Ondansetron Injection 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 is approved for patients aged 6 months and older.

Ondansetron Injection 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 is recommended even when the incidence of postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic Ondansetron Injection and experience nausea and/or vomiting postoperatively, Ondansetron Injection may be given to prevent further episodes.

Ondansetron Injection is approved for patients aged 1 month and older.

Important Preparation Instructions •     Dilution of Ondansetron Injection in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection is required before administration to adult and pediatric patients for the prevention of nausea and vomiting associated with emetogenic chemotherapy.

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.

•     Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously.

•     Do not mix Ondansetron Injection with solutions for which physical and chemical compatibility has not been established. In particular, this applies to alkaline solutions as a precipitate may form.

•     Inspect the diluted Ondansetron Injection solution for particulate matter and discoloration before administration; discard if present.

•     Storage: After dilution, do not use beyond 24 hours. Although Ondansetron Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.

•     Compatibility: Ondansetron Injection is compatible and stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% 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

•     Dilution of Ondansetron Injection is not required before administration to adult and pediatric patients.

•     Inspect Ondansetron Injection visually for particulate matter and discoloration before administration; discard if present.

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/or Vomiting

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="1pt"/> <col width="91.05pt"/> <col width="166.65pt"/> <col width="112.9pt"/> <tbody class="Headless"> <tr class="First"> <td> <p class="First"> <span class="Bold">P</span><span class="Bold">opulation</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Recommended</span> </p> <p> <span class="Bold">Single Dose</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Administration Instructions</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Timing of</span> </p> <p> <span class="Bold">Administration</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Adults and</p> <p>pediatric patients older than 12 years of age</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4 mg<span class="Sup">1</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">May be administered intravenously</p> <p>or intramuscularly:</p> <ul class="Disk"> <li>Intravenously: infuse undiluted syringe contents (4 mg) over at least 30 seconds and preferably longer (over 2 to 5 minutes)</li> <li>Intramuscularly: inject undiluted syringe contents (4 mg)</li> </ul> </td><td class="Botrule Lrule Rrule Toprule" rowspan="3"> <p class="First"> <br/> <br/>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<span class="Sup">2,3</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pediatric patients 1 month to 12 years and more than 40 kg</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4 mg</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Infuse intravenously over at least 30 seconds and preferably longer (over 2 to 5 minutes).</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pediatric patients 1 month to 12 years and 40 kg or less</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.1 mg/kg</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Infuse intravenously over at least 30 seconds and preferably longer (over 2 to 5 minutes).</p> </td> </tr> </tbody> </table></div>

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, USP, 2 mg/mL, is a clear, colorless, nonpyrogenic, sterile solution available as a 2 mL single dose vial and 20 mL multiple dose vial.

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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)].

{ "type": "p", "children": [], "text": "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)].\n" }

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.

{ "type": "p", "children": [], "text": "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-HT3 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. Electrocardiogram (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-HT3 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-HT3 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)].

Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm appears to be the most common underlying cause. Therefore, do not exceed the recommended infusion rate of Ondansetron Injection and monitor patients for signs and symptoms of myocardial ischemia during and after administration [see Dosage and Administration (2.1, 2.2) and Adverse Reactions (6.2)].

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. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

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 Injection (ondansetron) was unclear in many cases.

Chemotherapy-Induced Nausea and Vomiting

Table 2. Adverse Reactions Reported in >5% of Adult Patients Who Received Ondansetron at a Dosage of Three 0.15-mg/kg Doses 

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold"> </span> </p> <p> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Number of Adult Patients With Reaction</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Ondansetron Injection<br/> </span><span class="Bold"> </span><span class="Bold">0.15 mg/kg x 3 <br/> </span><span class="Bold">(n = 419)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold">Met</span><span class="Bold">oclopramide<br/> </span><span class="Bold">(</span><span class="Bold">n = 156)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold">P</span><span class="Bold">lacebo<br/> </span><span class="Bold">(</span><span class="Bold">n = 34)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">16%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">44%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">18%</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">7%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">15%</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">Fever</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">8%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">5%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3%</p> </td> </tr> </tbody> </table></div>

Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations, hypotension, and tachycardia have been reported.

Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients receiving multiday ondansetron.

Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been reported to exceed twice the upper limit of normal in approximately 5% of patients. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur.

Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron.

Neurological: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving Ondansetron Injection, and rare cases of grand mal seizure.

Other: Rare cases of hypokalemia have been reported.

Postoperative Nausea and/or Vomiting

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.

Table 3. Adverse Reactions Reported in ≥2% (and with Greater Frequency than the Placebo Group) of Adult Patients Receiving Ondansetron at a Dosage of 4 mg Intravenous Over 2 to 5 Minutes

<div class="scrollingtable"><table> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Adverse Reaction<span class="Sup">a,b</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Ondansetron Injection<br/>4 mg Intravenous<br/>(n = 547)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Placebo<br/>(n = 547)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">92 (17%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">77 (14%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Drowsiness/Sedation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">44 (8%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">37 (7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Injection-site reaction</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">21 (4%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">18 (3%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Fever</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">10 (2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">6 (1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Cold sensation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">9 (2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">8 (1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">9 (2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">3 (&lt;1%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Paresthesia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">9 (2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">2 (&lt;1%)</p> </td> </tr> </tbody> </table></div>

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.

Pediatric Use: Rates of adverse reactions were similar in both the ondansetron and placebo groups in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg) administered intravenously over at least 30 seconds. Diarrhea was seen more frequently in patients taking Ondansetron Injection (2%) compared with placebo (<1%) in the 1-month to 24-month age-group. These patients were receiving multiple concomitant perioperative and postoperative medications.

The following adverse reactions have been identified during postapproval 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.

Cardiovascular

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)].

Myocardial ischemia was reported predominately with intravenous administration [see Warnings and Precautions (5.4)].

General

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.

Hepatobiliary

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.

Local Reactions

Pain, redness, and burning at site of injection.

Lower Respiratory

Hiccups.

Neurological

Oculogyric crisis, appearing alone, as well as with other dystonic reactions. Transient dizziness during or shortly after intravenous infusion.

Skin

Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Eye Disorders

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, has 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 of tramadol.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including SSRIs and 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.

Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy [see Data]. Available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes. 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 (BSA), respectively [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriages, or other adverse outcomes. 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.

Human Data

Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders. Ondansetron exposure in utero has not been associated with overall major congenital malformations in aggregate analyses. One large retrospective cohort study examined 1970 women who received a prescription for ondansetron during pregnancy and reported no association between ondansetron exposure and major congenital malformations, miscarriage, stillbirth, preterm delivery, infants of low birth weight, or infants small for gestational age.

 Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings. Relative risks (RR) ranged from 0.97 (95% CI 0.86 to 1.10) to 1.62 (95% CI 1.04, 2.54). A subset analysis in one of the cohort studies observed that ondansetron was specifically associated with cardiac septal defects (RR 2.05, 95% CI 1.19, 3.28); however this association was not confirmed in other studies.  Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings. A retrospective cohort study of 1.8 million pregnancies in the US Medicaid Database showed an increased risk of oral clefts among 88,467 pregnancies in which oral ondansetron was prescribed in the first trimester (RR 1.24, 95% CI 1.03, 1.48), but no such association was reported with intravenous ondansetron in 23,866 pregnancies (RR 0.95, 95% CI 0.63, 1.43). In the subgroup of women who received both forms of administration, the RR was 1.07 (95% CI 0.59, 1.93). Two case-control studies, using data from birth defects surveillance programs, reported conflicting associations between maternal use of ondansetron and isolated cleft palate (OR 1.6 [95% CI 1.1, 2.3] and 0.5 [95% CI 0.3, 1.0]). 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). 

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 BSA.

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 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.

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. When a drug is present in animal milk, it is likely that the drug will be present in human milk. 

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 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)].

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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-HT3 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:

{ "type": "p", "children": [], "text": "The active ingredient of Ondansetron Injection, USP is ondansetron hydrochloride, a selective blocking agent of the serotonin 5-HT3 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:" }

The molecular formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9 g/mol. Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline.

{ "type": "p", "children": [], "text": "The molecular formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9 g/mol. 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 2 mL single dose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 9 mg of sodium chloride, USP; and 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for Injection, USP.

{ "type": "p", "children": [], "text": "Each 1 mL of aqueous solution in the 2 mL single dose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 9 mg of sodium chloride, USP; and 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for Injection, USP." }

Each 1 mL of aqueous solution in the 20 mL multiple dose 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.

{ "type": "p", "children": [], "text": "Each 1 mL of aqueous solution in the 20 mL multiple dose 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.

{ "type": "p", "children": [], "text": "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-HT3 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 6 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 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 Injection, 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.

Table 4. Pharmacokinetics in Normal Adult Volunteers

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">Age-group (years)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">n</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">Peak Plasma<br/>Concentration<br/>(ng/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">Mean Elimination<br/>Half-life <br/> </span><span class="Bold">(h)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">Plasma Clearance<br/>(L/h/kg)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">19-40</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">102</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">3.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">0.381</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">61-74</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">106</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">4.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">0.319</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">≥75</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">170</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">5.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First">0.262</p> </td> </tr> </tbody> </table></div>

Absorption

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 area under curve (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.

Distribution

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.

Elimination

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.

Excretion: In adult cancer patients, the mean ondansetron elimination half-life was 4.0 hours, and there was no difference in the multidose pharmacokinetics over a 4-day period. In a dose-proportionality trial, systemic exposure to 32 mg of ondansetron was not proportional to dose as measured by comparing dose-normalized AUC values with an 8-mg dose. This is consistent with a small decrease in systemic clearance with increasing plasma concentrations.

Specific Populations

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)].

Pediatric Patients: Pharmacokinetic samples were collected from 74 cancer patients aged 6 to 48 months, who received a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours for 3 doses during a safety and efficacy trial. These data were combined with sequential pharmacokinetics data from 41 surgery patients aged 1 month to 24 months, who received a single dose of 0.1 mg/kg of intravenous ondansetron prior to surgery with general anesthesia, and a population pharmacokinetic analysis was performed on the combined data set. The results of this analysis are included in Table 5 and are compared with the pharmacokinetic results in cancer patients aged 4 to 18 years.

Table 5. Pharmacokinetics in Pediatric Cancer Patients Aged 1 Month to 18 Years

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2">  <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold"> </span> </p> <p> <span class="Bold"> </span> </p> <p> <span class="Bold">Sub</span><span class="Bold">ject</span><span class="Bold">s and Age-group</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2">  <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold"> </span> </p> <p> <span class="Bold"> </span> </p> <p> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold">CL <br/> </span><span class="Bold">(L/h/kg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold">Vd</span><span class="Bold"><span class="Sub">ss</span> <br/> </span><span class="Bold">(</span><span class="Bold">L</span><span class="Bold">/kg)<br/> </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold">t</span><span class="Bold"><span class="Sub">½</span> <br/> </span><span class="Bold"> </span><span class="Bold">(</span><span class="Bold">h</span><span class="Bold">)<br/> </span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2">  <p class="First"> <span class="Bold">G</span><span class="Bold">e</span><span class="Bold">o</span><span class="Bold">me</span><span class="Bold">t</span><span class="Bold">r</span><span class="Bold">ic Mean</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First"> <span class="Bold">Me</span><span class="Bold">an</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  <p class="First">Pediatric Cancer Patients <br/>4 to 18 years</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First">N = 21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First">0.599</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First">1.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First">2.8</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">  <p class="First">Population PK Patients<span class="Sup">a </span> <br/>1 month to 48 months</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First">N = 115</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First">0.582</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First">3.65</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First">4.9</p> </td> </tr> </tbody> </table></div>

a    Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.

Based on the population pharmacokinetic analysis, cancer patients aged 6 to 48 months who receive a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours for 3 doses would be expected to achieve a systemic exposure (AUC) consistent with the exposure achieved in previous pediatric trials in cancer patients (4 to 18 years) at similar doses.

In a trial of 21 pediatric patients (3 to 12 years) who were undergoing surgery requiring anesthesia for a duration of 45 minutes to 2 hours, a single intravenous dose of ondansetron, 2 mg (3 to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to anesthesia induction. Mean weight-normalized clearance and volume of distribution values in these pediatric surgical patients were similar to those previously reported for young adults. Mean terminal half-life was slightly reduced in pediatric patients (range: 2.5 to 3 hours) in comparison with adults (range: 3 to 3.5 hours).

In a trial of 51 pediatric patients (aged 1 month to 24 months) who were undergoing surgery requiring general anesthesia, a single intravenous dose of ondansetron, 0.1 or 0.2 mg/kg, was administered prior to surgery. As shown in Table 6, the 41 patients with pharmacokinetic data were divided into 2 groups, patients aged 1 month to 4 months and patients aged 5 to 24 months, and are compared with pediatric patients aged 3 to 12 years.

Table 6. Pharmacokinetics in Pediatric Surgery Patients Aged 1 Month to 12 Years

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule">  </td><td align="center" class="Botrule Lrule Rrule Toprule">  </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First"> <span class="Bold">CL<br/>(L/h/kg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First"> <span class="Bold">Vd<span class="Sub">ss</span> <br/>(L/kg) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule">  <p class="First"> <span class="Bold"><span class="Bold">t</span><span class="Bold"><span class="Sub">½</span></span> <br/>(h)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <span class="Bold"> Subjects </span><span class="Bold">and Age-group</span></td><td align="center" class="Botrule Lrule Rrule Toprule"> <span class="Bold"> N</span></td><td class="Botrule Lrule Rrule Toprule" colspan="2"> <span class="Bold"> Geometric Mean</span></td><td class="Botrule Lrule Rrule Toprule"> <span class="Bold"> Mean</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  <p class="First">Pediatric Surgery Patients<br/>3 to 12 years </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> N = 21 </td><td align="center" class="Botrule Lrule Rrule Toprule">  0.439</td><td align="center" class="Botrule Lrule Rrule Toprule">  1.65</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.9 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  <p class="First">Pediatric Surgery Patients<span class="Bold"> </span> <br/>5 to 24 months </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> N = 22 </td><td align="center" class="Botrule Lrule Rrule Toprule">  0.581</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.3</td><td align="center" class="Botrule Lrule Rrule Toprule"> 2.9</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">  <p class="First">Pediatric Surgery Patients<br/>1 month to 4 months </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> N = 19 </td><td align="center" class="Botrule Lrule Rrule Toprule">  0.401 </td><td align="center" class="Botrule Lrule Rrule Toprule"> 3.5 </td><td align="center" class="Botrule Lrule Rrule Toprule"> 6.7 </td> </tr> </tbody> </table></div>

In general, surgical and cancer pediatric patients younger than 18 years tend to have a higher ondansetron clearance compared with adults leading to a shorter half-life in most pediatric patients. In patients aged 1 month to 4 months, a longer half-life was observed due to the higher volume of distribution in this age-group.

In a trial of 21 pediatric cancer patients (aged 4 to 18 years) who received three intravenous doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years exhibited ondansetron pharmacokinetic parameters similar to those of adults.

Patients with Renal Impairment: Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron mean plasma clearance was reduced by about 41% in patients with severe renal impairment (creatinine clearance <30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life [see Use in Specific Populations (8.7)].

Patients with Hepatic Impairment: In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared with 5.7 hours in those without hepatic impairment. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Drug Interaction Studies

CYP3A4 Inducers: Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic trial of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, a reduction in AUC, Cmax, and t½ of ondansetron was observed. This resulted in a significant increase in the clearance of ondansetron. In a pharmacokinetic study of 10 healthy subjects receiving a single-dose intravenous dose of ondansetron 8 mg after 600 mg rifampin once daily for five days, the AUC and the t½  of ondansetron were reduced by 48% and 46%, respectively.  These changes in ondansetron exposure with CYP3A4 inducers are not thought to be clinically relevant [see Drug Interactions (7.3)].

Chemotherapeutic Agents: Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron [see Drug Interactions (7.6)].

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 BSA). 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 BSA) did not affect fertility or general reproductive performance of male and female rats.

Adults

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.

Cisplatin-Based Chemotherapy: In a double-blind trial in 28 patients, Ondansetron Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin-based chemotherapy. Therapeutic response was as shown in Table 7.

Table 7. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-day Cisplatin Therapya in Adults

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold"> Ondansetron Injection<br/>(0.15 mg/kg x 3)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold">Placebo </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold"> <span class="Italics">P</span>-Value<span class="Sup">b</span></span></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom">  Number of patients</td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 14 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 14 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">  Treatment response</td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">      0 Emetic episodes</td><td align="center" class="Lrule Rrule" valign="bottom"> 2 (14%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 0 (0%) </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">      1-2 Emetic episodes</td><td align="center" class="Lrule Rrule" valign="bottom"> 8 (57%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 0 (0%) </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">      3-5 Emetic episodes</td><td align="center" class="Lrule Rrule" valign="bottom"> 2 (14%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 1 (7%) </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">      More than 5 emetic episodes/rescued</td><td align="center" class="Lrule Rrule" valign="bottom"> 2 (14%) </td><td align="center" class="Lrule Rrule" valign="bottom">  13 (93%)</td><td align="center" class="Lrule Rrule" valign="bottom">  0.001</td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="bottom">  Median number of emetic episodes</td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> 1.5 </td><td align="center" class="Lrule Rrule Toprule" valign="bottom">  Undefined<span class="Sup">c</span></td><td align="center" class="Lrule Rrule Toprule" valign="bottom">  </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  Median time to first emetic episode (h)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  11.6</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  2.8</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  0.001</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  Median nausea scores (0-100)<span class="Sup">d</span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  3</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  59</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  0.034</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  Global satisfaction with control of nausea and vomiting (0-100)<span class="Sup">e</span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  96</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 10.5 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  0.009</td> </tr> </tbody> </table></div>

a Chemotherapy was high dose (100 and 120 mg/m2; Ondansetron Injection n = 6, placebo n = 5) or moderate dose (50 and 80 mg/m2; Ondansetron Injection n = 8, placebo n = 9). Other chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There was no difference between treatments in the types of chemotherapy that would account for differences in response. b Efficacy based on "all-patients-treated" analysis. c Median undefined since at least 50% of the patients were rescued or had more than five emetic episodes. d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be. e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.

Ondansetron injection (0.15-mg/kg x 3 doses) was compared with metoclopramide (2 mg/kg x 6 doses) in a single-blind trial in 307 patients receiving cisplatin ≥100 mg/m2 with or without other chemotherapeutic agents. Patients received the first dose of ondansetron or metoclopramide 30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later, or five additional metoclopramide doses were administered 2, 4, 7, 10, and 13 hours later. Cisplatin was administered over a period of 3 hours or less. Episodes of vomiting and retching were tabulated over the period of 24 hours after cisplatin. The results of this trial are summarized in Table 8.

Table 8. Therapeutic Response in Prevention of Vomiting Induced by Cisplatin (≥100 mg/m2) Single-day Therapya in Adults

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Ondansetron Injection <br/> </span><span class="Bold"> </span><span class="Bold">0.15 mg/kg x 3</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold">Metoclopramide <br/> </span><span class="Bold"> </span><span class="Bold">2 mg/kg x 6</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold"><span class="Italics">P-</span>Value</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Number of patients in efficacy population</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">136</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">138</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Treatment response<br/>    0 Emetic episodes<br/>    1-2 Emetic episodes<br/>    3-5 Emetic episodes<br/>    More than 5 emetic episodes/rescued</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">54 (40%)<br/>34 (25%)<br/>19 (14%)<br/>29 (21%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">41 (30%)<br/>30 (22%)<br/>18 (13%)<br/>49 (36%)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="bottom"> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Comparison of treatments with respect to<br/>    0 Emetic episodes<br/>    More than 5 emetic episodes/rescued</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">54/136<br/>29/136</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">41/138<br/>49/138</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0.083<br/>0.009</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Median number of emetic episodes</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0.005</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Median time to first emetic episode (h)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">20.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">4.3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">&lt; 0.001</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Global satisfaction with control of nausea and vomiting (0-100)<span class="Sup">b</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">85</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">63</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0.001</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Acute dystonic reactions</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0.005</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Akathisia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0.002</p> </td> </tr> </tbody> </table></div>

a In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments in the types of chemotherapy that would account for differences in response. b Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.

Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled trial of Ondansetron Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide (500 to 600 mg/m2) chemotherapy, Ondansetron Injection was significantly more effective than placebo in preventing nausea and vomiting. The results are summarized in Table 9.

Table 9. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-day Cyclophosphamide Therapya in Adults

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Ondansetron Injection<br/>(0.15 mg/kg x 3) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold">Placebo </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold"><span class="Italics"> P-</span>Value<span class="Sup">b</span></span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Number of patients </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">  Treatment response</td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom"> <p class="First">    0 Emetic episodes</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">7 (70%)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">0 (0%)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">0.001</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom"> <p class="First">    1-2 Emetic episodes</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">0 (0%)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">2 (20%)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom"> <p class="First">    3-5 Emetic episodes</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">2 (20%)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">4 (40%)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom"> <p class="First">    More than 5 emetic episodes/rescued</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">1 (10%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">4 (40%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">0.131</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Median number of emetic episodes</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0.008</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Median time to first emetic episode (h)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Undefined<span class="Sup">c</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">8.79</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Median nausea scores (0-100)<span class="Sup"> d</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">60</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0.001</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Global satisfaction with control of nausea and vomiting (0-100)<span class="Sup"> e</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">100</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">52</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">0.008</p> </td> </tr> </tbody> </table></div>

a Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between treatments in the type of chemotherapy that would account for differences in response. b Efficacy based on "all-patients-treated" analysis. c Median undefined since at least 50% of patients did not have any emetic episodes. d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be. e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.

Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose, 100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with ondansetron and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median: 2; range: 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes occurred in 217 (81%) re-treatment courses.

Pediatrics

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 aged 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.

Adults

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.

Table 10. Therapeutic Response in Prevention of Postoperative Nausea and/or Vomiting in Adult Patients

<div class="scrollingtable"><table> <caption> <span> </span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Ondansetron<br/>4 mg<br/>Intravenous </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold">Placebo </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold"><span class="Italics">P-</span>Value </span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold">Study 1</span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="bottom"> <p class="First">Emetic episodes:<br/>Number of patients</p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> 136</td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> 139</td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom"> Treatment response over 24-h postoperative period</td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">      0 Emetic episodes</td><td align="center" class="Lrule Rrule" valign="bottom">  103 (76%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 64 (46%) </td><td align="center" class="Lrule Rrule" valign="bottom">  &lt;0.001</td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">      1 Emetic episode</td><td align="center" class="Lrule Rrule" valign="bottom"> 13 (10%) </td><td align="center" class="Lrule Rrule" valign="bottom"> 17 (12%) </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">      More than 1 emetic episode/rescued</td><td align="center" class="Lrule Rrule" valign="bottom"> 20 (15%) </td><td align="center" class="Lrule Rrule" valign="bottom">  58 (42%)</td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Nausea assessments:<br/>Number of patients<br/>No nausea over 24-h postoperative period</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">134<br/>56 (42%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">136<br/>39 (29%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold">Study 2</span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="bottom"> <p class="First">Emetic episodes:<br/>Number of patients</p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> 136 </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> 143</td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">  Treatment response over 24-h postoperative period</td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">     0 Emetic episodes</td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">85 (63%)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">63 (44%) </p> </td><td align="center" class="Lrule Rrule" valign="bottom">  0.002</td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">     1 Emetic episode</td><td align="center" class="Lrule Rrule" valign="bottom"> 16 (12%) </td><td align="center" class="Lrule Rrule" valign="bottom"> 29 (20%) </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">     More than 1 emetic episode/rescued</td><td align="center" class="Lrule Rrule" valign="bottom"> 35 (26%) </td><td align="center" class="Lrule Rrule" valign="bottom"> 51 (36%) </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Nausea assessments:<br/>Number of patients<br/>No nausea over 24-h postoperative period</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">125<br/>48 (38%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">133<br/>42 (32%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> </td> </tr> </tbody> </table></div>

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.

Pediatrics

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.

Table 11. Therapeutic Response in Prevention of Postoperative Nausea and/or Vomiting in Pediatric Patients Aged 2 to 12 Years

<div class="scrollingtable"><table> <caption> <span> </span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Treatment Response Over<br/>24 Hours</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Ondansetron<br/>n (%) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Placebo<br/>n (%) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold"><span class="Italics">P-</span>Value </span></td> </tr> <tr> <td class="Lrule Rrule Toprule"> <span class="Bold">Study 1</span></td><td align="center" class="Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Lrule Rrule Toprule">  </td> </tr> <tr> <td class="Lrule Rrule"> Number of patients</td><td align="center" class="Lrule Rrule" valign="bottom">  205</td><td align="center" class="Lrule Rrule" valign="bottom"> 210</td><td align="center" class="Lrule Rrule"> </td> </tr> <tr> <td class="Lrule Rrule"> 0 Emetic episodes</td><td align="center" class="Lrule Rrule" valign="bottom">  140 (68%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 82 (39%)</td><td align="center" class="Lrule Rrule"> ≤0.001 </td> </tr> <tr> <td class="Botrule Lrule Rrule"> Failure<span class="Sup">a</span></td><td align="center" class="Botrule Lrule Rrule" valign="bottom">  65 (32%)</td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 128 (61%) </td><td align="center" class="Botrule Lrule Rrule">  </td> </tr> <tr> <td class="Lrule Rrule"> <span class="Bold">Study 2 </span></td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule">  </td> </tr> <tr> <td class="Lrule Rrule"> Number of patients</td><td align="center" class="Lrule Rrule" valign="bottom">  112</td><td align="center" class="Lrule Rrule" valign="bottom"> 110 </td><td align="center" class="Lrule Rrule"> </td> </tr> <tr> <td class="Lrule Rrule"> 0 Emetic episodes</td><td align="center" class="Lrule Rrule" valign="bottom"> 68 (61%) </td><td align="center" class="Lrule Rrule" valign="bottom">  38 (35%)</td><td align="center" class="Lrule Rrule"> ≤0.001</td> </tr> <tr> <td class="Botrule Lrule Rrule"> Failure<span class="Sup">a</span></td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 44 (39%) </td><td align="center" class="Botrule Lrule Rrule" valign="bottom">  72 (65%)</td><td align="center" class="Botrule Lrule Rrule">  </td> </tr> <tr> <td class="Lrule Rrule"> <span class="Bold">Study 3 </span></td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule"> Number of patients</td><td align="center" class="Lrule Rrule" valign="bottom"> 206 </td><td align="center" class="Lrule Rrule" valign="bottom"> 206 </td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule"> 0 Emetic episodes</td><td align="center" class="Lrule Rrule" valign="bottom"> 123 (60%) </td><td align="center" class="Lrule Rrule" valign="bottom"> 96 (47%) </td><td align="center" class="Lrule Rrule" valign="bottom"> ≤0.01</td> </tr> <tr> <td class="Lrule Rrule"> Failure<span class="Sup">a</span></td><td align="center" class="Lrule Rrule" valign="bottom"> 83 (40%) </td><td align="center" class="Lrule Rrule" valign="bottom"> 110 (53%) </td><td align="center" class="Lrule Rrule" valign="bottom"> </td> </tr> <tr> <td class="Lrule Rrule Toprule"> Nausea assessments<span class="Sup">b</span>:</td><td align="center" class="Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Lrule Rrule Toprule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule"> Number of patients</td><td align="center" class="Lrule Rrule" valign="bottom">  185</td><td align="center" class="Lrule Rrule" valign="bottom">  191</td><td align="center" class="Lrule Rrule" valign="bottom">  </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule"> None</td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 119 (64%)</td><td align="center" class="Botrule Lrule Rrule" valign="bottom">  99 (52%)</td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> ≤0.01</td> </tr> </tbody> </table></div>

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.

Adults

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.

Table 12. Therapeutic Response in Prevention of Further Postoperative Nausea and/or Vomiting in Adult Patients

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">Ondansetron<br/>4 mg<br/>Intravenous</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold">Placebo </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold"><span class="Italics">P-</span>Value</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold">Study 1 </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">  <p class="First">Emetic episodes:<br/>Number of patients</p> </td><td align="center" valign="bottom"> 104</td><td align="center" class="Lrule Rrule" valign="bottom"> 117 </td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">  <p class="First">Treatment response 24 h after study drug<br/>     0 Emetic episodes</p> </td><td align="center" valign="bottom"> 49 (47%) </td><td align="center" class="Lrule Rrule" valign="bottom"> 19 (16%) </td><td align="center" class="Rrule" valign="bottom"> &lt;0.001 </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">     1 Emetic episode</td><td align="center" valign="bottom"> 12 (12%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 9 (8%) </td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">     More than 1 emetic episode/rescued</td><td align="center" valign="bottom"> 43 (41%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 89 (76%)</td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom"> Median time to first emetic episode (min)<span class="Sup">a</span></td><td align="center" valign="bottom"> 55.0</td><td align="center" class="Lrule Rrule" valign="bottom"> 43.0</td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="bottom">  <p class="First">Nausea assessments:<br/>Number of patients</p> </td><td align="center" class="Toprule" valign="bottom">  <p class="First">98</p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> 102</td><td align="center" class="Rrule Toprule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">Mean nausea score over 24-h postoperative period<span class="Sup">b</span></td><td align="center" valign="bottom">  1.7</td><td align="center" class="Lrule Rrule" valign="bottom">  3.1</td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <span class="Bold">Study 2</span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">  <p class="First">Emetic episodes:<br/>Number of patients</p> </td><td align="center" valign="bottom"> 112 </td><td align="center" class="Lrule Rrule" valign="bottom"> 108</td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom"> Treatment response 24 h after study drug</td><td align="center" valign="bottom">  </td><td align="center" class="Lrule Rrule" valign="bottom">  </td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">     0 Emetic episodes </td><td align="center" valign="bottom"> 49 (44%) </td><td align="center" class="Lrule Rrule" valign="bottom"> 28 (26%)</td><td align="center" class="Rrule" valign="bottom"> 0.006 </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">     1 Emetic episode</td><td align="center" valign="bottom"> 14 (13%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 3 (3%)</td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">     More than 1 emetic episode/rescued </td><td align="center" valign="bottom"> 49 (44%)</td><td align="center" class="Lrule Rrule" valign="bottom"> 77 (71%)</td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom"> Median time to first emetic episode (min)<span class="Sup">a</span></td><td align="center" valign="bottom"> 60.5</td><td align="center" class="Lrule Rrule" valign="bottom"> 34.0 </td><td align="center" class="Rrule" valign="bottom">  </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="bottom">  <p class="First">Nausea assessments:<br/>Number of patients</p> </td><td align="center" class="Toprule" valign="bottom"> 105 </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> 85</td><td align="center" class="Rrule Toprule" valign="bottom">  </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="bottom">Mean nausea score over 24-h postoperative period<span class="Sup">b</span></td><td align="center" class="Botrule" valign="bottom"> 1.9</td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2.9 </td><td align="center" class="Botrule Rrule" valign="bottom">  </td> </tr> </tbody> </table></div>

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.

Repeat Dosing in Adults: In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of ondansetron 4 mg postoperatively does not provide additional control of nausea and vomiting.

Pediatrics

One double-blind, placebo-controlled, US trial was performed in 351 male and female outpatients (aged 2 to 12 years) who received general anesthesia with nitrous oxide and no prophylactic antiemetics. Surgical procedures were unrestricted. Patients who experienced two or more emetic episodes within 2 hours following discontinuation of nitrous oxide 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 administered over at least 30 seconds. Ondansetron was significantly more effective than placebo in preventing further episodes of nausea and vomiting. The results of the trial are summarized in Table 13.

Table 13. Therapeutic Response in Prevention of Further Postoperative Nausea and/or Vomiting in Pediatric Patients Aged 2 to 12 Years

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">Treatment Response Over 24 Hours</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">Ondansetron<br/> n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold">Placebo<br/> n (%) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">  <p class="First"> <span class="Bold"><span class="Italics">P-</span>Value</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">  <p class="First">Number of patients</p> </td><td align="center" valign="bottom">  <p class="First">180</p> </td><td align="center" class="Lrule Rrule" valign="bottom">  <p class="First">171</p> </td><td align="center" class="Rrule" valign="bottom"> </td> </tr> <tr> <td class="Lrule Rrule" valign="bottom">  <p class="First">0 Emetic episodes</p> </td><td align="center" valign="bottom">  <p class="First">96 (53%)</p> </td><td align="center" class="Lrule Rrule" valign="bottom">  <p class="First">29 (17%)</p> </td><td align="center" class="Rrule" valign="bottom">  <p class="First">≤ 0.001</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="bottom">  <p class="First">Failure<span class="Sup">a </span> </p> </td><td align="center" class="Botrule" valign="bottom">  <p class="First">84 (47%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom">  <p class="First">142 (83%)</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> </td> </tr> </tbody> </table></div>

a    Failure was one or more emetic episodes, rescued, or withdrawn.

Ondansetron Injection, USP, 2 mg/mL, is available as follows:

{ "type": "p", "children": [], "text": "Ondansetron Injection, USP, 2 mg/mL, is available as follows:" }

2 mL Single Dose Vial packaged in 25s (NDC 0641-6080-25)

{ "type": "p", "children": [], "text": "2 mL Single Dose Vial packaged in 25s (NDC 0641-6080-25)" }

20 mL Multiple Dose Vial packaged individually (NDC 0641-6286-01)

{ "type": "p", "children": [], "text": "20 mL Multiple Dose Vial packaged individually (NDC 0641-6286-01)" }

This product, including the packaging components, is not made with natural rubber latex.

{ "type": "p", "children": [], "text": "This product, including the packaging components, is not made with natural rubber latex." }

Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Protect from light.

{ "type": "p", "children": [], "text": "\nStore at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Protect from light.\n" }

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

{ "type": "p", "children": [], "text": "To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch." }

For Product Inquiry call 1-877-845-0689.

{ "type": "p", "children": [], "text": "For Product Inquiry call 1-877-845-0689." }

Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\nHypersensitivity Reactions\n" }

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 [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "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 [see Warnings and Precautions (5.1)]." }

QT Prolongation

{ "type": "p", "children": [], "text": "\nQT Prolongation\n" }

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.

{ "type": "p", "children": [], "text": "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:

{ "type": "p", "children": [], "text": "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:" }

•  Patients with a personal or family history of abnormal heart rhythms, such as congenital long QT syndrome;

{ "type": "p", "children": [], "text": "•  Patients with a personal or family history of abnormal heart rhythms, such as congenital long QT syndrome;" }

•  Patients who take medications, such as diuretics, which may cause electrolyte abnormalities;

{ "type": "p", "children": [], "text": "•  Patients who take medications, such as diuretics, which may cause electrolyte abnormalities;" }

•  Patients with hypokalemia or hypomagnesemia.

{ "type": "p", "children": [], "text": "•  Patients with hypokalemia or hypomagnesemia." }

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 [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "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 [see Warnings and Precautions (5.2)].\n" }

Drug Interactions

{ "type": "p", "children": [], "text": "\nDrug Interactions\n" }

•     Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and Ondansetron Injection may cause a significant drop in blood pressure and loss of consciousness.

{ "type": "p", "children": [], "text": "•     Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and Ondansetron Injection may cause a significant drop in blood pressure and loss of consciousness." }

•     Advise patients of the possibility of serotonin syndrome with concomitant use of Ondansetron Injection and another serotonergic agent, such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [see Warnings and Precautions (5.3)]. 

{ "type": "p", "children": [], "text": "•     Advise patients of the possibility of serotonin syndrome with concomitant use of Ondansetron Injection and another serotonergic agent, such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [see Warnings and Precautions (5.3)]. " }

Myocardial Ischemia Inform patients that Ondansetron Injection may cause myocardial ischemia during or after the administration. Advise patients to seek immediate medical help if any symptoms suggestive of a myocardial ischemia occur, such as sudden chest pain or chest tightness [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "\nMyocardial Ischemia\n\n\nInform patients that Ondansetron Injection may cause myocardial ischemia during or after the administration. Advise patients to seek immediate medical help if any symptoms suggestive of a myocardial ischemia occur, such as sudden chest pain or chest tightness [see Warnings and Precautions (5.4)]." }

Masking of Progressive Ileus and Gastric Distention

{ "type": "p", "children": [], "text": "\nMasking of Progressive Ileus and Gastric Distention\n" }

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 [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "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 [see Warnings and Precautions (5.5)]." }

Manufactured by:

{ "type": "p", "children": [], "text": "\nManufactured by:\n" }

Hikma Pharmaceuticals USA Inc.

{ "type": "p", "children": [], "text": "Hikma Pharmaceuticals USA Inc." }

Berkeley Heights, NJ 07922

{ "type": "p", "children": [], "text": "Berkeley Heights, NJ 07922" }

Novaplus is a registered trademark of Vizient, Inc.

{ "type": "p", "children": [], "text": "Novaplus is a registered trademark of Vizient, Inc." }

novaplus+

{ "type": "p", "children": [], "text": "\nnovaplus+\n" }

Revised February 2024                                                                                         

{ "type": "p", "children": [], "text": "Revised February 2024                                                                                         " }

462-568-13

{ "type": "p", "children": [], "text": "462-568-13" }

NDC 0641-6080-01 Rx ONLY Ondansetron Injection, USP For IV or IM Injection 4 mg per 2 mL (2 mg/mL) Protect from light 2 mL Single Dose Vial

{ "type": "p", "children": [], "text": "NDC 0641-6080-01\nRx ONLY\nOndansetron Injection, USP\nFor IV or IM Injection\n4 mg per 2 mL (2 mg/mL)\nProtect from light\n2 mL Single Dose Vial" }

NDC 0641-6080-25   Rx ONLY Ondansetron Injection, USP For Intravenous or Intramuscular Injection 4 mg per 2 mL (2 mg/mL)* 25 x 2 mL Single Dose Vials

{ "type": "p", "children": [], "text": "NDC 0641-6080-25   Rx ONLY\n\nOndansetron Injection, USP\nFor Intravenous or Intramuscular Injection\n4 mg per 2 mL (2 mg/mL)*\n25 x 2 mL Single Dose Vials" }

NDC 0641-6286-01 Rx ONLY Ondansetron Injection, USP For IV or IM Injection 40 mg per 20 mL (2 mg/mL) Protect from light 20 mL Multiple Dose Vial

{ "type": "p", "children": [], "text": "NDC 0641-6286-01\nRx ONLY\nOndansetron Injection, USP\nFor IV or IM Injection\n40 mg per 20 mL (2 mg/mL)\nProtect from light\n20 mL Multiple Dose Vial" }

NDC 0641-6286-01   Rx ONLY Ondansetron Injection, USP For Intravenous or Intramuscular Injection 40 mg per 20 mL (2 mg/mL)* 1 x 20 mL Multiple Dose Vials

{ "type": "p", "children": [], "text": "NDC 0641-6286-01   Rx ONLY\n\nOndansetron Injection, USP\nFor Intravenous or Intramuscular Injection\n40 mg per 20 mL (2 mg/mL)* 1 x 20 mL Multiple Dose Vials" }

Ondansetron oral solution is indicated for the prevention of nausea and vomiting associated with:

{ "type": "p", "children": [], "text": "Ondansetron oral solution is indicated for the prevention of nausea and vomiting associated with: " }

{ "type": "ul", "children": [ "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 " ], "text": "" }

Ondansetron oral solution is also indicated for the prevention of postoperative nausea and/or vomiting.

{ "type": "p", "children": [], "text": "Ondansetron oral solution is also indicated for the prevention of postoperative nausea and/or vomiting." }

The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively.

Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="859px"> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Indication</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Dosage Regimen</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Highly Emetogenic Cancer Chemotherapy</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">A single 24-mg dose administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatingreater than or equal to50 mg/m<span class="Sup">2</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Moderately Emetogenic Cancer Chemotherapy</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8-mg dose 8 hours after the first dose.</p> <p>Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Radiotherapy</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">For total body irradiation:8 mg administered 1 to 2 hours before each fraction of radiotherapy each day.</p> <p>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.</p> <p>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.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Postoperative</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16 mg administered 1 hour before induction of anesthesia.</p> </td> </tr> </tbody> </table></div>

Table 2: Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="859px"> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Indication</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Dosage Regimen</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Moderately Emetogenic Cancer Chemotherapy</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12 to 17 years of age:8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8-mg dose8 hours after the first dose.</p> <p>Then administer 8 mg twice a day (every 12 hours)for 1 to 2 days after completion of chemotherapy.</p> <p>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.</p> <p>Then administer 4 mg three times a day for 1 to 2 days after completion of chemotherapy.</p> </td> </tr> </tbody> </table></div>

In 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)].

Ondansetron oral solution, USP, 4 mg/5 mL, is a clear, colorless liquid with a characteristic strawberry odor available in a 50-mL bottle.

{ "type": "p", "children": [], "text": "Ondansetron oral solution, USP, 4 mg/5 mL, is a clear, colorless liquid with a characteristic strawberry odor available in a 50-mL bottle." }

Ondansetron is contraindicated in patients:

{ "type": "p", "children": [], "text": "Ondansetron is contraindicated in patients:" }

{ "type": "ul", "children": [ "known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation [see Adverse Reactions (6.2)]\n", "receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness" ], "text": "" }

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 practice.

The following adverse reactions have been reported in clinical trials of patients treated with ondansetron, the active ingredient of ondansetron. A causal relationship to therapy with ondansetron was unclear in many cases.

Prevention of Chemotherapy-Induced Nausea and Vomiting

The most common adverse reactions reported in  greater than or equal to 4% of 300 adults receiving a single 24-mg dose of ondansetron orally in 2 trials for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (cisplatin  greater than or equal to 50 mg/m2) were: headache (11%) and diarrhea (4%).

The most common adverse reactions reported in 4 trials in adults for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (primarily cyclophosphamide-based regimens) are shown in Table 3.

Table 3: Most Common Adverse Reactions in Adults1 for the Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Chemotherapy [Primarily Cyclophosphamide-based Regimens]

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Adverse Reaction </span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Ondansetron 8 mg Twice Daily <br/> (n = 242)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo </span> </p> <p> <span class="Bold">(n = 262)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Headache </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">58 (24%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">34 (13%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Malaise/Fatigue </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">32 (13%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (2%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Constipation </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">22 (9%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1 (&lt; 1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Diarrhea </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">15 (6%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10 (4%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Sup">1</span> Reported in greater than or equal to 5% of patients treated with ondansetron and at a rate that exceeded placebo.</p> </td> </tr> </tbody> </table></div>

Less Common Adverse Reactions

Central Nervous System: Extrapyramidal reactions (less than 1% of patients).

Hepatic: Aspartate transaminase (AST) and/or alanine transaminase (ALT) values exceeded twice the upper limit of normal in approximately 1% to 2% of 723 patients receiving ondansetron and cyclophosphamide-based chemotherapy in US clinical trials. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes is unclear.

Liver failure and death has been reported in cancer patients receiving concurrent medications, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.

Integumentary: Rash (approximately 1% of patients).

Other (less than 2%): Anaphylaxis, bronchospasm, tachycardia, angina, hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures. Except for bronchospasm and anaphylaxis, the relationship to ondansetron is unclear.

Prevention of Radiation-Induced Nausea and Vomiting

The most common adverse reactions (greater than or equal to 2%) reported in patients receiving ondansetron and concurrent radiotherapy were similar to those reported in patients receiving ondansetron and concurrent chemotherapy and were headache, constipation, and diarrhea.

Prevention of Postoperative Nausea and/or Vomiting

The most common adverse reactions reported in adults in trial(s) of prevention of postoperative nausea and vomiting are shown in Table 4. In these trial(s), patients were receiving multiple concomitant perioperative and postoperative medications in both treatment groups.

Table 4: Most Common Adverse Reactions in Adults1 for the Prevention of Postoperative Nausea and Vomiting

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Ondansetron</span><span class="Bold"> 16 mg as a Single <br/> Dose (n = 550)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo (n = 531)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Headache </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">49 (9%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">27 (5%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Hypoxia </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">49 (9%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">35 (7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pyrexia </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">45 (8%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">34 (6%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">36 (7%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">34 (6%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Gynecological disorder </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">36 (7%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">33 (6%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Anxiety/Agitation </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">33 (6%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">29 (5%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Urinary retention </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">28 (5%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">18 (3%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pruritus </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">27 (5%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">20 (4%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Sup">1</span> Reported in greater than or equal to 5% of patients treated with ondansetron and at a rate that exceeded placebo. </p> </td> </tr> </tbody> </table></div>

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.

Cardiovascular

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 interval prolongation have been reported.

Myocardial ischemia was reported predominately with intravenous administration [see Warnings and Precautions (5.4)]. General

Flushing: 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.

Hepatobiliary

Liver enzyme abnormalities.

Lower Respiratory

Hiccups.

Neurology

Oculogyric crisis, appearing alone, as well as with other dystonic reactions.

Skin

Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Eye Disorders

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.

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor 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)].

Electrocardiogram (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)].

The development of serotonin syndrome has been reported with 5-HT3 receptor 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-HT3 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 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)].

 Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm appears to be the most common underlying cause. Therefore, monitor or advise patients for signs or symptoms of myocardial ischemia after oral administration of ondansetron [see Adverse Reactions (6.2)].

The 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.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including SSRIs and SNRIs. Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ondansetron and initiate supportive treatment [see Warnings and Precautions (5.3)].

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver [see Clinical Pharmacology (12.3)]. 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. 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 no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small trials indicate that when used together, ondansetron may increase patient-controlled administration of tramadol. Monitor patients to ensure adequate pain control when ondansetron is administered with tramadol.

Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase systemic concentrations of high-dose methotrexate.

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

Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy (see Data). Available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes. Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered during organogenesis at approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/day, based on body surface area (BSA), respectively (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriages, or other adverse outcomes. 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

Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders.

Ondansetron exposure in utero has not been associated with overall major congenital malformations in aggregate analyses. One large retrospective cohort study examined 1,970 women who received a prescription for ondansetron during pregnancy and reported no association between ondansetron exposure and major congenital malformations, miscarriage, stillbirth, preterm delivery, infants of low birth weight, or infants small for gestational age.

Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings. Relative risks (RR) ranged from 0.97 (95% CI 0.86 to 1.10) to 1.62 (95% CI 1.04, 2.54). A subset analysis in one of the cohort studies observed that ondansetron was specifically associated with cardiac septal defects (RR 2.05, 95% CI 1.19, 3.28); however, this association was not confirmed in other studies.

Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings. A retrospective cohort study of 1.8 million pregnancies in the US Medicaid Database showed an increased risk of oral clefts among 88,467 pregnancies in which oral ondansetron was prescribed in the first trimester (RR 1.24, 95% CI 1.03, 1.48), but no such association was reported with intravenous ondansetron in 23,866 pregnancies (RR 0.95, 95% CI 0.63, 1.43). In the subgroup of women who received both forms of administration, the RR was 1.07 (95% CI 0.59, 1.93). Two case-control studies, using data from birth defects surveillance programs, reported conflicting associations between maternal use of ondansetron and isolated cleft palate (OR 1.6 [95% CI 1.1, 2.3] and 0.5 [95% CI 0.3, 1.0]). 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).

Animal Data

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 BSA.

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 BSA.

Risk Summary

Ondansetron is unlikely to result in clinically relevant exposures in breastfed infants when administered intravenously at doses up to 4 mg/day to women who are breastfeeding. Available data from a lactation study involving pharmacokinetic samples from 80 lactating women and 20 infants indicate that ondansetron is present at low levels in human milk and in the plasma of breastfed infants. Both are estimated daily infant dose (DID) of ondansetron (0.002 mg/kg/day), and the relative infant dose (RID) (3.7%) were low (see Data).

In the same study, no adverse effects attributed to ondansetron were reported in infants exposed to ondansetron through breast milk. There are no data on the effects of ondansetron on milk production.

Data

A pharmacokinetic study utilizing opportunistic sampling of a convenience sample of 80 lactating women receiving intravenous ondansetron for the treatment of post-operative nausea and vomiting and 20 breastfed infants showed that ondansetron was present in breast milk with an average milk to plasma ratio of 0.91 following a median (range) dose of ondansetron of 4 (4 to 8) mg/dose. Using the average milk concentration over 24 hours to estimate the DID and the RID, the DID was 0.002 mg/kg/day and the RID was 3.7% of a weight-adjusted single maternal dose of 4 mg. Among the 20 infant plasma samples, seven concentrations (35%) were below the limit of quantification. Among the 13 infants with a quantifiable plasma concentration, the median (range) concentration was 0.78 (0 to 7.2) ng/mL. The highest observed concentration among these 13 infants was approximately 10 times lower than the median maximum concentration (76.6 ng/mL) observed in an open-label, single-dose pharmacokinetic study conducted in pediatric surgical patients aged 1 to 24 months who received a single 0.1 mg/kg dose of intravenous ondansetron.

The safety and effectiveness of orally administered ondansetron have been established in pediatric patients 4 years and older for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Use of ondansetron in these age-groups is supported by evidence from adequate and well-controlled studies of ondansetron in adults with additional data from 3 open-label, uncontrolled, non-US trials in 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens [see Dosage and Administration (2.2), Clinical Studies (14.1)].

Additional information on the use of ondansetron in pediatric patients may be found in ondansetron Injection prescribing information.

The safety and effectiveness of orally administered ondansetron have not been established in pediatric patients for:

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there were subgroup analyses, 938 (19%) were aged 65 years and older.

No overall differences in safety or effectiveness were observed between subjects 65 years of age 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. No dosage adjustment is needed in elderly patients.

No 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)].

No dosage adjustment is recommended for patients with any degree of renal impairment (mild, moderate, or severe). There is no experience beyond first-day administration of ondansetron [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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy." }

In addition to the adverse reactions listed above, the following adverse reactions 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 a patient that took 48 mg of ondansetron 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 adverse reactions resolved completely.

{ "type": "p", "children": [], "text": "In addition to the adverse reactions listed above, the following adverse reactions 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 a patient that took 48 mg of ondansetron 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 adverse reactions resolved completely." }

Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg per 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.

{ "type": "p", "children": [], "text": "Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg per 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 in ondansetron oral solution, USP is ondansetron hydrochloride, USP as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it 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:

{ "type": "p", "children": [], "text": "The active ingredient in ondansetron oral solution, USP is ondansetron hydrochloride, USP as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it 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:" }

The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9 g/mol.

{ "type": "p", "children": [], "text": "The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9 g/mol." }

Ondansetron hydrochloride dihydrate is a white to off-white powder that is soluble in water and normal saline.

{ "type": "p", "children": [], "text": "Ondansetron hydrochloride dihydrate is a white to off-white powder that is soluble in water and normal saline." }

Each 5 mL of ondansetron oral solution, USP contains 5 mg of ondansetron hydrochloride dihydrate equivalent to 4 mg of ondansetron. Ondansetron oral solution, USP contains the inactive ingredients citric acid anhydrous, glycerin, purified water, saccharin sodium, sodium benzoate, sodium citrate and strawberry flavor.

{ "type": "p", "children": [], "text": "Each 5 mL of ondansetron oral solution, USP contains 5 mg of ondansetron hydrochloride dihydrate equivalent to 4 mg of ondansetron. Ondansetron oral solution, USP contains the inactive ingredients citric acid anhydrous, glycerin, purified water, saccharin sodium, sodium benzoate, sodium citrate and strawberry flavor." }

Ondansetron is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting reflex.

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

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) milliseconds and 5.6 (7.4) milliseconds after 15 minute intravenous infusions of 32 mg and 8 mg of ondansetron injection, 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 (16.3) milliseconds. 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) milliseconds. In this study, the 8-mg dose infused over 15 minutes did not prolong the QT interval to any clinically relevant extent.

Absorption

Ondansetron is absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%.

Ondansetron systemic exposure does not increase proportionately to dose. The area under curve (AUC) from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses.

Food Effects: Bioavailability is also slightly enhanced by the presence of food.

Distribution

Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.

Elimination

Metabolism and Excretion: Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The metabolites are observed in the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.

In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination.

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.

Specific Populations

Age: Geriatric Population: A reduction in clearance and increase in elimination half-life are seen in patients older than 75 years compared to younger subjects [see Use in Specific Populations (8.5)].

Sex: Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of absorption are greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron concentrations. These higher plasma concentrations may in part be explained by differences in body weight between men and women. It is not known whether these sex-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 5 and 6.

Table 5: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of an Ondansetron 8-mg Tablet

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="859px"> <col width="98.0469px"/> <col width="98.1875px"/> <col width="88.5625px"/> <col width="111.047px"/> <col width="111.047px"/> <col width="94.5px"/> <col width="52.5938px"/> <col width="74.0156px"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Age-group</span> </p> <p> <span class="Bold">(years)</span> </p> <p> <span class="Bold">Sex (M/F)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Mean</span> </p> <p> <span class="Bold">Weight</span> </p> <p> <span class="Bold">(kg)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Peak Plasma</span> </p> <p> <span class="Bold">Concentration</span> </p> <p> <span class="Bold">(ng/mL)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Time of</span> </p> <p> <span class="Bold">Peak Plasma</span> </p> <p> <span class="Bold">Concentration</span> </p> <p> <span class="Bold">(h)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Mean</span> </p> <p> <span class="Bold">Elimination</span> </p> <p> <span class="Bold">Half-life</span> </p> <p> <span class="Bold">(h)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Systemic</span> </p> <p> <span class="Bold">Plasma</span> </p> <p> <span class="Bold">Clearance</span> </p> <p> <span class="Bold">L/h/kg</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Absolute</span> </p> <p> <span class="Bold">Bioavailability</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">18 to 40 M</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">69</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">26.2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3.1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.403</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.483</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">F</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">62.7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">42.7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3.5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.354</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.663</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">61 to 74 M</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">77.5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">24.1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4.1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.384</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.585</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">F</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">60.2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">52.4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4.9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.255</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.643</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">≥ 75 M</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">78</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">37</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4.5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.277</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.619</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">F</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">67.6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">46.1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6.2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.249</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.747</p> </td> </tr> </tbody> </table></div>

Table 6: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of an Ondansetron 24-mg Tablet

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="859px"> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Age-group (years) Sex (M/F)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Mean Weight (kg)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">N</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Peak Plasma Concentration (ng/mL)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Time of Peak Plasma Concentration (h)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Mean Elimination Half-life (h)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First">18 to 43 M F</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">84.1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">125.8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4.7</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">71.8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">194.4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5.8</p> </td> </tr> </tbody> </table></div>

Renal Impairment: Renal impairment is not expected to significantly influence the total clearance of ondansetron as renal clearance represents only 5% of the overall clearance. However, the mean plasma clearance of ondansetron was reduced by about 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/min). The reduction in clearance was variable and not consistent with an increase in half-life [see Use in Specific Populations (8.7)].

Hepatic Impairment: In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared with 5.7 hours in healthy subjects. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced 2- fold to 3- fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].

Drug Interaction Studies

CYP 3A4 Inducers: Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic trial of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, a reduction in AUC, Cmax, and t&frac12; of ondansetron was observed. This resulted in a significant increase in the clearance of ondansetron. However, this increase is not thought to be clinically relevant [see Drug Interactions (7.2)].

Chemotherapeutic Agents: Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron [see Drug Interactions (7.4)].

Antacids: Concomitant administration of antacids does not alter the absorption of ondansetron.

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 mg/kg per day and 30 mg/kg per day, respectively (approximately 4 and 6 times the maximum recommended human oral dose of 24 mg per day, based on BSA).

Ondansetron was not mutagenic in standard tests for mutagenicity.

Oral administration of ondansetron up to 15 mg/kg per day (approximately 6 times the maximum recommended human oral dose of 24 mg per day, based on BSA) did not affect fertility or general reproductive performance of male and female rats.

Highly Emetogenic Chemotherapy

In 2 randomized, double-blind, monotherapy trials, a single 24-mg oral dose of ondansetron was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin  greater than or equal to 50 mg/m2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose  greater than or equal to 50 mg/m2 in the historical placebo comparator, experienced vomiting in the absence of antiemetic therapy.

The first trial compared oral doses of ondansetron 24 mg as a single dose, 8 mg every 8 hours for 2 doses, and 32 mg as a single dose in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin  greater than or equal to 50 mg/m2. The first or single dose was administered 30 minutes prior to chemotherapy. A total of 66% of patients in the ondansetron 24-mg once-a-day group, 55% in the ondansetron 8-mg twice-a-day group, and 55% in the ondansetron 32-mg once-a-day group, completed the 24-hour trial period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control.

In the same trial, 56% of patients receiving a single 24-mg oral dose of ondansetron experienced no nausea during the 24-hour trial period, compared with 36% of patients in the oral ondansetron 8-mg twice-a-day group (P = 0.001) and 50% in the oral ondansetron 32-mg once-a-day group. Dosage regimens of ondansetron 8 mg twice daily and 32 mg once daily are not recommended for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy [see Dosage and Administration (2.1)].

In a second trial, efficacy of a single 24-mg oral dose of ondansetron for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin  greater than or equal to 50 mg/m2, was confirmed.

Moderately Emetogenic Chemotherapy

A randomized, placebo-controlled, double-blind trial was conducted in the US in 67 patients receiving a cyclophosphamide-based chemotherapy regimen containing doxorubicin. The first 8-mg dose of ondansetron was administered 30 minutes before the start of chemotherapy, with a subsequent dose 8 hours after the first dose, followed by 8 mg of ondansetron twice a day for 2 days after the completion of chemotherapy. Ondansetron was significantly more effective than placebo in preventing vomiting. Treatment response was based on the total number of emetic episodes over the 3-day trial period. The results of this trial are summarized in Table 7.

Table 7: Emetic Episodes-Treatment Response in Patients Receiving Moderately Emetogenic Chemotherapy (Cyclophosphamide-based Regimen Containing Doxorubicin)

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <br/> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Ondansetron<br/> (n = 33)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo <br/> (n = 34)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold"><span class="Italics">P-</span>Value</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Treatment response 0 Emetic episodes 1 to 2 Emetic episodes More than 2 emetic episodes/withdrawn </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">20 (61%) </p> <p>6 (18%) </p> <p>7 (21%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2 (6%)</p> <p>8 (24%)</p> <p>24 (71%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">&lt; 0.001</p> <p>&lt; 0.001</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Median number of emetic episodes </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Undefined<span class="Sup">1</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Median time to first emetic episode (hours) </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Undefined<span class="Sup">2</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6.5</p> </td><td class="Botrule Lrule Rrule Toprule"> <br/> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Sup">1</span> Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. </p> <p> <span class="Sup">2</span> Median undefined since at least 50% of patients did not have any emetic episodes.</p> </td> </tr> </tbody> </table></div>

In a double-blind, US trial in 336 patients receiving a cyclophosphamide-based chemotherapy regimen containing either methotrexate or doxorubicin, ondansetron 8 mg administered twice a day, was as effective as ondansetron 8 mg administered 3 times a day in preventing nausea and vomiting. Ondansetron 8 mg three times daily is not a recommended regimen for the treatment of moderately emetogenic chemotherapy [see Dosage and Administration (2.1)].

Treatment response was based on the total number of emetic episodes over the 3-day trial period. See Table 8 for the details of the dosage regimens studied and results of this trial.

Table 8: Emetic Episodes-Treatment Response After Ondansetron Tablets Administered Twice a Day and Three Times a Day

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="17pt"/> <col width="17pt"/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <br/> </td><td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Ondansetron Tablets</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <br/> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">8 mg Twice Daily<span class="Sup">1</span> <br/> (n = 165)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">8 mg Three Times a Day<span class="Sup">2</span> <br/> (n = 171)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Treatment response </p> <p>0 Emetic episodes </p> <p>1-2 Emetic episodes </p> <p>More than 2 emetic episodes/withdrawn </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">101 (61%) </p> <p>16 (10%) </p> <p>48 (29%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">99 (58%) </p> <p>17 (10%) </p> <p>55 (32%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Median number of emetic episodes </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Median time to first emetic episode (h) </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Undefined<span class="Sup">3</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Undefined<span class="Sup">3</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Median nausea scores (0 to 100)<span class="Sup">4</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Sup">1</span> The first 8-mg dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent 8-mg dose 8 hours after the first dose, followed by 8 mg administered twice a day for 2 days after the completion of chemotherapy. </p> <p> <span class="Sup">2</span> The first 8-mg dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent 8-mg doses at 4 hours and 8 hours after the first dose, followed by 8 mg administered 3 times a day for 2 days after the completion of chemotherapy.</p> <p> <span class="Sup">3</span> Median undefined since at least 50% of patients did not have any emetic episodes. </p> <p> <span class="Sup">4</span> Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.</p> </td> </tr> </tbody> </table></div>

Re-treatment

In single-arm trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ondansetron 8 mg three times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the re-treatment courses.

Pediatric Trials

Three open-label, single-arm, non-US trials have been performed with 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens. The initial dose of ondansetron injection ranged from 0.04 mg to 0.87 mg per kg (total dose of 2.16 mg to 12 mg) followed by the administration of oral doses of ondansetron ranging from 4 mg to 24 mg daily for 3 days. In these trials, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on Day 1. In 2 trials, the response rates to ondansetron 4 mg three times a day in patients younger than 12 years was similar to ondansetron 8 mg three times daily in patients 12 to 18 years. Prevention of emesis in these pediatric patients was essentially the same as for adults.

Total Body Irradiation

In a randomized, placebo-controlled, double-blind trial in 20 patients, 8 mg of ondansetron administered 1.5 hours before each fraction of radiotherapy for 4 days was significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 2 fractions on Day 4.

Single High-Dose Fraction Radiotherapy

In an active-controlled, double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of greater than or equal to 80 cm2 to the abdomen, ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes). Patients received the first dose of ondansetron (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 8 mg of ondansetron or 10 mg of metoclopramide was administered in the late afternoon and repeated again before bedtime. If radiotherapy was given in the afternoon, patients took 8 mg of ondansetron or 10 mg of metoclopramide only once before bedtime. Patients continued the doses of oral medication three times daily for 3 days.

Daily Fractionated Radiotherapy

In an active-controlled, double-blind trial in 135 patients receiving a 1- to 4- week course of fractionated radiotherapy (180 cGy doses) over a field size of greater than or equal to 100 cm2 to the abdomen, ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes). Patients received the first dose of ondansetron (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the first daily radiotherapy fraction, with subsequent 8-mg doses approximately every 8 hours on each day of radiotherapy.

In 2 placebo-controlled, double-blind trials (one conducted in the US and the other outside the US) in 865 females undergoing inpatient surgical procedures, ondansetron 16 mg as a single dose or placebo was administered one hour before the induction of general balanced anesthesia (barbiturate, opioid, nitrous oxide, neuromuscular blockade, and supplemental isoflurane or enflurane), ondansetron tablets was significantly more effective than placebo in preventing postoperative nausea and vomiting.

No trials have been performed in males.

{ "type": "ul", "children": [ "Ondansetron oral solution, USP a clear, colorless liquid with a characteristic strawberry odor, contains 5 mg of ondansetron hydrochloride dihydrate equivalent to 4 mg of ondansetron per 5 mL in amber glass bottles of 50 mL with child-resistant closures (NDC 65162-691-79). It is also available as:" ], "text": "" }

5 mL unit dose cup                                                                 NDC 65162-691-37

{ "type": "p", "children": [], "text": "5 mL unit dose cup                                                                 NDC 65162-691-37" }

10 unit dose cups in a tray                                                      NDC 65162-691-19

{ "type": "p", "children": [], "text": "10 unit dose cups in a tray                                                      NDC 65162-691-19" }

Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15º to 30º C (59º to 86ºF) [see USP Controlled Room Temperature]. Protect from light. Store bottles upright in cartons.

{ "type": "p", "children": [], "text": "Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15º to 30º C (59º to 86ºF) [see USP Controlled Room Temperature]. Protect from light. Store bottles upright in cartons." }

Hypersensitivity Reactions

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Inform patients that ondansetron may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. Instruct patients to immediately report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems to their healthcare provider [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Inform patients that ondansetron may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. Instruct patients to immediately report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems to their healthcare provider [see Warnings and Precautions (5.1)]." }

QT Prolongation

{ "type": "p", "children": [], "text": "\nQT Prolongation\n" }

Inform patients that ondansetron may cause serious cardiac arrhythmias, such as QT prolongation. Instruct patients 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 [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients that ondansetron may cause serious cardiac arrhythmias, such as QT prolongation. Instruct patients 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 [see Warnings and Precautions (5.2)]." }

Drug Interactions

{ "type": "p", "children": [], "text": "Drug Interactions" }

{ "type": "", "children": [], "text": "" }

Myocardial Ischemia

{ "type": "p", "children": [], "text": "\nMyocardial Ischemia\n" }

Inform patients that ondansetron may cause myocardial ischemia. Advise patients to seek immediate medical help if any symptoms suggestive of a myocardial ischemia occur, such as sudden chest pain or chest tightness [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Inform patients that ondansetron may cause myocardial ischemia. Advise patients to seek immediate medical help if any symptoms suggestive of a myocardial ischemia occur, such as sudden chest pain or chest tightness [see Warnings and Precautions (5.4)].\n" }

Masking of Progressive Ileus and Gastric Distension

{ "type": "p", "children": [], "text": "Masking of Progressive Ileus and Gastric Distension" }

Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that ondansetron 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 [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that ondansetron 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 [see Warnings and Precautions (5.5)]." }

Distributed by:

{ "type": "p", "children": [], "text": "Distributed by:" }

Amneal Pharmaceuticals LLC

{ "type": "p", "children": [], "text": "\nAmneal Pharmaceuticals LLC\n" }

Bridgewater, NJ 08807

{ "type": "p", "children": [], "text": "Bridgewater, NJ 08807" }

Rev. 06-2025-08

{ "type": "p", "children": [], "text": "Rev. 06-2025-08" }

Ondansetron orally disintegrating tablets are indicated for the prevention of nausea and vomiting associated with:

{ "type": "p", "children": [], "text": "Ondansetron orally disintegrating tablets are indicated for the prevention of nausea and vomiting associated with:" }

{ "type": "ul", "children": [ "highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m\n \n 2\n", "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   " ], "text": "" }

Ondansetron orally disintegrating tablets also indicated for the prevention of postoperative nausea and/or vomiting.

{ "type": "p", "children": [], "text": "Ondansetron orally disintegrating tablets also indicated for the prevention of postoperative nausea and/or vomiting." }

The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively. Corresponding doses of ondansetron tablets, ondansetron orally disintegrating tablets and ondansetron oral solution may be used interchangeably. 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting</span> </caption> <col width="23.08%"/> <col width="76.92%"/> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">Indication</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Dosage Regimen</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Highly Emetogenic Cancer Chemotherapy</span> <br/> </td><td align="justify" class="Rrule" valign="top">A 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/m <span class="Sup">2</span>. <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Moderately Emetogenic Cancer Chemotherapy</span> <br/> </td><td align="justify" class="Rrule" valign="top">8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose. <br/>   <br/> Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Radiotherapy</span> <br/> </td><td align="justify" class="Rrule" valign="top"><span class="Underline">For total body irradiation:</span>8 mg administered 1 to 2 hours before each fraction of radiotherapy each day. <br/>   <br/> <span class="Underline">For single high-dose fraction radiotherapy to the abdomen:</span>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. <br/>   <br/> <span class="Underline">For daily fractionated radiotherapy to the abdomen:</span>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. <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"><span class="Bold">Postoperative</span> <br/> </td><td class="Rrule" valign="top">16 mg administered 1 hour before induction of anesthesia. <br/> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 2: Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting</span> </caption> <col width="16.2%"/> <col width="83.8%"/> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">Indication</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Dosage Regimen</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"><span class="Bold">Moderately Emetogenic Cancer Chemotherapy</span> <br/> </td><td align="justify" class="Rrule" valign="top"><span class="Underline">12 to 17 years of age:</span>8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose. <br/> Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.   <br/>   <br/> <span class="Underline">4 to 11 years of age:</span>4 mg administered 30 minutes before the start of chemotherapy, with a subsequent 4 mg dose 4 and 8 hours after the first dose.   <br/>   <br/> Then administer 4 mg three times a day for 1 to 2 days after completion of chemotherapy. <br/> </td> </tr> </tbody> </table></div>

In 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)] .

Do not attempt to push ondansetron orally disintegrating tablets through the foil backing. With dry hands, remove the tablet from the bottle or PEEL BACK the foil backing of 1 blister and GENTLY remove the tablet. IMMEDIATELY place the ondansetron orally disintegrating tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary.

Ondansetron Orally Disintegrating Tablets USP, 8 mgare white to off-white, round tablets debossed with ‘7’ on one side and ‘E’ on the other side with an embossed circular edge.

{ "type": "p", "children": [], "text": "\nOndansetron Orally Disintegrating Tablets USP, 8 mgare white to off-white, round tablets debossed with ‘7’ on one side and ‘E’ on the other side with an embossed circular edge.\n " }

Ondansetron orally disintegrating tablets are contraindicated in patients:

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{ "type": "ul", "children": [ "known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation\n \n [see\n \n Adverse Reactions (6.2)]\n \n \n", "receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness   " ], "text": "" }

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3receptor 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)] .

Electrocardiogram (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)] .

The development of serotonin syndrome has been reported with 5-HT 3receptor 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-HT 3receptor 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)] .

Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm appears to be the most common underlying cause. Therefore, monitor or advise patients for signs or symptoms of myocardial ischemia after oral administration of ondansetron [see Adverse Reactions (6.2)].

The 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.

Phenylketonuric patients should be informed that ondansetron orally disintegrating tablets contain phenylalanine (a component of aspartame). Each 4 mg orally disintegrating tablet contains 1.68 mg phenylalanine and 8 mg orally disintegrating tablet contains 3.37 mg phenylalanine.

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 practice. The following adverse reactions have been reported in clinical trials of patients treated with ondansetron, the active ingredient of ondansetron orally disintegrating tablets. A causal relationship to therapy with ondansetron was unclear in many cases. Prevention of Chemotherapy-Induced Nausea and Vomiting The most common adverse reactions reported in greater than or equal to 4% of 300 adults receiving a single 24 mg dose of ondansetron orally in 2 trials for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (cisplatin greater than or equal to 50 mg/m 2) were: headache (11%) and diarrhea (4%). The most common adverse reactions reported in 4 trials in adults for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (primarily cyclophosphamide-based regimens) are shown in Table 3.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 3: Most Common Adverse Reactions in Adults <span class="Sup">a</span>for the Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Chemotherapy [Primarily Cyclophosphamide-based Regimens] </span> </caption> <col width="27.42%"/> <col width="36.3%"/> <col width="36.28%"/> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">a</span>Reported in greater than or equal to 5% of patients treated with ondansetron orally disintegrating tablets and at a rate that exceeded placebo. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Adverse Reaction</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ondansetron Orally</span> <br/> <span class="Bold">Disintegrating Tablets</span> <br/> <span class="Bold">8 mg Twice Daily</span> <br/> <span class="Bold">(n</span><span class="Bold">= 242)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo</span><span class="Bold"></span> <br/> <span class="Bold">(n</span><span class="Bold">= 262)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Headache <br/> </td><td align="center" class="Rrule" valign="middle">58 (24%) <br/> </td><td align="center" class="Rrule" valign="middle">34 (13%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Malaise/Fatigue <br/> </td><td align="center" class="Rrule" valign="middle">32 (13%) <br/> </td><td align="center" class="Rrule" valign="middle">6 (2%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Constipation <br/> </td><td align="center" class="Rrule" valign="middle">22 (9%) <br/> </td><td align="center" class="Rrule" valign="middle">1 (&lt; 1%) <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">   Diarrhea <br/> </td><td align="center" class="Rrule" valign="middle">15 (6%) <br/> </td><td align="center" class="Rrule" valign="middle">10 (4%) <br/> </td> </tr> </tbody> </table></div>

Less Common Adverse Reactions Central Nervous System:Extrapyramidal reactions (less than 1% of patients). Hepatic: Aspartate transaminase (AST) and/or alanine transaminase (ALT) values exceeded twice the upper limit of normal in approximately 1% to 2% of 723 patients receiving ondansetron and cyclophosphamide-based chemotherapy in U.S. clinical trials. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes is unclear. Liver failure and death has been reported in cancer patients receiving concurrent medications, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Integumentary: Rash (approximately 1% of patients). Other (less than 2%): Anaphylaxis, bronchospasm, tachycardia, angina, hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures. Except for bronchospasm and anaphylaxis, the relationship to ondansetron is unclear. Prevention of Radiation-Induced Nausea and Vomiting The most common adverse reactions (greater than or equal to 2%) reported in patients receiving ondansetron and concurrent radiotherapy were similar to those reported in patients receiving ondansetron and concurrent chemotherapy and were headache, constipation, and diarrhea. Prevention of Postoperative Nausea and/or Vomiting The most common adverse reactions reported in adults in trial(s) of prevention of postoperative nausea and vomiting are shown in Table 4. In these trial(s), patients were receiving multiple concomitant perioperative and postoperative medications in both treatment groups.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="98%"> <caption> <span>Table 4: Most Common Adverse Reactions in Adults <span class="Sup">a</span>for the Prevention of Postoperative Nausea and Vomiting </span> </caption> <col width="32.58%"/> <col width="33.7%"/> <col width="33.7%"/> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">a</span>Reported in greater than or equal to 5% of patients treated with ondansetron orally disintegrating tablets and at a rate that exceeded placebo. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Adverse Reaction</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ondansetron Orally</span> <br/> <span class="Bold">Disintegrating Tablets</span> <br/> <span class="Bold"> </span><span class="Bold">16 mg as a Single Dose</span> <br/> <span class="Bold">(n</span><span class="Bold">= 550)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo <br/> </span><span class="Bold"> </span><span class="Bold">(n</span><span class="Bold">= 531)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   Headache <br/> </td><td align="center" class="Rrule" valign="top">49 (9%) <br/> </td><td align="center" class="Rrule" valign="top">27 (5%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   Hypoxia <br/> </td><td align="center" class="Rrule" valign="top">49 (9%) <br/> </td><td align="center" class="Rrule" valign="top">35 (7%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   Pyrexia <br/> </td><td align="center" class="Rrule" valign="top">45 (8%) <br/> </td><td align="center" class="Rrule" valign="top">34 (6%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   Dizziness <br/> </td><td align="center" class="Rrule" valign="top">36 (7%) <br/> </td><td align="center" class="Rrule" valign="top">34 (6%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   Gynecological disorder <br/> </td><td align="center" class="Rrule" valign="top">36 (7%) <br/> </td><td align="center" class="Rrule" valign="top">33 (6%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   Anxiety/Agitation <br/> </td><td align="center" class="Rrule" valign="top">33 (6%) <br/> </td><td align="center" class="Rrule" valign="top">29 (5%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   Urinary retention <br/> </td><td align="center" class="Rrule" valign="top">28 (5%) <br/> </td><td align="center" class="Rrule" valign="top">18 (3%) <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">   Pruritus <br/> </td><td align="center" class="Rrule" valign="top">27 (5%) <br/> </td><td align="center" class="Rrule" valign="top">20 (4%) <br/> </td> </tr> </tbody> </table></div>

In a crossover study with 25 subjects, headache was reported in 6 subjects administered ondansetron orally disintegrating tablets with water (24%) as compared with 2 subjects administered ondansetron orally disintegrating tablets without water (8%).

The following adverse reactions have been identified during postapproval 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. Cardiovascular 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 interval prolongation have been reported. Myocardial ischemia was reported predominately with intravenous administration [see Warnings and Precautions (5.4)]. General Flushing: 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. Hepatobiliary Liver enzyme abnormalities. Lower Respiratory Hiccups. Neurology Oculogyric crisis, appearing alone, as well as with other dystonic reactions. Skin Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Eye Disorders 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.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3receptor antagonists and other serotonergic drugs, including SSRIs and SNRIs. Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ondansetron and initiate supportive treatment [see Warnings and Precautions (5.3)] .

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver [see Clinical Pharmacology (12.3)] . 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. 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 no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small trials indicate that when used together, ondansetron may increase patient-controlled administration of tramadol. Monitor patients to ensure adequate pain control when ondansetron is administered with tramadol.

Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase systemic concentrations of high-dose methotrexate.

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

Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy (see Data). Available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes. Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered during organogenesis at approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/day, based on body surface area (BSA), respectively (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown.  All pregnancies have a background risk of birth defect, miscarriages, or other adverse outcomes. In the U.S. 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

Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders.

Ondansetron exposure in utero has not been associated with overall major congenital malformations in aggregate analyses. One large retrospective cohort study examined 1970 women who received a prescription for ondansetron during pregnancy and reported no association between ondansetron exposure and major congenital malformations, miscarriage, stillbirth, preterm delivery, infants of low birth weight, or infants small for gestational age.

Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings. Relative risks (RR) ranged from 0.97 (95% CI 0.86 to 1.10) to 1.62 (95% CI 1.04, 2.54). A subset analysis in one of the cohort studies observed that ondansetron was specifically associated with cardiac septal defects (RR 2.05, 95% CI 1.19, 3.28); however, this association was not confirmed in other studies.

Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings. A retrospective cohort study of 1.8 million pregnancies in the U.S. Medicaid Database showed an increased risk of oral clefts among 88,467 pregnancies in which oral ondansetron was prescribed in the first trimester (RR 1.24, 95% CI 1.03, 1.48), but no such association was reported with intravenous ondansetron in 23,866 pregnancies (RR 0.95, 95% CI 0.63, 1.43). In the subgroup of women who received both forms of administration, the RR was 1.07 (95% CI 0.59, 1.93). Two case-control studies, using data from birth defects surveillance programs, reported conflicting associations between maternal use of ondansetron and isolated cleft palate (OR 1.6 [95% CI 1.1, 2.3] and 0.5 [95% CI 0.3, 1.0]). 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).

Animal Data

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 BSA.

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 BSA.

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. When a drug is present in animal milk, it is likely that the drug will be present in human milk. 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 breastfed infant from ondansetron or from the underlying maternal condition.

The safety and effectiveness of orally administered ondansetron have been established in pediatric patients 4 years and older for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Use of ondansetron in these age-groups is supported by evidence from adequate and well- controlled studies of ondansetron in adults with additional data from 3 open-label, uncontrolled, non-U.S. trials in 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens [see Dosage and Administration (2.2), Clinical Studies (14.1)] . Additional information on the use of ondansetron in pediatric patients may be found in ondansetron Injection prescribing information. The safety and effectiveness of orally administered ondansetron have not been established in pediatric patients for:

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in U.S.- and foreign-controlled clinical trials, for which there were subgroup analyses, 938 (19%) were aged 65 years and older. No overall differences in safety or effectiveness were observed between subjects 65 years of age 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. No dosage adjustment is needed in elderly patients.

No 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)] .

No dosage adjustment is recommended for patients with any degree of renal impairment (mild, moderate, or severe). There is no experience beyond first-day administration of ondansetron [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.

{ "type": "p", "children": [], "text": "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. In addition to the adverse reactions listed above, the following adverse reactions 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 a patient that took 48 mg of ondansetron 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 adverse reactions resolved completely. Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg per 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.

{ "type": "p", "children": [], "text": "There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. \n \n In addition to the adverse reactions listed above, the following adverse reactions 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 a patient that took 48 mg of ondansetron 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 adverse reactions resolved completely. \n \n Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg per 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.\n " }

The active ingredient in ondansetron orally disintegrating tablets, USP is ondansetron base, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT 3receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one. It has the following structural formula: The molecular formula is C 18H 19N 3O representing a molecular weight of 293.4 g/mol. Ondansetron is a white to off-white powder. Each 4 mg ondansetron orally disintegrating tablet, USP for oral administration contains 4 mg ondansetron base. Each 8 mg ondansetron orally disintegrating tablet, USP for oral administration contains 8 mg ondansetron base. Each ondansetron orally disintegrating tablet, USP also contains the inactive ingredients mannitol, crospovidone, lactose monohydrate, microcrystalline cellulose, aspartame, strawberry guarana flavor, colloidal silicon dioxide, and magnesium stearate. The strawberry guarana flavor contains maltodextrin, propylene glycol, artificial flavors, and acetic acid. Ondansetron orally disintegrating tablets, USP are orally administered formulation of ondansetron which disintegrates on the tongue and does not require water to aid dissolution or swallowing. Meets USP Disintegration Test 2. 

{ "type": "p", "children": [], "text": "The active ingredient in ondansetron orally disintegrating tablets, USP is ondansetron base, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT\n \n 3receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one. It has the following structural formula: \n \n\n\n The molecular formula is C\n \n 18H\n \n 19N\n \n 3O representing a molecular weight of 293.4 g/mol. Ondansetron is a white to off-white powder. \n \n Each 4 mg ondansetron orally disintegrating tablet, USP for oral administration contains 4 mg ondansetron base. Each 8 mg ondansetron orally disintegrating tablet, USP for oral administration contains 8 mg ondansetron base. Each ondansetron orally disintegrating tablet, USP also contains the inactive ingredients mannitol, crospovidone, lactose monohydrate, microcrystalline cellulose, aspartame, strawberry guarana flavor, colloidal silicon dioxide, and magnesium stearate. The strawberry guarana flavor contains maltodextrin, propylene glycol, artificial flavors, and acetic acid. Ondansetron orally disintegrating tablets, USP are orally administered formulation of ondansetron which disintegrates on the tongue and does not require water to aid dissolution or swallowing. \n \n Meets USP Disintegration Test 2. \n\n " }

Ondansetron is a selective 5-HT 3receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT 3type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT 3receptors and initiate the vomiting reflex.

In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects. Ondansetron has no effect on plasma-prolactin concentrations. 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) milliseconds and 5.6 (7.4) milliseconds after 15­-minute intravenous infusions of 32 mg and 8 mg of ondansetron injection, 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) milliseconds. 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) milliseconds. In this study, the 8 mg dose infused over 15 minutes did not prolong the QT interval to any clinically relevant extent.  

Absorption Ondansetron is absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8 mg tablet, is approximately 56%. Ondansetron systemic exposure does not increase proportionately to dose. The area under curve (AUC) from a 16 mg tablet was 24% greater than predicted from an 8 mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. Food Effects : Bioavailability is also slightly enhanced by the presence of food. Distribution Plasma protein binding of ondansetron as measured in vitrowas 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes. Elimination Metabolism and Excretion: Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The metabolites are observed in the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. 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. Specific Populations Age:Geriatric Population: A reduction in clearance and increase in elimination half-life are seen in patients older than 75 years compared to younger subjects [see Use in Specific Populations (8.5)] . Sex: Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of absorption are greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron concentrations. These higher plasma concentrations may in part be explained by differences in body weight between men and women. It is not known whether these sex-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 5 and 6. 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 5: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 8 mg Tablet</span> </caption> <col width="9.22%"/> <col width="9.62%"/> <col width="4.04%"/> <col width="16.78%"/> <col width="16.78%"/> <col width="14.18%"/> <col width="12.48%"/> <col width="16.9%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Age-group (years) Sex (M/F)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Mean</span> <br/> <span class="Bold">Weight</span> <br/> <span class="Bold">(kg)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">N</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Peak Plasma</span> <br/> <span class="Bold">Concentration</span> <br/> <span class="Bold">(ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Time of</span> <br/> <span class="Bold">Peak Plasma</span> <br/> <span class="Bold">Concentration</span> <br/> <span class="Bold">(h)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Mean</span> <br/> <span class="Bold">Elimination</span> <br/> <span class="Bold">Half-life</span> <br/> <span class="Bold">(h)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Systemic</span> <br/> <span class="Bold">Plasma</span> <br/> <span class="Bold">Clearance</span> <br/> <span class="Bold">L/h/kg</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Absolute</span> <br/> <span class="Bold">Bioavailability</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">18 to 40 M <br/>               F <br/> </td><td align="center" class="Rrule" valign="middle">69.0 <br/> 62.7 <br/> </td><td align="center" class="Rrule" valign="middle">6 <br/> 5 <br/> </td><td align="center" class="Rrule" valign="middle">26.2 <br/> 42.7 <br/> </td><td align="center" class="Rrule" valign="middle">2.0 <br/> 1.7 <br/> </td><td align="center" class="Rrule" valign="middle">3.1 <br/> 3.5 <br/> </td><td align="center" class="Rrule" valign="middle">0.403 <br/> 0.354 <br/> </td><td align="center" class="Rrule" valign="middle">0.483 <br/> 0.663 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">61 to 74 M <br/>               F <br/> </td><td align="center" class="Rrule" valign="middle">77.5 <br/> 60.2 <br/> </td><td align="center" class="Rrule" valign="middle">6 <br/> 6 <br/> </td><td align="center" class="Rrule" valign="middle">24.1 <br/> 52.4 <br/> </td><td align="center" class="Rrule" valign="middle">2.1 <br/> 1.9 <br/> </td><td align="center" class="Rrule" valign="middle">4.1 <br/> 4.9 <br/> </td><td align="center" class="Rrule" valign="middle">0.384 <br/> 0.255 <br/> </td><td align="center" class="Rrule" valign="middle">0.585 <br/> 0.643 <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">≥ 75   M <br/>          F <br/> </td><td align="center" class="Rrule" valign="middle">78.0 <br/> 67.6 <br/> </td><td align="center" class="Rrule" valign="middle">5 <br/> 6 <br/> </td><td align="center" class="Rrule" valign="middle">37.0 <br/> 46.1 <br/> </td><td align="center" class="Rrule" valign="middle">2.2 <br/> 2.1 <br/> </td><td align="center" class="Rrule" valign="middle">4.5 <br/> 6.2 <br/> </td><td align="center" class="Rrule" valign="middle">0.277 <br/> 0.249 <br/> </td><td align="center" class="Rrule" valign="middle">0.619 <br/> 0.747 <br/> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 6: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 24 mg Tablet</span> </caption> <col width="13.42%"/> <col width="15.58%"/> <col width="4.1%"/> <col width="22.48%"/> <col width="21.74%"/> <col width="22.68%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Age-group</span><span class="Bold"></span><span class="Bold">(years)</span><span class="Bold"></span> <br/> <span class="Bold">Sex</span><span class="Bold">(M/F)</span> <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> <span class="Bold">Mean</span><span class="Bold"></span><span class="Bold">Weight</span><span class="Bold"></span><span class="Bold">(kg)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">N</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Peak</span><span class="Bold"></span><span class="Bold">Plasma</span><span class="Bold"></span><span class="Bold">Concentration</span><span class="Bold"></span><span class="Bold">(ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Time</span><span class="Bold">of Peak Plasma Concentration</span> <br/> <span class="Bold">(h)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Mean</span><span class="Bold"></span><span class="Bold">Elimination</span><span class="Bold"></span><span class="Bold">Half-life</span> <br/> <span class="Bold">(h)</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">18 to 43  M <br/>                F <br/> </td><td align="center" class="Rrule" valign="top">84.1 <br/> 71.8 <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> 8 <br/> </td><td align="center" class="Rrule" valign="top">125.8 <br/> 194.4 <br/> </td><td align="center" class="Rrule" valign="top">1.9 <br/> 1.6 <br/> </td><td align="center" class="Rrule" valign="top">4.7 <br/> 5.8 <br/> </td> </tr> </tbody> </table></div>

Renal Impairment:Renal impairment is not expected to significantly influence the total clearance of ondansetron as renal clearance represents only 5% of the overall clearance. However, the mean plasma clearance of ondansetron was reduced by about 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/min). The reduction in clearance was variable and not consistent with an increase in half-life [see Use in Specific Populations (8.7)] . Hepatic Impairment: In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared with 5.7 hours in healthy subjects. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours [see Dosage and Administration (2.2), Use in Specific Populations (8.6)] . Drug Interaction Studies CYP 3A4 Inducers: Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic trial of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, a reduction in AUC, C max, and t ½of ondansetron was observed. This resulted in a significant increase in the clearance of ondansetron. However, this increase is not thought to be clinically relevant [see Drug Interactions (7.2)] . Chemotherapeutic Agents: Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron [see Drug Interactions (7.4)] . Antacids: Concomitant administration of antacids does not alter the absorption of ondansetron.   

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 mg/kg per day and 30 mg/kg per day, respectively (approximately 4 and 6 times the maximum recommended human oral dose of 24 mg per day, based on BSA). Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg per day (approximately 6 times the maximum recommended human oral dose of 24 mg per day, based on BSA) did not affect fertility or general reproductive performance of male and female rats.

Highly Emetogenic Chemotherapy In 2 randomized, double-blind, monotherapy trials, a single 24 mg oral dose of ondansetron was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m 2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose greater than or equal to 50 mg/m 2in the historical-placebo comparator, experienced vomiting in the absence of antiemetic therapy. The first trial compared oral doses of ondansetron 24 mg as a single dose, 8 mg every 8 hours for 2 doses, and 32 mg as a single dose in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin greater than or equal to 50 mg/m 2. The first or single dose was administered 30 minutes prior to chemotherapy. A total of 66% of patients in the ondansetron 24 mg once-a-day group, 55% in the ondansetron 8 mg twice-a-day group, and 55% in the ondansetron 32 mg once-a-day group, completed the 24-hour trial period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control. In the same trial, 56% of patients receiving a single 24 mg oral dose of ondansetron experienced no nausea during the 24-hour trial period, compared with 36% of patients in the oral ondansetron 8 mg twice-a-day group ( P= 0.001) and 50% in the oral ondansetron 32 mg once-a-day group. Dosage regimens of ondansetron 8 mg twice daily and 32 mg once daily are not recommended for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy [see Dosage and Administration (2.1)] . In a second trial, efficacy of a single 24 mg oral dose of ondansetron for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m 2, was confirmed. Moderately Emetogenic Chemotherapy A randomized, placebo-controlled, double-blind trial was conducted in the U.S. in 67 patients receiving a cyclophosphamide-based chemotherapy regimen containing doxorubicin. The first 8 mg dose of ondansetron was administered 30 minutes before the start of chemotherapy, with a subsequent dose 8 hours after the first dose, followed by 8 mg of ondansetron twice a day for 2 days after the completion of chemotherapy. Ondansetron orally disintegrating tablets was significantly more effective than placebo in preventing vomiting. Treatment response was based on the total number of emetic episodes over the 3-day trial period. The results of this trial are summarized in Table 7.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 7: Emetic Episodes-Treatment Response in Patients Receiving Moderately Emetogenic Chemotherapy (Cyclophosphamide-based Regimen Containing Doxorubicin)</span> </caption> <col width="42.06%"/> <col width="27.28%"/> <col width="14.6%"/> <col width="16.06%"/> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">a</span>Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. <br/> <span class="Sup">b</span>Median undefined since at least 50% of patients did not have any emetic episodes. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ondansetron Orally Disintegrating Tablets</span> <br/> <span class="Bold">(n</span><span class="Bold">= 33)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo</span> <br/> <span class="Bold">(n</span><span class="Bold">= 34)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"><span class="Italics">P</span>-value </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Treatment response <br/>   0 Emetic episodes <br/>   1 to 2 Emetic episodes <br/>   More than 2 emetic episodes/withdrawn <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> 20 (61%) <br/> 6 (18%) <br/> 7 (21%) <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> 2 (6%) <br/> 8 (24%) <br/> 24 (71%) <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> &lt; 0.001 <br/>   <br/> &lt; 0.001 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Median number of emetic episodes <br/> </td><td align="center" class="Rrule" valign="middle">0.0 <br/> </td><td align="center" class="Rrule" valign="middle">Undefined <span class="Sup">a</span> <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  Median time to first emetic episode (hours) <br/> </td><td align="center" class="Rrule" valign="middle">Undefined <span class="Sup">b</span> <br/> </td><td align="center" class="Rrule" valign="middle">6.5 <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> </td> </tr> </tbody> </table></div>

In a double-blind, U.S. trial in 336 patients receiving a cyclophosphamide-based chemotherapy regimen containing either methotrexate or doxorubicin, ondansetron 8 mg administered twice a day, was as effective as ondansetron 8 mg administered 3 times a day in preventing nausea and vomiting. Ondansetron 8 mg three times daily is not a recommended regimen for the treatment of moderately emetogenic chemotherapy [see Dosage and Administration (2.1)] . Treatment response was based on the total number of emetic episodes over the 3-day trial period. See Table 8 for the details of the dosage regimens studied and results of this trial.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 8: Emetic Episodes-Treatment Response After Ondansetron Tablets Administered Twice a Day and Three Times a Day</span> </caption> <col width="42.06%"/> <col width="27.12%"/> <col width="30.8%"/> <tfoot> <tr class="First Last"> <td colspan="17"><span class="Sup">a</span>The first 8 mg dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose, followed by 8 mg administered twice a day for 2 days after the completion of chemotherapy. <br/> <span class="Sup">b</span>The first 8 mg dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent 8 mg doses at 4 hours and 8 hours after the first dose, followed by 8 mg administered 3 times a day for 2 days after the completion of chemotherapy. <br/> <span class="Sup">c</span>Median undefined since at least 50% of patients did not have any emetic episodes. <br/> <span class="Sup">d</span>Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.  </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="middle">  <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Ondansetron Tablets</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">8 mg Twice Daily <span class="Sup">a</span></span> <br/> <span class="Bold">(n</span><span class="Bold">= 165)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">8 mg Three Times a Day <span class="Sup">b</span></span> <br/> <span class="Bold">(n</span><span class="Bold">= 171)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Treatment response <br/>   0 Emetic episodes <br/>   1 to 2 Emetic episodes <br/>   More than 2 emetic episodes/withdrawn <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> 101 (61%) <br/> 16 (10%) <br/> 48 (29%) <br/> </td><td align="center" class="Rrule" valign="middle">  <br/> 99 (58%) <br/> 17 (10%) <br/> 55 (32%) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Median number of emetic episodes <br/> </td><td align="center" class="Rrule" valign="middle">0.0 <br/> </td><td align="center" class="Rrule" valign="middle">0.0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  Median time to first emetic episode (h) <br/> </td><td align="center" class="Rrule" valign="middle">Undefined <span class="Sup">c</span> <br/> </td><td align="center" class="Rrule" valign="middle">Undefined <span class="Sup">c</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">  Median nausea scores (0 to 100) <span class="Sup">d</span> <br/> </td><td align="center" class="Rrule" valign="middle">6 <br/> </td><td align="center" class="Rrule" valign="middle">6 <br/> </td> </tr> </tbody> </table></div>

Re-treatment In single-arm trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ondansetron 8 mg three times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the re-treatment courses. Pediatric Trials Three open-label, single-arm, non-U.S. trials have been performed with 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens. The initial dose of ondansetron injection ranged from 0.04 to 0.87 mg per kg (total dose of 2.16 mg to 12 mg) followed by the administration of oral doses of ondansetron ranging from 4 to 24 mg daily for 3 days. In these trials, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on Day 1. In 2 trials, the response rates to ondansetron 4 mg three times a day in patients younger than 12 years was similar to ondansetron 8 mg three times daily in patients 12 to 18 years. Prevention of emesis in these pediatric patients was essentially the same as for adults.

Total Body Irradiation In a randomized, placebo-controlled, double-blind trial in 20 patients, 8 mg of ondansetron administered 1.5 hours before each fraction of radiotherapy for 4 days was significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 2 fractions on Day 4. Single High-Dose Fraction Radiotherapy In an active-controlled, double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of greater than or equal to 80 cm 2to the abdomen, ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes). Patients received the first dose of ondansetron (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 8 mg of ondansetron or 10 mg of metoclopramide was administered in the late afternoon and repeated again before bedtime. If radiotherapy was given in the afternoon, patients took 8 mg of ondansetron or 10 mg of metoclopramide only once before bedtime. Patients continued the doses of oral medication three times daily for 3 days. Daily Fractionated Radiotherapy In an active-controlled, double-blind trial in 135 patients receiving a 1- to 4- week course of fractionated radiotherapy (180 cGy doses) over a field size of greater than or equal to 100 cm 2to the abdomen, ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes). Patients received the first dose of ondansetron (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the first daily radiotherapy fraction, with subsequent 8 mg doses approximately every 8 hours on each day of radiotherapy.

In 2 placebo-controlled, double-blind trials (one conducted in the U.S. and the other outside the U.S.) in 865 females undergoing inpatient surgical procedures, ondansetron 16 mg as a single dose or placebo was administered one hour before the induction of general balanced anesthesia (barbiturate, opioid, nitrous oxide, neuromuscular blockade, and supplemental isoflurane or enflurane), ondansetron was significantly more effective than placebo in preventing postoperative nausea and vomiting. No trials have been performed in males.

Ondansetron Orally Disintegrating Tablets USP, 8 mg are white to off-white, round tablets debossed with ‘7’ on one side and ‘E’ on the other side with an embossed circular edge.

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NDC: 70518-1551-00

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NDC: 70518-1551-01

{ "type": "p", "children": [], "text": "NDC: 70518-1551-01" }

NDC: 70518-1551-02

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PACKAGING: 6 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 6 in 1 BLISTER PACK" }

PACKAGING: 3 in 1 CARTON, 10 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 3 in 1 CARTON, 10 in 1 BLISTER PACK" }

PACKAGING: 10 in 1 BLISTER PACK

{ "type": "p", "children": [], "text": "PACKAGING: 10 in 1 BLISTER PACK" }

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.

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Repackaged and Distributed By:

{ "type": "p", "children": [], "text": "Repackaged and Distributed By:" }

Remedy Repack, Inc.

{ "type": "p", "children": [], "text": "Remedy Repack, Inc." }

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

{ "type": "p", "children": [], "text": "625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762" }

Hypersensitivity Reactions

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Inform patients that ondansetron may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. Instruct patients to immediately report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems to their healthcare provider [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Inform patients that ondansetron may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. Instruct patients to immediately report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems to their healthcare provider \n [see \n Warnings and Precautions (5.1)]. \n \n" }

QT Prolongation

{ "type": "p", "children": [], "text": "\nQT Prolongation\n" }

Inform patients that ondansetron may cause serious cardiac arrhythmias, such as QT prolongation. Instruct patients 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 [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients that ondansetron may cause serious cardiac arrhythmias, such as QT prolongation. Instruct patients 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 \n [see \n Warnings and Precautions (5.2)]. \n \n" }

Drug Interactions

{ "type": "p", "children": [], "text": "\nDrug Interactions\n" }

{ "type": "ul", "children": [ "Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and ondansetron may cause a significant drop in blood pressure and loss of consciousness.", "Advise patients of the possibility of serotonin syndrome with concomitant use of ondansetron and another serotonergic agent, such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms \n [see \n Warnings and Precautions (5.3)]. \n \n" ], "text": "" }

Myocardial Ischemia

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Inform patients that ondansetron may cause myocardial ischemia. Advise patients to seek immediate medical help if any symptoms suggestive of a myocardial ischemia occur, such as sudden chest pain or chest tightness [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Inform patients that ondansetron may cause myocardial ischemia. Advise patients to seek immediate medical help if any symptoms suggestive of a myocardial ischemia occur, such as sudden chest pain or chest tightness \n [see \n Warnings and Precautions (5.4)]. \n \n" }

Masking of Progressive Ileus and Gastric Distension

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Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that ondansetron 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 [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that ondansetron 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 \n [see \n Warnings and Precautions (5.5)]. \n \n" }

Administration of Ondansetron Orally Disintegrating Tablets

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Instruct patients not to remove ondansetron orally disintegrating tablets from the blister until just prior to dosing.

{ "type": "p", "children": [], "text": "Instruct patients not to remove ondansetron orally disintegrating tablets from the blister until just prior to dosing." }

{ "type": "ul", "children": [ "Do not attempt to push ondansetron orally disintegrating tablets through the foil backing.", "With dry hands, remove the tablet from the bottle or peel back the foil backing of 1 blister and gently remove the tablet.", "Immediately place the ondansetron orally disintegrating tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva.", "Administration with liquid is not necessary.", "Peelable illustrated stickers are affixed to the product carton that can be provided with the prescription to ensure proper use and handling of the product." ], "text": "" }

Repackaged By / Distributed By: RemedyRepack Inc.

{ "type": "p", "children": [], "text": "Repackaged By / Distributed By: RemedyRepack Inc." }

625 Kolter Drive, Indiana, PA 15701

{ "type": "p", "children": [], "text": "625 Kolter Drive, Indiana, PA 15701" }

(724) 465-8762

{ "type": "p", "children": [], "text": "(724) 465-8762" }

DRUG: Ondansetron

{ "type": "p", "children": [], "text": "DRUG: Ondansetron" }

GENERIC: Ondansetron

{ "type": "p", "children": [], "text": "GENERIC: Ondansetron" }

DOSAGE: TABLET, ORALLY DISINTEGRATING

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ADMINSTRATION: ORAL

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NDC: 70518-1551-0

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NDC: 70518-1551-1

{ "type": "p", "children": [], "text": "NDC: 70518-1551-1" }

NDC: 70518-1551-2

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COLOR: white

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FLAVOR: GUARANA

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SHAPE: ROUND

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SCORE: No score

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SIZE: 7 mm

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IMPRINT: 7;E

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PACKAGING: 6 in 1 BLISTER PACK

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PACKAGING: 3 in 1 CARTON, 10 in 1 BLISTER PACK

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PACKAGING: 10 in 1 BLISTER PACK

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ACTIVE INGREDIENT(S):

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{ "type": "ul", "children": [ "ONDANSETRON 8mg in 1" ], "text": "" }

INACTIVE INGREDIENT(S):

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{ "type": "ul", "children": [ "MANNITOL", "CROSPOVIDONE (120 .MU.M)", "LACTOSE MONOHYDRATE", "MICROCRYSTALLINE CELLULOSE", "ASPARTAME", "SILICON DIOXIDE", "MAGNESIUM STEARATE" ], "text": "" }