The following Structured Product Label (SPL) was submitted to the FDA by Accord Healthcare, Inc. for the product Ondansetron (NDC 16729-298). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1.1 prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, 1.2 prevention of postoperative nausea and/or vomiting, 2.1 prevention of nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy, 2.2 prevention of postoperative nausea and vomiting, 2.3 dosage adjustment for patients with hepatic impairment, 3 dosage forms and strengths, 4 contraindications, 5.1 hypersensitivity reactions, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
Ondansetron Injection USP is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin.
Ondansetron Injection USP is approved for patients aged 6 months and older.
Ondansetron Injection USP is indicated for the prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients in whom nausea and/or vomiting must be avoided postoperatively, Ondansetron Injection USP is recommended even when the incidence of postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic Ondansetron Injection USP and experience nausea and/or vomiting postoperatively, Ondansetron Injection USP may be given to prevent further episodes.
Ondansetron Injection USP is approved for patients aged 1 month and older.
Important Preparation Instructions
For pediatric patients between 6 months and 1 year of age and/or 10 kg or less:
Depending on the fluid needs of the patient, Ondansetron Injection may be diluted in 10 to 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
Dosage and Administration
The recommended dosage for adult and pediatric patients 6 months of age and older for prevention of nausea and vomiting associated with emetogenic chemotherapy is 0.15-mg/kg per dose for 3 doses (maximum of 16 mg per dose).
Caution: Dilution of Ondansetron Injection is required in adult and pediatric patients prior to administration.
Infuse intravenously over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy and then repeat 4 and 8 hours after the first dose.
Important Preparation Instructions
Dosage and Administration
The recommended dose and administration instructions for adult and pediatric patients 1 month of age and older for prevention of postoperative nausea and vomiting are shown in Table 1.
Table 1. Recommended Dose and Administration of Ondansetron Injection for Prevention of Postoperative Nausea and Vomiting
Population | Recommended Single Dose | Administration Instructions | Timing of Administration |
Adults and pediatric patients older than 12 years of age | 4 mg 1 | May be administered intravenously or intramuscularly:
| Administer immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery 2,3 |
Pediatric patients 1 month to 12 years and more than 40 kg | 4 mg | Infuse intravenously over at least 30 seconds and preferably longer (over 2 to 5 minutes). | |
Pediatric patients 1 month to 12 years and 40 kg or less | 0.1 mg/kg | Infuse intravenously over at least 30 seconds and preferably longer (over 2 to 5 minutes). |
1. Few patients above 80 kg have been studied.
2. Administration of a second intravenous dose of 4 mg ondansetron postoperatively in adult patients who received a 4 mg prophylactic dose does not provide additional control of nausea and vomiting
[see Clinical Studies (14.3)].
3. For pediatric patients (1 month to 12 years) prevention of nausea and vomiting was only studied in patients who had not received prophylactic ondansetron.
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron in these patients [see Use in Specific Populations (8.6)].
Ondansetron Injection: 40 mg/20 mL clear, colorless, nonpyrogenic, sterile solution in a multiple-dose vial.
Ondansetron Injection is contraindicated for patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Anaphylactic reactions have been reported in patients taking ondansetron. [See Adverse Reactions (6.2).]
The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron.
Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists.
Ondansetron prolongs the QT interval in a dose-dependent manner [see Clinical Pharmacology (12.2)] . In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid Ondansetron Injection 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.
The development of serotonin syndrome has been reported with 5-HT 3 receptor antagonists. 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 Injection alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT 3 receptor 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 Injection and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Ondansetron Injection and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Ondansetron Injection is used concomitantly with other serotonergic drugs [see Drug Interactions (7.5), Overdosage (10), Patient Counseling Information (17)] .
The use of Ondansetron Injection in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and gastric distention.
Ondansetron Injection is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The following adverse reactions have been reported in clinical trials of adult patients treated with ondansetron, the active ingredient of intravenous Ondansetron Injection across a range of dosages. A causal relationship to therapy with ondansetron was unclear in many cases.
Number of Adult Patients with Reaction | |||
Adverse Reaction | Ondansetron Injection 0.15 mg/kg x 3 (n = 419) | Metoclopramide (n = 156) | Placebo (n = 34) |
Diarrhea | 16% | 44% | 18% |
Headache | 17% | 7% | 15% |
Fever | 8% | 5% | 3% |
The adverse reactions in Table 3 have been reported in ≥ 2% of adults receiving ondansetron at a dosage of 4 mg intravenous over 2 to 5 minutes in clinical trials.
Adverse Reaction a,b | Ondansetron Injection 4 mg Intravenous (n = 547) | Placebo (n = 547) |
Headache | 92 (17%) | 77 (14%) |
Drowsiness/sedation | 44 (8%) | 37 (7%) |
Injection site reaction | 21 (4%) | 18 (3%) |
Fever | 10 (2%) | 6 (1%) |
Cold sensation | 9 (2%) | 8 (1%) |
Pruritus | 9 (2%) | 3 (< 1%) |
Paresthesia | 9 (2%) | 2 (< 1%) |
a Adverse reactions: Rates of these reactions were not significantly different in the ondansetron and placebo groups.
b Patients were receiving multiple concomitant perioperative and postoperative medications.
The 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. The reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ondansetron.
Arrhythmias (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/QTc interval prolongation have been reported [see Warnings and Precautions (5.2)] .
Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylactic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported. A positive lymphocyte transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron.
Liver enzyme abnormalities have been reported. Liver failure and death have been reported in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics.
Pain, redness, and burning at site of injection.
Oculogyric crisis, appearing alone, as well as with other dystonic reactions. Transient dizziness during or shortly after intravenous infusion.
Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Cases 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. Transient blurred vision, in some cases associated with abnormalities of accommodation, have also been reported.
Ondansetron does not appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron [see Clinical Pharmacology (12.3)] . On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs.
Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with ondansetron is contraindicated [see Contraindications (4)].
In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs [see Clinical Pharmacology (12.3)] .
Although there are no data on pharmacokinetic drug interactions between ondansetron and tramadol, data from two small trials indicate that concomitant use of ondansetron may result in reduced analgesic activity of tramadol. Patients on concomitant ondansetron self administered tramadol more frequently in these trials, leading to an increased cumulative dose in patient-controlled administration (PCA) of tramadol.
Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.3)] .
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase blood levels of high-dose methotrexate.
The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.
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.
Risk Summary
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.
Data
Human Data
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 6 th and 9 th 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.
Risk Summary
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.
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 age > 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).]
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.
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)] .
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)] .
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies.
There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose.
In addition to the adverse reactions listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of ondansetron hydrochloride tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely.
Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg/kg) in young children. Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure. Patients required supportive care, including intubation in some cases, with complete recovery without sequelae within 1 to 2 days.
The active ingredient of Ondansetron Injection USP is ondansetron hydrochloride, a selective blocking agent of the serotonin 5-HT 3 receptor type. Its chemical name is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula:
Ondansetron Chemical Structure (Ondansetron Structure)
The empirical formula is C 18H 19N 3O•HCl•2H 2O, representing a molecular weight of 365.9.
Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline.
Each 1 mL of aqueous solution in the 20-mL multidose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in Water for Injection, USP.
Ondansetron Injection USP is a clear, colorless, nonpyrogenic, sterile solution for intravenous use. The pH of the injection solution is 3.3 to 4.0.
Ondansetron is a selective 5-HT 3 receptor antagonist. While ondansetron’s mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist.
In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. In another trial in six normal male volunteers, a 16 mg dose infused over 5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. In a gender balanced pharmacodynamic trial (n = 56), ondansetron 4 mg administered intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting using the ipecacuanha model of emesis.
Cardiac Electrophysiology
QTc interval prolongation was studied in a double-blind, single intravenous dose, placebo-and positive-controlled, crossover trial in 58 healthy subjects. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 19.5 (21.8) ms and 5.6 (7.4) ms after 15-minute intravenous infusions of 32 mg and 8 mg Ondansetron, respectively. A significant exposure-response relationship was identified between ondansetron concentration and ΔΔQTcF. Using the established exposure-response relationship, 24 mg infused intravenously over 15 minutes had a mean predicted (95% upper prediction interval) ΔΔQTcF of 14.0 (16.3) ms. In contrast, 16 mg infused intravenously over 15 minutes using the same model had a mean predicted (95% upper prediction interval) ΔΔQTcF of 9.1 (11.2) ms. In this study, the 8-mg dose infused over 15 minutes did not prolong the QT interval to any clinically relevant extent.
In normal adult volunteers, the following mean pharmacokinetic data have been determined following a single 0.15-mg/kg intravenous dose.
Age-group (years) | n | Peak Plasma Concentration (ng/mL) | Mean Elimination Half-life (h) | Plasma Clearance (L/h/kg) |
19-40 | 11 | 102 | 3.5 | 0.381 |
61-74 | 12 | 106 | 4.7 | 0.319 |
≥ 75 | 11 | 170 | 5.5 | 0.262 |
A trial was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of a single 4-mg dose administered as a 5-minute infusion compared with a single intramuscular injection. Systemic exposure as measured by mean AUC were equivalent, with values of 156 [95% CI: 136, 180] and 161 [95% CI: 137, 190] ng●h/mL for intravenous and intramuscular groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI: 33.8, 54.4] ng/mL at 10 minutes after intravenous infusion and 31.9 [95% CI: 26.3, 38.6] ng/mL at 41 minutes after intramuscular injection.
Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, over the pharmacologic concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.
Metabolism: Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. The metabolites are observed in the urine.
In vitro metabolism studies have shown that ondansetron is a substrate for multiple human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 plays a predominant role while formation of the major in vivo metabolites is apparently mediated by CYP1A2. The role of CYP2D6 in ondansetron in vivo metabolism is relatively minor.
The pharmacokinetics of intravenous ondansetron did not differ between subjects who were poor metabolizers of CYP2D6 and those who were extensive metabolizers of CYP2D6, further supporting the limited role of CYP2D6 in ondansetron disposition in vivo.
Geriatric Patients: A reduction in clearance and increase in elimination half-life are seen in patients older than 75 years of age [see Use in Specific Populations (8.5)].
Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day, respectively (approximately 3.6 and 5.4 times the recommended human intravenous dose of 0.15 mg/kg given three times a day, based on body surface area). Ondansetron was not mutagenic in standard tests for mutagenicity.
Oral administration of ondansetron up to 15 mg/kg per day (approximately 3.8 times the recommended human intravenous dose, based on body surface area) did not affect fertility or general reproductive performance of male and female rats.
The clinical efficacy of ondansetron hydrochloride, the active ingredient of Ondansetron Injection was assessed in clinical trials as described below.
In a double-blind trial of three different dosing regimens of Ondansetron Injection 0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the 0.15-mg/kg dosing regimen.
Adult surgical patients who received ondansetron immediately before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) were evaluated in two double-blind US trials involving 554 patients. Ondansetron Injection (4 mg) intravenous given over 2 to 5 minutes was significantly more effective than placebo. The results of these trials are summarized in Table 10.
Ondansetron 4 mg Intravenous | Placebo | P Value | |
Study 1 | |||
Emetic episodes: | |||
Number of patients | 136 | 139 | |
Treatment response over 24-h postoperative period | |||
| 103 (76%) | 64 (46%) | < 0.001 |
| 13 (10%) | 17 (12%) | |
| 20 (15%) | 58 (42%) | |
Nausea assessments: | |||
Number of patients | 134 | 136 | |
No nausea over 24-h postoperative period | 56 (42%) | 39 (29%) | |
Study 2 | |||
Emetic episodes: | |||
Number of patients | 136 | 143 | |
Treatment response over 24-h postoperative period | |||
| 85 (63%) | 63 (44%) | 0.002 |
| 16 (12%) | 29 (20%) | |
| 35 (26%) | 51 (36%) | |
Nausea assessments: | |||
Number of patients | 125 | 133 | |
No nausea over 24-h postoperative period | 48 (38%) | 42 (32%) |
The populations in
Table 10 consisted mainly of females undergoing laparoscopic procedures.
In a placebo-controlled trial conducted in 468 males undergoing outpatient procedures, a single 4-mg intravenous ondansetron dose prevented postoperative vomiting over a 24-hour period in 79% of males receiving drug compared with 63% of males receiving placebo ( P < 0.001)
Two other placebo-controlled trials were conducted in 2,792 patients undergoing major abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg intravenous ondansetron dose for prevention of postoperative nausea and vomiting over a 24-hour period. At the 4-mg dosage, 59% of patients receiving ondansetron versus 45% receiving placebo in the first trial ( P < 0.001) and 41% of patients receiving ondansetron versus 30% receiving placebo in the second trial ( P = 0.001) experienced no emetic episodes. No additional benefit was observed in patients who received intravenous ondansetron 8 mg compared with patients who received intravenous ondansetron 4 mg.
Adult surgical patients receiving general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) who received no prophylactic antiemetics and who experienced nausea and/or vomiting within 2 hours postoperatively were evaluated in two double-blind US trials involving 441 patients. Patients who experienced an episode of postoperative nausea and/or vomiting were given Ondansetron Injection (4 mg) intravenously over 2 to 5 minutes, and this was significantly more effective than placebo. The results of these trials are summarized in Table 12.
Ondansetron 4 mg Intravenous | Placebo | P Value | |
Study 1 | |||
Emetic episodes: | |||
Number of patients | 104 | 117 | |
Treatment response 24 h after study drug | |||
| 49 (47%) | 19 (16%) | < 0.001 |
| 12 (12%) | 9 (8%) | |
| 43 (41%) | 89 (76%) | |
Median time to first emetic episode (min) a | 55.0 | 43.0 | |
Nausea assessments: | |||
Number of patients | 98 | 102 | |
Mean nausea score over 24-h postoperative period b | 1.7 | 3.1 | |
Study 2 | |||
Emetic episodes: | |||
Number of patients | 112 | 108 | |
Treatment response 24 h after study drug | |||
| 49 (44%) | 28 (26%) | 0.006 |
| 14 (13%) | 3 (3%) | |
| 49 (44%) | 77 (71%) | |
Median time to first emetic episode (min) a | 60.5 | 34.0 | |
Nausea assessments: | |||
Number of patients | 105 | 85 | |
Mean nausea score over 24-h postoperative period b | 1.9 | 2.9 |
a After administration of study drug.
b Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
The populations in Table 12 consisted mainly of women undergoing laparoscopic procedures.
Four open-label, noncomparative (one US, three foreign) trials have been performed with 209 pediatric cancer patients aged 4 to 18 years given a variety of cisplatin or noncisplatin regimens. In the three foreign trials, the initial dose of Ondansetron Injection ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration of ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial, Ondansetron Injection was administered intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2 to 39 mg. In these trials, 58% of the 196 evaluable patients had a complete response (no emetic episodes) on Day 1. Thus, prevention of vomiting in these pediatric patients was essentially the same as for patients older than 18 years.
An open-label, multicenter, noncomparative trial has been performed in 75 pediatric cancer patients 6 to 48 months receiving at least one moderately or highly emetogenic chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were American Hispanic, and 15% were black patients. Ondansetron Injection was administered intravenously over 15 minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before the start of chemotherapy; the second and third doses were administered 4 and 8 hours after the first dose, respectively. Eighteen patients (25%) received routine prophylactic dexamethasone (i.e., not given as rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic episodes) on Day 1. Thus, prevention of vomiting in these pediatric patients was comparable to the prevention of vomiting in patients aged 4 years and older.
Three double-blind, placebo-controlled trials have been performed (one US, two foreign) in 1,049 male and female patients (aged 2 to 12 years) undergoing general anesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or without adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomized to either single intravenous doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo. Study drug was administered over at least 30 seconds, immediately prior to or following anesthesia induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these trials are summarized in Table 11.
Treatment Response Over 24 Hours | Ondansetron n (%) | Placebo n (%) | P Value |
Study 1 | |||
Number of patients | 205 | 210 | |
0 Emetic episodes | 140 (68%) | 82 (39%) | ≥ 0.001 |
Failure a | 65 (32%) | 128 (61%) | |
Study 2 | |||
Number of patients | 112 | 110 | |
0 Emetic episodes | 68 (61%) | 38 (35%) | ≥ 0.001 |
Failure a | 44 (39%) | 72 (65%) | |
Study 3 | |||
Number of patients | 206 | 206 | |
0 Emetic episodes | 123 (60%) | 96 (47%) | ≥ 0.01 |
Failure a | 83 (40%) | 110 (53%) | |
Nausea assessments b: | |||
Number of patients | 185 | 191 | |
None | 119 (64%) | 99 (52%) | ≥ 0.01 |
a Failure was one or more emetic episodes, rescued, or withdrawn.
b Nausea measured as none, mild, or severe.
A double-blind, multicenter, placebo-controlled trial was conducted in 670 pediatric patients aged 1 month to 24 months who were undergoing routine surgery under general anesthesia. Seventy-five percent (75%) were males; 64% were white, 15% were black, 13% were American Hispanic, 2% were Asian, and 6% were “other race” patients. A single 0.1-mg/kg intravenous dose of ondansetron administered within 5 minutes following induction of anesthesia was statistically significantly more effective than placebo in preventing vomiting. In the placebo group, 28% of patients experienced vomiting compared with 11% of subjects who received ondansetron ( P ≤ 0.01). Overall, 32 (10%) of placebo patients and 18 (5%) of patients who received ondansetron received antiemetic rescue medication(s) or prematurely withdrew from the trial.
Ondansetron Injection USP, 2 mg/mL, is supplied as follows:
NDC 16729-298-05 20-mL multiple-dose vial (Singles)
Storage: Store at 20˚C to 25˚C (68˚F to 77˚F); excursions permitted to 15˚C to 30˚C (59˚F to 86˚F). [See USP Controlled Room Temperature.] Protect from light.
QT Prolongation
Patients should be informed that Ondansetron Injection may cause serious cardiac arrhythmias such as QT prolongation. Patients should be instructed to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.
Patients should be informed that the chances of developing severe cardiac arrhythmias such as QT prolongation and Torsade de Pointes are higher in the following people:
Ondansetron Injection should be avoided in these patients, since they may be more at risk for cardiac arrhythmias such as QT prolongation and Torsade de Pointes.
Hypersensitivity Reactions
Inform patients that Ondansetron Injection may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. The patient should report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems.
Masking of Progressive Ileus and Gastric Distension
Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that Ondansetron Injection may mask signs and symptoms of bowel obstruction.
Instruct patients to immediately report any signs or symptoms consistent with a potential bowel obstruction to their healthcare provider.
Drug Interactions
Manufactured For:
Accord Healthcare, Inc.,
1009, Slater Road,
Suite 210-B,
Durham, NC 27703,
USA .
Manufactured By:
Intas Pharmaceuticals Limited
Plot No. : 457, 458,
Village – Matoda,
Bavla Road, Ta.- Sanand,
Dist. Ahmedabad - 382 210,
India.
10 19630674824
Issued April, 2017
Ondansetron Injection, USP 40 mg/20 mL-Label
40 mg/20 mL (2 mg/mL)
2 mg/ mL Multiple Dose Vial
For Intravenous or Intramuscular Use Only
Principal Display Panel (2 mg/mL Vial Label)
Ondansetron Injection, USP 40 mg/20 mL Vial-Carton
40 mg/20 mL (2 mg/mL)
20 mL Multiple Dose Vial
For Intravenous or Intramuscular Use Only
Principal Display Panel (2 mg/mL Vial Carton)
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