Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.
Available data do not reliably inform the association of ondansetron and adverse fetal outcomes. Published epidemiological studies on the association between ondansetron and fetal outcomes have reported inconsistent findings and have important methodological limitations hindering interpretation [see Data]. Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered intravenously during organogenesis at approximately 3.6 and 2.9 times the maximum recommended human intravenous dose of 0.15 mg/kg given three times a day, based on body surface area, respectively [see Data].
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Methodological limitations of the epidemiology studies preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of ondansetron in pregnancy. Two large retrospective cohort studies of ondansetron use in pregnancy have been published. In one study with 1,349 infants born to women who reported the use of ondansetron or received an ondansetron prescription in the first trimester, no increased risk for major congenital malformations was seen in aggregate analysis. In this same study, however, a sub-analysis for specific malformations reported an association between ondansetron exposure and cardiovascular defect (odds ratio (OR) 1.62 [95% CI (1.04, 2.14)]) and cardiac septal defect (OR 2.05 [95% CI (1.19, 3.28)]). The second study examined 1970 women who received ondansetron prescription during pregnancy and reported no association between ondansetron exposure and major congenital malformations, miscarriage or stillbirth, and infants of low birth weight or small for gestational age. Important methodological limitations with these studies include the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, and other unadjusted confounders that may account for the study findings.
A case-control study evaluating associations between several common non-cardiac malformations and multiple antiemetic drugs reported an association between maternal use of ondansetron and isolated cleft palate (reported adjusted OR = 2.37 [95% CI (1.18, 4.76)]). However, this association could be a chance finding, given the large number of drugs-birth defect comparisons in this study. It is unknown whether ondansetron exposure in utero in the cases of cleft palate occurred during the time of palate formation (the palate is formed between the 6th and 9th weeks of pregnancy) or whether mothers of infants with cleft palate used other medications or had other risk factors for cleft palate in the offspring. In addition, no cases of isolated cleft palate were identified in the aforementioned two large retrospective cohort studies. At this time, there is no clear evidence that ondansetron exposure in early pregnancy can cause cleft palate.
Animal Data
In embryo-fetal development studies in rats and rabbits, pregnant animals received intravenous doses of ondansetron up to 10 mg/kg/day and 4 mg/kg/day, respectively, during the period of organogenesis. With the exception of short periods of maternal weight loss and a slight increase in the incidence of early uterine deaths at the high dose level in rabbits, there were no significant effects of ondansetron on the maternal animals or the development of the offspring. At doses of 10 mg/kg/day in rats and 4 mg/kg/day in rabbits, the maternal exposure margin was approximately 3.6 and 2.9 times the maximum recommended human oral dose of 0.15 mg/kg given three times a day, respectively, based on body surface area.
No intravenous pre-and post-natal developmental toxicity study was performed with ondansetron. In an oral pre-and post-natal development study pregnant rats received doses of ondansetron up to 15 mg/kg/day from Day 17 of pregnancy to litter Day 21. With the exception of a slight reduction in maternal body weight gain, there were no effects upon the pregnant rats and the pre-and postnatal development of their offspring, including reproductive performance of the mated F1 generation.
It is not known whether ondansetron is present in human milk. There are no data on the effects of ondansetron on the breastfed infant or the effects on milk production. However, it has been demonstrated that ondansetron is present in the milk of rats.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ondansetron and any potential adverse effects on the breast-fed infant from ondansetron or from the underlying maternal condition.
8.4 Pediatric Use
Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month [see Clinical Studies (14.2)]. Little information is available about the use of ondansetron in pediatric cancer patients younger than 6 months [see Clinical Studies (14.1), Dosage and Administration (2)].
The clearance of ondansetron in pediatric patients aged 1 month to 4 months is slower and the half-life is ~2.5-fold longer than patients who are aged >4 to 24 months. As a precaution, it is recommended that patients younger than 4 months receiving this drug be closely monitored [see Clinical Pharmacology (12.3)].
8.5 Geriatric Use
Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting US- and foreign-controlled clinical trials, 862 were aged 65 years and older. No overall differences in safety or effectiveness were observed between subjects 65 years and older and younger subjects. A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects [see Clinical Pharmacology 12.3)]. There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age-group. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65.
8.6 Hepatic Impairment
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life [see Clinical Pharmacology (12.3)]. In such patients, a total daily dose of 8 mg should not be exceeded [see Dosage and Administration (2.3)].
8.7 Renal Impairment
Although plasma clearance is reduced in patients with severe renal impairment (creatinine clearance <30 mL/min), no dosage adjustment is recommended [see Clinical Pharmacology (12.3)].