Ondansetron
(Ondansetron Hydrochloride)Ondansetron Prescribing Information
Ondansetron is indicated for the prevention of nausea and vomiting associated with:
- highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m2.
- initial and repeat courses of moderately emetogenic cancer chemotherapy.
- radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen.
Ondansetron is also indicated for the prevention of postoperative nausea and/or vomiting.
- See full prescribing information for the recommended dosage in adults and pediatrics. ()
2 DOSAGE AND ADMINISTRATION- See full prescribing information for the recommended dosage in adults and pediatrics.
- Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg.
2.1 DosageThe recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively.
Corresponding doses of ondansetron tablets and ondansetron oral solution may be used interchangeably.
Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Highly Emetogenic Cancer ChemotherapyA single 24-mg dose administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin greater than or equal to 50 mg/m2 Moderately Emetogenic Cancer Chemotherapy8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8-mg dose 8 hours after the first dose. Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.
RadiotherapyFor total body irradiation:8 mg administered 1 to 2 hours before each fraction of radiotherapy each day.For single high-dose fraction radiotherapy to the abdomen:8 mg administered 1 to 2 hours before radiotherapy, with subsequent 8-mg doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.For daily fractionated radiotherapy to the abdomen:8 mg administered 1 to 2 hours before radiotherapy, with subsequent 8-mg doses every 8 hours after the first dose for each day radiotherapy is given.Postoperative16 mg administered 1 hour before induction of anesthesia. Table 2: Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Moderately Emetogenic Cancer Chemotherapy12 to 17 years of age:8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8-mg dose 8 hours after the first dose.Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.
4 to 11 years of age:4 mg administered 30 minutes before the start of chemotherapy, with a subsequent 4-mg dose 4 and 8 hours after the first dose.Then administer 4 mg three times a day for 1 to 2 days after completion of chemotherapy.
2.2 Dosage in Hepatic ImpairmentIn patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total daily dose of 8 mg
[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. - Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg. (,
2.2 Dosage in Hepatic ImpairmentIn patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total daily dose of 8 mg
[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].)8.6 Hepatic ImpairmentNo dosage adjustment is needed in patients with mild or moderate hepatic impairment.
In patients with severe hepatic impairment, clearance is reduced and the apparent volume of distribution is increased, resulting in a significant increase in the half-life of ondansetron. Therefore, do not exceed a total daily dose of 8 mg in patients with severe hepatic impairment (Child-Pugh score of 10 or greater)
[see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
Ondansetron oral solution USP, 4 mg/5 mL, is a clear, colorless to light yellow liquid with a characteristic strawberry odor available in a 50-mL bottle.
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 [
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 6thand 9thweeks 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.
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ondansetron up to 15 mg/kg/day and 30 mg/kg/day, respectively, during the period of organogenesis. With the exception of a slight decrease in maternal body weight gain in the rabbits, there were no significant effects of ondansetron on the maternal animals or the development of the offspring. At doses of 15 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal exposure margin was approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/day, respectively, based on body surface area.
In a pre- and postnatal developmental toxicity study, pregnant rats received oral 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. At a dose of 15 mg/kg/day in rats, the maternal exposure margin was approximately 6 times the maximum recommended human oral dose of 24 mg/day, based on body surface area.
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 6thand 9thweeks 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.
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ondansetron up to 15 mg/kg/day and 30 mg/kg/day, respectively, during the period of organogenesis. With the exception of a slight decrease in maternal body weight gain in the rabbits, there were no significant effects of ondansetron on the maternal animals or the development of the offspring. At doses of 15 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal exposure margin was approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/day, respectively, based on body surface area.
In a pre- and postnatal developmental toxicity study, pregnant rats received oral 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. At a dose of 15 mg/kg/day in rats, the maternal exposure margin was approximately 6 times the maximum recommended human oral dose of 24 mg/day, based on body surface area.
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.
Ondansetron is contraindicated in patients:
- known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation [see.]
6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of ondansetron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
CardiovascularArrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.
GeneralFlushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylactic reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported.
Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron.
HepatobiliaryLiver enzyme abnormalities.
Lower RespiratoryHiccups.
NeurologyOculogyric crisis, appearing alone, as well as with other dystonic reactions.
SkinUrticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Eye DisordersCases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.
- receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness.
- Hypersensitivity reactions including anaphylaxis and bronchospasm:Discontinue ondansetron if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve. ()
5.1 Hypersensitivity ReactionsHypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3receptor antagonists. If hypersensitivity reactions occur, discontinue use of ondansetron; treat promptly per standard of care and monitor until signs and symptoms resolve
[see Contraindications (4)]. - QT interval prolongation and Torsade de Pointes: Avoid in patients with congenital long QT syndrome; monitor with electrocardiograms (ECGs) if concomitant electrolyte abnormalities, cardiac failure or arrhythmias, or use of other QT prolonging drugs. ()
5.2 QT ProlongationElectrocardiogram (ECG) changes including QT interval prolongation have been seen in patients receiving ondansetron. In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking other medicinal products that lead to QT prolongation
[see Clinical Pharmacology (12.2)]. - Serotonin syndrome:Reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue ondansetron and initiate supportive treatment. If concomitant use of ondansetron with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. ()
5.3 Serotonin SyndromeThe development of serotonin syndrome has been reported with 5-HT3receptor antagonists alone. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of ondansetron alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.
Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ondansetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue ondansetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if ondansetron is used concomitantly with other serotonergic drugs
[see Drug Interactions (7.1), Overdosage (10)]. - Masking of progressive ileus and/or gastric distention following abdominal surgery or chemotherapy-induced nausea and vomiting: Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. ()
5.4 Masking of Progressive Ileus and Gastric DistensionThe use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.
Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.