 7 days of receiving ondansetron. No patients developed TdP or died as a direct result of ondansetron administration (n = 0; event rate = 0.0 per 10,000, 95% CI 0.0 to 1.1 per 10,000). Forty-six of 32,737 surgical patients had documented monomorphic ventricular tachycardia (VT) (n = 14; event rate = 4.3 per 10,000, 95% CI 2.3 to 7.2 per 10,000) or died (n = 32; event rate = 9.8 per 10,000, 95% CI 6.7 to 13.8 per 10,000) within 48 h of ondansetron administration. All monomorphic VT episodes were precipitated by existing cardiovascular disease; and 7 of 14 patients had documented monomorphic VT prior to receiving ondansetron. Of the 32 surgical patients who died, all deaths were precipitated by pre-existing disease., Conclusion: No episodes of TdP were identified in patients receiving ondansetron perioperatively. This suggests that low-dose ondansetron does not contribute to the development of TdP., (© 2022 Pharmacotherapy Publications, Inc.)

Background: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting. However, this medication has also been associated with QT prolongation. Pharmacogenomic information on therapeutic response to ondansetron exists, but no investigation has been performed on genetic factors that influence the cardiac safety of this medication., Methods: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62). Electrocardiograms were conducted at baseline, and 5- and 30-min post-ondansetron administration, to determine the effect of ondansetron treatment on QT interval. Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data., Results: In the entire cohort, 62 patients (24.1%) met the criteria for prolonged QT, with 1.2% of the cohort exhibiting unsafe QT prolongation. The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9.8 × 10 -4 ). CYP2D6 activity score was not associated with prolonged QT. Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2.00 × 10 -7 ) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1.97 × 10 -7 )., Conclusions: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits. These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives/hypothesis: The objective of this study is to evaluate the impact of patient and surgical factors, including approach and reconstruction type, on postoperative nausea and vomiting episodes following endoscopic skull base surgery., Study Design: Retrospective review., Methods: We performed a retrospective chart review from July 2018 to August 2020 of 99 consecutive patients undergoing endoscopic skull base surgery at a tertiary academic skull base surgery program. All patients were treated with a standardized postoperative protocol consisting of scheduled ondansetron, along with promethazine and scopolamine for breakthrough nausea and vomiting episodes. Cumulative nausea and vomiting episodes throughout hospital stay were recorded for each patient., Results: Of the 99 patients identified, the mean number of nausea and vomiting episodes per patient were 0.4 ± 1.2 and 0.3 ± 0.7, respectively. Female sex (β = .65, P = .034) and extended surgical approach (β = .90, P = .027) were associated with increased risk for postoperative nausea. Furthermore, female sex (β = .44, P = .018), cavernous sinus dissection (β = .52, P = .002), and extended approach (β = .79, P = .025) significantly increased odds of postoperative vomiting episodes. There was no association between total operative time or total postoperative opioid dose and nausea and vomiting episodes (all Ps > .05). Neither increased nausea nor vomiting episodes significantly increased odds of prolonged hospitalization (P = .105 and .164, respectively)., Conclusion: This report highlights novel risk factors for patients undergoing endoscopic skull base surgery. Upfront standing antiemetic therapy may be considered when treating patients with independent predictors of postoperative nausea and vomiting, including female sex, cavernous sinus dissection, and extended surgical approach., Level of Evidence: 4 Laryngoscope, 132:761-768, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

At several out-of-hours services primary care, a single dose of ondansetron was compared with standard care (oral rehydration solution (ORS)) in young children with gastroenteritis and persistent vomiting. Although vomiting decreased more often in the ondansetron group compared to the control group in the first hours, ondansetron had no effect on ORS use and did not lead to fewer referrals to the hospital. Unfortunately, the outcome measure diarrhoea was missing as a possible adverse effect of ondansetron. Diarrhoea was reported around 2-3 times more often with ondansetron compared to placebo in four of five other studies in children with gastroenteritis and vomiting. It is therefore questionable whether the limited clinical benefit of ondansetron in children with vomiting due to gastroenteritis outweighs the possible (as yet insufficiently investigated) side effect diarrhoea.

The incidence rates of spinal anaesthesia-induced hypotension vary depending on the surgical procedures. This systematic review and meta-analysis evaluates the efficacy of prophylactic ondansetron in reducing the incidence of spinal anaesthesia-induced hypotension in non-caesarean delivery. Thirteen trials consisting of 1166 patients were included for analysis. Compared to placebo, there is a low quality of evidence that ondansetron was effective in reducing the incidence of spinal anaesthesia-induced hypotension (RR 0.62, 95% CI 0.44 to 0.87; p  = 0.005) and bradycardia (RR 0.54, 95% CI 0.32 to 0.90; p  = 0.02). We also found a moderate quality of evidence that ondansetron lowered the number of rescue ephedrine (RR 0.61, 95% CI 0.43 to 0.87; p  = 0.007). Patients treated with ondansetron have higher mean arterial pressure 15 to 20 minutes after spinal anaesthesia induction and higher systolic arterial pressure 5, 10, 15 and 20 minutes after spinal anaesthesia. The evidence suggests that prophylactic administration of ondansetron results in the reduction of the incidence of spinal anaesthesia-induced hypotension, bradycardia and rescue ephedrine in patients undergoing non-caesarean delivery under spinal anaesthesia.

Although there is no recommendation in France relating to the treatment of nausea and vomiting of pregnancy, there are some in other countries, where ondansetron, widely used, appears to be an effective second-line treatment option behind doxylamine/vitamin B6 association and metoclopramide. However, based on some recent publication suggesting an increased risk of orofacial clefts and congenital heart defects in fetuses exposed in utero to ondansetron in the 1st trimester of pregnancy, the European Medicines Agency now states that this drug should not longer be used during this period. This 2019 decision is controversial and whether ondansetron can be used in pregnant women with severe vomiting during pregnancy is still in question., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background: In mildly to moderately dehydrated patients with acute gastroenteritis (AGE), oral rehydration therapy (ORT) is the treatment of choice. Though ondansetron is a very effective antiemetics and leads to succeed ORT, there have been reports QT prolongation in patients using it. We investigated the effect of oral ondansetron on QT interval in mildly to moderately dehydrated children with AGE., Methods: This retrospective observational study was conducted in a single pediatric emergency department (ED) of a tertiary university hospital. We collected the medical records of patients with a primary diagnosis of AGE who received oral ondansetron and underwent an electrocardiogram between January 2017 and June 2018. A pediatric emergency physician calculated the corrected QT interval (QTc) by Bazett's method, and the calculations were reviewed by a pediatric cardiologist. QTc values before (preQTc) and after (postQTc) ondansetron administration were analyzed. ΔQTc was calculated as the change from preQTc to postQTc. We also investigated any cardiac complications from oral ondansetron., Results: Total 80 patients were included. The mean age of the patients was 53.31 ± 32.42 months, and 45% were male. The mean dose of oral ondansetron was 0.18 ± 0.04 mg/kg. The mean interval from administration of ondansetron to performance of the electrocardiogram was 65 ± 26 min. The mean preQTc was 403.3 ± 24.0 ms, and the mean postQTc was 407.2 ± 26.7 ms. Two patients had a preQTc ≥460 ms, and one patient had a postQTc ≥460 ms. ΔQTc was ≥30 ms in seven patients (8.8%). No ΔQTc was ≥60 ms. No pre- or postQTc was ≥500 ms. No patient had a fatal cardiac arrhythmia after taking ondansetron., Conclusion: Oral administration of a single dose of ondansetron in children with AGE did not cause high-risk QTc prolongation or fatal arrhythmia., (© 2021. The Author(s).)

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT 3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT 3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT 3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT 3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT 3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT 3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Prospective data evaluating the effect of ondansetron on the corrected QT (QTc) interval is lacking in emergency department clinical use. As part of a randomized trial of a 24-mg bimodal-release ondansetron (RHB-102) pill, we tested the effect of RHB-102 compared to placebo on QTc change., Methods: This was a planned safety outcome analysis within a multicenter, double-blind, placebo-controlled trial. The trial compared the effects of RHB-102 among patients ≥12 years who presented to 21 centers with symptoms of acute gastroenteritis. Patients with an initial baseline electrocardiogram as well as a follow-up electrocardiogram 4 h later were included in the analysis. The safety endpoint for this analysis was the change from baseline in QTc interval at 4 h, the median time at which ondansetron serum level peaks., Results: A total of 147 patients were included with a mean baseline QTc in the RHB-102 and placebo arms of 410 and 406 ms, respectively. There was no difference in the change in QTc at 4 h post-study drug administration between the RHB-102 (+4, 95% CI 1-8 ms) and placebo group (+5, 95% CI 1-9 ms). In the RHB-102 arm, 6.6% of patients had a QTc change >30 ms and in the placebo arm 3.6% (p = 0.48). No patient in either arm had a QTc change >60 ms after study drug administration., Conclusion: In patients with normal baseline QTc, 24-mg bimodal-release ondansetron did not prolong the QTc in comparison to placebo., Competing Interests: Declaration of competing interest Grant money for commercial research: JM, SH, LL, AM, BH, JA, and RS report grant money to their institutions from RedHill Biopharma for the performance of this trial. Employment: TP, RS, IK, and RF are employed by RedHill Biopharma, which manufacturers a product related to the subject matter., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision., (© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Importance: Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes., Objective: To study the association between ondansetron exposure during pregnancy and the risks of spontaneous abortion, stillbirth, and major congenital malformations., Design, Setting, and Participants: This is a cohort study conducted in 3 countries, with a meta-analysis. Participants included women and girls aged 12 to 55 years who experienced spontaneous abortion, induced abortion, stillbirth, or live birth between April 2002 and March 2016, as recorded in administrative data from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, and Ontario), the US IBM MarketScan Research Databases, and the UK Clinical Practice Research Datalink. The statistical analysis was completed in October 2020., Exposures: Exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication., Main Outcomes and Measures: The primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. Secondary outcomes were the 2 components of the primary outcome and major congenital malformations identified during the year after a live birth. Adjusted hazard ratios were estimated using Cox proportional hazards models with time-dependent drug exposures and were adjusted using high-dimensional propensity scores. For major congenital malformations, adjusted odds ratios were estimated from logistic models. Site-level results were pooled using random-effects meta-analysis. Sensitivity analyses considered second-line antiemetic exposure and exposure specifically during 4 to 10 weeks of gestation., Results: Data from 456 963 pregnancies were included in this study of fetal death (249 787 [54.7%] in Canada, 197 913 [43.3%] in the US, and 9263 [2.0%] in the UK; maternal age, ≤24 years, 93 201 patients [20.4%]; 25-29 years, 149 117 patients [32.6%]; 30-34 years, 142 442 patients [31.2%]; and ≥35 years, 72 203 patients [15.8%]). Fetal death occurred in 12 907 (7.9%) of 163 810 pregnancies exposed to ondansetron, and 17 476 (5.7%) of 306 766 pregnancies exposed to other antiemetics. The adjusted hazard ratios were 0.91 (95% CI, 0.67-1.23) for fetal death with time-dependent ondansetron exposure during pregnancy, 0.82 (95% CI, 0.64-1.04) for spontaneous abortion, and 0.97 (95% CI, 0.79-1.20) for stillbirth. For major congenital malformations, the estimated odds ratio was 1.06 (95% CI, 0.91-1.22). Results of sensitivity analyses were generally consistent with those of the primary analyses., Conclusions and Relevance: In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs.

Background: Ondansetron is commonly used to treat nausea and vomiting in pregnancy despite inconclusive evidence of its safety. Previous studies have reported no increase in risk of miscarriage but relied on methods that failed to account for gestational weeks at risk and non-user comparators, which may increase the potential for unmeasured confounding. Our objective was to estimate the risk of miscarriage among women prescribed ondansetron vs alternative antiemetics during the first 20 weeks of pregnancy., Methods: A pregnancy cohort was created using electronic health record data from a health care system in North Carolina. Women were classified as exposed to either ondansetron or comparator antiemetics (metoclopramide or promethazine) based on the first antiemetic prescription received in the first 20 weeks of gestation. Cumulative incidence of miscarriage at 20 weeks was estimated in each antiemetic group. Hazard ratios (HR) were estimated with 95% confidence intervals and measured confounding was controlled using inverse probability of treatment weights. Sensitivity analyses assessed the potential impact of exposure misclassification, latency period, and selection bias., Results: We identified 2620 eligible pregnancies with antiemetic orders; 65% had a first ondansetron order and 35% had a first comparator antiemetic order. In total, 95 women had a miscarriage. After adjustment, there was no difference in risk of miscarriage (HR 1.21, 95% CI 0.77, 1.90). Results from the per-protocol and other sensitivity analyses were similar to the main analysis., Conclusions: We did not observe an increase in the risk of miscarriage for pregnancies exposed to ondansetron vs comparator antiemetics., (© 2020 John Wiley & Sons Ltd.)

Background: The effects of ondansetron, used off-label to treat nausea and vomiting during pregnancy, on common pregnancy complications are understudied. Modest effects of a commonly used drug could result in adverse events for large numbers of pregnant women. Therefore, our objective was to compare the risk of stillbirth, preterm birth, gestational hypertensive disorders, small for gestational age, and differences in birth weight between women prescribed ondansetron and women prescribed alternative antiemetics in early pregnancy., Methods: A cohort of pregnant women receiving a prescription for ondansetron or comparator antiemetics (metoclopramide or promethazine) during the first 20 weeks of pregnancy was identified using electronic health record data from a health care system in North Carolina, USA. Confounding by multiple covariates was controlled using stabilized inverse probability of treatment weights. Weighted hazard ratios (HR) and 95% confidence intervals (CI) accounted for competing events., Results: We identified 2677 eligible pregnancies with antiemetic orders, 66% for ondansetron. The small number of stillbirths (n = 15) resulted in an imprecise estimate of the association with ondansetron (HR = 1.60; 95%CI 0.51, 4.97). No association was observed for preterm birth (HR = 0.90; 95%CI 0.67, 1.20) or gestational hypertensive disorders (HR = 0.87; 95%CI 0.68, 1.12). We observed an association with small for gestational age (HR = 1.37; 95%CI 0.98, 1.90), however mean birth weight among term births was similar between groups., Conclusions: Our results do not suggest that ondansetron increases the risk of preterm birth or gestational hypertensive disorders. The weak association observed between ondansetron use and small for gestational age warrants further investigation., (© 2020 John Wiley & Sons Ltd.)

Domperidone, ondansetron and olanzapine can prolong the QT interval. The clinical use of combinations of these drugs is not uncommon. Our study aimed to determine the presence of any QTc prolonging effect of the combination when used as antiemetic in patients receiving cancer chemotherapy. We carried out a prospective, observational study of patients with malignancy who were to receive domperidone, ondansetron and olanzapine-containing antiemetic regimen. Electrocardiograms were recorded before and during the administration of antiemetics, for three consecutive days. A blinded assessor determined the QTc interval using Bazett and Fridericia formulae. Thirty-six patients completed the study; 23 (63.9%) were females. There was a statistically significant change in QTc with time (Fridericia, χ 2 (4) = 15.629, p = 0.004; Bazett, χ 2 (4) = 15.910, p = 0.003); QTc on Day 1 was more than that during baseline (p < 0.001); these differences were significant in females (Fridericia, χ 2 (4) = 13.753, p = 0.008; Bazett, χ 2 (4) = 13.278, p = 0.010) but not in males (Fridericia, χ 2 (4) = 4.419, p = 0.352; Bazett, χ 2 (4) = 4.280, p = 0.369). Two female patients had an absolute QTc prolongation (Bazett correction) of > 500 ms. However, no clinically significant adverse events occurred. The findings show that QTc prolongation is a concern with olanzapine alone and in combination with domperidone and ondansetron, and needs to be investigated further.

Purpose: We assessed the efficacy of aprepitant (APR) or 10 or 5 mg OLN (OLN10 or OLN5) plus ondansetron and dexamethasone for chemotherapy-induced nausea/vomiting (CINV) prophylaxis in patients receiving high-emetogenic chemotherapy (HEC)., Methods: Patients who received doxorubicin + cyclophosphamide or cisplatin were given intravenous ondansetron and dexamethasone prior to chemotherapy and oral dexamethasone on days 2-4 and randomized 1:1:1 to receive APR125 on day 1 and APR80 on days 2-3 or OLN10 or OLN5 on days 1-4. Matched placebo controls were used. The primary endpoint was no nausea in ≤ 120 h. Secondary endpoints included CINV severity, complete response (CR) rate, adverse effects (AE), and quality of life., Results: Of 141 patients, 104 received AC and 37 received cisplatin. The no-nausea rates were 33% (APR), 43.2% (OLN10; p = 0.24), and 37% (OLN5; p = 0.87). Grades 2-4 nausea were experienced by fewer patients for OLN10 than for APR (24-120 h, 8.7% vs. 27.7%, respectively; p = 0.02; overall period, 19.6% vs. 40.4%, respectively; p = 0.03). The median visual analog scale nausea score from 24 to 120 h was significantly lower for OLN10 (2.3) than for APR (1.2, p = 0.03). The degrees of vomiting, CR, and AE were similar between the APR and OLN10 groups. CINV was similar between the OLN5 and APR groups., Conclusions: Nausea was less severe for OLN10 than for APR in patients receiving HEC, but other measures were similar. CINV prevention efficacy was comparable between OLN5 and APR.