Browse the corpus

1 INDICATIONS AND USAGE Ondansetron is indicated for the prevention of nausea and vomiting associated with: • highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m 2 • initial and repeat courses of moderately emetogenic cancer chemotherapy • radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen Ondansetron is also indicated for the prevention of postoperative nausea and/or vomiting. Ondansetron is a 5-HT 3 receptor antagonist indicated for the prevention of: • nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m 2 . ( 1 ) • nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. ( 1 ) • nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen. ( 1 ) • postoperative nausea and/or vomiting. ( 1 )

2 DOSAGE AND ADMINISTRATION • See full prescribing information for the recommended dosage in adults and pediatrics. ( 2 ) • Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg. ( 2.2 , 8.6 ) 2.1 Dosage The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively. Corresponding doses of ondansetron tablets, and ondansetron orally disintegrating tablets may be used interchangeably. Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Highly Emetogenic Cancer Chemotherapy 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 2 . Moderately Emetogenic Cancer Chemotherapy 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8-mg dose 8 hours after the first dose. Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. Radiotherapy For total body irradiation: 8 mg administered 1 to 2 hours before each fraction of radiotherapy each day. For single high-dose fraction radiotherapy to the abdomen: 8 mg administered 1 to 2 hours before radiotherapy, with subsequent 8-mg doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. For daily fractionated radiotherapy to the abdomen: 8 mg administered 1 to 2 hours before radiotherapy, with subsequent 8-mg doses every 8 hours after the first dose for each day radiotherapy is given. Postoperative 16 mg administered 1 hour before induction of anesthesia. Table 2: Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Moderately Emetogenic Cancer Chemotherapy 12 to 17 years of age: 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8-mg dose 8 hours after the first dose. Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. 4 to 11 years of age: 4 mg administered 30 minutes before the start of chemotherapy, with a subsequent 4-mg dose 4 and 8 hours after the first dose. Then administer 4 mg three times a day for 1 to 2 days after completion of chemotherapy. 2.2 Dosage in Hepatic Impairment 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 )] . 2.3 Administration Instructions for Ondansetron Orally Disintegrating Tablets Do not attempt to push ondansetron orally disintegrating tablets through the foil backing. With dry hands, 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.

3 DOSAGE FORMS AND STRENGTHS Ondansetron Tablets, USP are oval, standard convex, film-coated tablets and are available in the following strengths: • 4 mg - white tablet with ‘4’ on one side and ‘G1’ logo on the other side • 8 mg - yellow tablet with ‘8’ on one side and ‘G1’ logo on the other side Ondansetron Orally Disintegrating Tablets, USP are white, circular, flat faced, uncoated tablets and are available in the following strengths: • 4 mg - ‘G’ engraved on one side and ‘4’ on the other side • 8 mg - ‘G’ engraved on one side and ‘8’ on the other side • Tablets: 4 mg and 8 mg ( 3 ) • Orally Disintegrating Tablets: 4 mg and 8 mg ( 3 )

4 CONTRAINDICATIONS Ondansetron is contraindicated in patients: • known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation [see Adverse Reactions ( 6.2 )] • receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness Patients known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any components of the formulation. ( 4 ) • Concomitant use of apomorphine ( 4 )

5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions Including Anaphylaxis and Bronchospasm : Discontinue ondansetron if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve. ( 5.1 ) • QT Interval Prolongation and Torsade de Pointes : Avoid in patients with congenital long QT syndrome; monitor with electrocardiograms (ECGs) if concomitant electrolyte abnormalities, cardiac failure or arrhythmias, or use of other QT prolonging drugs. ( 5.2 ) • Serotonin Syndrome : Reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue ondansetron and initiate supportive treatment. If concomitant use of ondansetron with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. ( Error! Hyperlink reference not valid. ) • Myocardial Ischemia : Monitor or advise patients for signs and symptoms of myocardial ischemia after oral administration. ( 5.4 ) • Masking of Progressive Ileus and/or Gastric Distension Following Abdominal Surgery or Chemotherapy-Induced Nausea and Vomiting : Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. ( 5.5 ) • Phenylketonuria : Patients should be informed that ondansetron orally disintegrating tablets contain phenylalanine (a component of aspartame). Each 4-mg and 8-mg orally disintegrating tablet contains 1.5 mg and 3 mg of phenylalanine, respectively. ( 5.6 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 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 )]. 5.2 QT Prolongation 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 )]. 5.3 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 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-HT 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

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 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ondansetron 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 )] . 5.4 Myocardial Ischemia 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 )] . 5.5 Masking of Progressive Ileus and Gastric Distension 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. 5.6 Phenylketonuria Phenylketonuric patients should be informed that ondansetron orally disintegrating tablets contain phenylalanine (a component of aspartame). Each 4-mg and 8-mg orally disintegrating tablet contains 1.5 mg and 3 mg of phenylalanine, respectively.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] • QT Prolongation [see Warnings and Precautions ( 5.2 )] • Serotonin Syndrome [see Warnings and Precautions ( Error! Hyperlink reference not valid. )] • Myocardial Ischemia [see Warnings and Precautions ( 5.4 )] • Masking of Progressive Ileus and Gastric Distension [see Warnings and Precautions ( 5.5 )] The most common adverse reactions in adults for the: • prevention of chemotherapy-induced (≥5%) are: headache, malaise/fatigue, constipation, diarrhea. ( 6.1 ) • prevention of radiation-induced nausea and vomiting (≥2%) are: headache, constipation, and diarrhea. ( 6.1 ) • prevention of postoperative nausea and vomiting (≥9%) are: headache and hypoxia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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/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. Table 3: Most Common Adverse Reactions in Adults a for the Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Chemotherapy [Primarily Cyclophosphamide-based Regimens] Adverse Reaction Ondansetron 8 mg Twice Daily (n = 242) Placebo (n = 262) Headache 58 (24%) 34 (13%) Malaise/Fatigue 32 (13%) 6 (2%) Constipation 22 (9%) 1 (<1%) Diarrhea 15 (6%) 10 (4%) a Reported in greater than or equal to 5% of patients treated with ondansetron and at a rate that exceeded placebo. 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.

alues 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 Adults a for the Prevention of Postoperative Nausea and Vomiting Adverse Reaction Ondansetron 16 mg as a Single Dose (n = 550) Placebo (n = 531) Headache 49 (9%) 27 (5%) Hypoxia 49 (9%) 35 (7%) Pyrexia 45 (8%) 34 (6%) Dizziness 36 (7%) 34 (6%) Gynecological disorder 36 (7%) 33 (6%) Anxiety/Agitation 33 (6%) 29 (5%) Urinary retention 28 (5%) 18 (3%) Pruritus 27 (5%) 20 (4%) a Reported in greater than or equal to 5% of patients treated with ondansetron and at a rate that exceeded placebo. 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%). 6.2 Postmarketing Experience 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.

<table width="100%"><caption>Table 3: Most Common Adverse Reactions in Adults^a for the Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Chemotherapy [Primarily Cyclophosphamide-based Regimens]</caption><col width="33%"/><col width="49%"/><col width="18%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Ondansetron 8 mg Twice Daily</content></paragraph><paragraph><content styleCode="bold">(n = 242)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 262)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>58 (24%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>34 (13%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Malaise/Fatigue</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>32 (13%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6 (2%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>22 (9%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1 (&lt;1%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15 (6%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10 (4%)</paragraph></td></tr></tbody></table>

/paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15 (6%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10 (4%)</paragraph></td></tr></tbody></table> <table width="100%"><caption>Table 4: Most Common Adverse Reactions in Adults^a for the Prevention of Postoperative Nausea and Vomiting</caption><col width="34%"/><col width="50%"/><col width="16%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Ondansetron 16 mg as a Single Dose</content></paragraph><paragraph><content styleCode="bold">(n = 550)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 531)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>49 (9%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27 (5%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypoxia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>49 (9%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>35 (7%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>45 (8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>34 (6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>36 (7%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>34 (6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gynecological disorder</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>36 (7%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>33 (6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anxiety/Agitation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>33 (6%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>29 (5%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Urinary retention</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28 (5%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18 (3%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27 (5%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20 (4%)</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS 7.1 Serotonergic Drugs Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including SSRIs and SNRIs. Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ondansetron and initiate supportive treatment [see Warnings and Precautions ( Error! Hyperlink reference not valid. )] . 7.2 Drugs Affecting Cytochrome P-450 Enzymes 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 )] . 7.3 Tramadol 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. 7.4 Chemotherapy 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. 7.5 Alfentanil and Atracurium 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 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).

ssociations 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. 8.2 Lactation 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. 8.4 Pediatric Use 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: • prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy • prevention of nausea and vomiting associated with radiotherapy • prevention of postoperative nausea and/or vomiting 8.5 Geriatric Use 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 )] .

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. 8.6 Hepatic Impairment 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 )] . 8.7 Renal Impairment 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 )] .

8.1 Pregnancy 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 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).

ssociations 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.

8.4 Pediatric Use 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: • prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy • prevention of nausea and vomiting associated with radiotherapy • prevention of postoperative nausea and/or vomiting

8.5 Geriatric Use 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.

10 OVERDOSAGE 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.

11 DESCRIPTION The active ingredient in Ondansetron Tablets, USP is ondansetron hydrochloride, USP as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT 3 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 C 18 H 19 N 3 O•HCl•2H 2 O, representing a molecular weight of 365.85 g/mol. Ondansetron hydrochloride, USP (dihydrate) is a white to off-white powder that is sparingly soluble in water and in alcohol; soluble in methanol, slightly soluble in isopropyl alcohol, and in dichloromethane; very slightly soluble in acetone, in chloroform and in ethyl acetate. 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 3 receptor 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 empirical formula is C 18 H 19 N 3 O representing a molecular weight of 293.4 g/mol. Each 4-mg Ondansetron Tablet, USP for oral administration contains ondansetron hydrochloride, USP (dihydrate) equivalent to 4 mg of ondansetron. Each 8-mg Ondansetron Tablet, USP for oral administration contains ondansetron hydrochloride, USP (dihydrate) equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients colloidal silicon dioxide, hypromellose, iron oxide yellow (8 mg tablet only), lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, titanium dioxide and triacetin. 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 aspartame, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, sodium stearyl fumarate and strawberry flavor. Ondansetron Orally Disintegrating Tablets, USP are an orally administered formulation of ondansetron which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. This product disintegrates in approximately 60 seconds. Ondansetron Orally Disintegrating Tablets, USP meet USP Disintegration Test 2. structure-hcl structure-base

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ondansetron is a selective 5‑HT 3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine‑receptor antagonist. Serotonin receptors of the 5‑HT 3 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‑HT 3 receptors and initiate the vomiting reflex. 12.2 Pharmacodynamics 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. 12.3 Pharmacokinetics 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.

cretion: 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 a Ondansetron 8mg Tablet Age-group (years) Sex (M/F) Mean Weight (kg) N Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) Systemic Plasma Clearance L/h/kg Absolute Bioavailability 18 to 40 M 69 6 26.2 2 3.1 0.403 0.483 F 62.7 5 42.7 1.7 3.5 0.354 0.663 61 to 74 M 77.5 6 24.1 2.1 4.1 0.384 0.585 F 60.2 6 52.4 1.9 4.9 0.255 0.643 ≥75 M 78 5 37 2.2 4.5 0.277 0.619 F 67.6 6 46.1 2.1 6.2 0.249 0.747 Table 6: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 24-mg Tablet Age-group (years) Sex (M/F) Mean Weight (kg) N Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) 18 to 43 M 84.1 8 125.8 1.9 4.7 F 71.8 8 194.4 1.6 5.8 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.

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 ½ 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.

12.1 Mechanism of Action Ondansetron is a selective 5‑HT 3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine‑receptor antagonist. Serotonin receptors of the 5‑HT 3 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‑HT 3 receptors and initiate the vomiting reflex.

12.2 Pharmacodynamics 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.

12.3 Pharmacokinetics 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.

esulted 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 a Ondansetron 8mg Tablet Age-group (years) Sex (M/F) Mean Weight (kg) N Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) Systemic Plasma Clearance L/h/kg Absolute Bioavailability 18 to 40 M 69 6 26.2 2 3.1 0.403 0.483 F 62.7 5 42.7 1.7 3.5 0.354 0.663 61 to 74 M 77.5 6 24.1 2.1 4.1 0.384 0.585 F 60.2 6 52.4 1.9 4.9 0.255 0.643 ≥75 M 78 5 37 2.2 4.5 0.277 0.619 F 67.6 6 46.1 2.1 6.2 0.249 0.747 Table 6: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 24-mg Tablet Age-group (years) Sex (M/F) Mean Weight (kg) N Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) 18 to 43 M 84.1 8 125.8 1.9 4.7 F 71.8 8 194.4 1.6 5.8 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 ½ 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.

<table cellpadding="4.3pt" width="100%"><caption>Table 5: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 8mg Tablet</caption><col width="18%"/><col width="9%"/><col width="3%"/><col width="15%"/><col width="15%"/><col width="13%"/><col width="11%"/><col width="15%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Age-group</content></paragraph><paragraph><content styleCode="bold">(years) </content></paragraph><paragraph><content styleCode="bold">Sex (M/F)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Mean</content></paragraph><paragraph><content styleCode="bold">Weight</content></paragraph><paragraph><content styleCode="bold">(kg)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Peak Plasma</content></paragraph><paragraph><content styleCode="bold">Concentration</content></paragraph><paragraph><content styleCode="bold">(ng/mL)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Time of</content></paragraph><paragraph><content styleCode="bold">Peak Plasma</content></paragraph><paragraph><content styleCode="bold">Concentration</content></paragraph><paragraph><content styleCode="bold">(h)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Mean</content></paragraph><paragraph><content styleCode="bold">Elimination</content></paragraph><paragraph><content styleCode="bold">Half-life</content></paragraph><paragraph><content styleCode="bold">(h)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Systemic</content></paragraph><paragraph><content styleCode="bold">Plasma</content></paragraph><paragraph><content styleCode="bold">Clearance</content></paragraph><paragraph><content styleCode="bold">L/h/kg</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Absolute</content></paragraph><paragraph><content styleCode="bold">Bioavailability</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>18 to 40 M</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>69</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>26.2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.403</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.483</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption> F</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>62.7</paragraph></td><td align="center" styleCode="Rrule Botrule

"Rrule " valign="top"><paragraph>0.483</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption> F</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>62.7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>42.7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.354</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.663</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>61 to 74 M</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>77.5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>24.1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4.1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.384</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.585</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption> F</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>60.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>52.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.255</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.643</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>&#x2265;75 M</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>78</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>37</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4.5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.277</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.619</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="ordered"><item><caption> </caption> F</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>67.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>46.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.249</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.747</paragraph></td></tr></tbody></table>

raph>2.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.249</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.747</paragraph></td></tr></tbody></table> <table cellpadding="4.3pt" width="100%"><caption>Table 6: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 24-mg Tablet</caption><col width="25%"/><col width="12%"/><col width="4%"/><col width="21%"/><col width="21%"/><col width="17%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Age-group</content></paragraph><paragraph><content styleCode="bold">(years)</content></paragraph><paragraph><content styleCode="bold">Sex (M/F)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Mean</content></paragraph><paragraph><content styleCode="bold">Weight</content></paragraph><paragraph><content styleCode="bold">(kg)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Peak Plasma</content></paragraph><paragraph><content styleCode="bold">Concentration</content></paragraph><paragraph><content styleCode="bold">(ng/mL)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Time of</content></paragraph><paragraph><content styleCode="bold">Peak Plasma</content></paragraph><paragraph><content styleCode="bold">Concentration</content></paragraph><paragraph><content styleCode="bold">(h)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Mean</content></paragraph><paragraph><content styleCode="bold">Elimination</content></paragraph><paragraph><content styleCode="bold">Half-life</content></paragraph><paragraph><content styleCode="bold">(h)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="bottom"><list listType="unordered"><item><caption> </caption>18 to 43 M</item></list></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>84.1</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>125.8</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>1.9</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>4.7</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="bottom"><list listType="ordered"><item><caption> </caption> F</item></list></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>71.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>194.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>5.8</paragraph></td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

14 CLINICAL STUDIES 14.1 Prevention of Chemotherapy-Induced Nausea and Vomiting 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 2 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/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 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) Ondansetron (n = 33) Placebo (n = 34) P -value Treatment response 0 Emetic episodes 20 (61%) 2 (6%) <0.001 1 to 2 Emetic episodes 6 (18%) 8 (24%) More than 2 emetic episodes/withdrawn 7 (21%) 24 (71%) <0.001 Median number of emetic episodes 0 Undefined a Median time to first emetic episode (hours) Undefined b 6.5 a Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. b Median undefined since at least 50% of patients did not have any emetic episodes.

7 (21%) 24 (71%) <0.001 Median number of emetic episodes 0 Undefined a Median time to first emetic episode (hours) Undefined b 6.5 a Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. b Median undefined since at least 50% of patients did not have any emetic episodes. 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 Ondansetron Tablets 8 mg Twice Daily a (n = 165) 8 mg Three Times a Day b (n = 171) Treatment response 0 Emetic episodes 101 (61%) 99 (58%) 1 to 2 Emetic episodes 16 (10%) 17 (10%) More than 2 emetic episodes/withdrawn 48 (29%) 55 (32%) Median number of emetic episodes 0 0 Median time to first emetic episode (h) Undefined c Undefined c Median nausea scores (0 to 100) d 6 6 a 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. b 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. c Median undefined since at least 50% of patients did not have any emetic episodes. d Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be. 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 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. 14.2 Radiation-Induced Nausea and Vomiting 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.

h 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 2 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 cm 2 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. 14.3 Postoperative Nausea and/ or Vomiting 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.

<table width="100%"><caption>Table 7: Emetic Episodes - Treatment Response in Patients Receiving Moderately Emetogenic Chemotherapy (Cyclophosphamide-based Regimen Containing Doxorubicin)</caption><col width="50%"/><col width="20%"/><col width="17%"/><col width="13%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="bottom"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Ondansetron</content></paragraph><paragraph><content styleCode="bold">(n = 33)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 34)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold"><content styleCode="italics">P</content>-value</content></paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>Treatment response</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Lrule " valign="top"><paragraph>0 Emetic episodes</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>20 (61%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2 (6%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;0.001</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>1 to 2 Emetic episodes</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>6 (18%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8 (24%)</paragraph></td><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>More than 2 emetic episodes/withdrawn</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (21%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>24 (71%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&lt;0.001</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Median number of emetic episodes</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Undefined^a</paragraph></td><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Median time to first emetic episode (hours)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Undefined^b</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5</paragraph></td><td styleCode="Rrule Botrule " valign="top"/></tr></tbody></table>

e to first emetic episode (hours)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Undefined^b</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5</paragraph></td><td styleCode="Rrule Botrule " valign="top"/></tr></tbody></table> <table width="100%"><caption>Table 8: Emetic Episodes - Treatment Response After Ondansetron Tablets Administered Twice a Day and Three Times a Day</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td rowspan="2" styleCode="Lrule Toprule " valign="bottom"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Ondansetron Tablets</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">8 mg Twice Daily^a</content></paragraph><paragraph><content styleCode="bold">(n = 165)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">8 mg Three Times a Day^b</content></paragraph><paragraph><content styleCode="bold">(n = 171)</content></paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>Treatment response</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Lrule " valign="top"><paragraph>0 Emetic episodes</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>101 (61%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>99 (58%)</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph>1 to 2 Emetic episodes</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>16 (10%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>17 (10%)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>More than 2 emetic episodes/withdrawn</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48 (29%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>55 (32%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Median number of emetic episodes</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Median time to first emetic episode (h)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Undefined^c</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Undefined^c</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Median nausea scores (0 to 100)^d</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions 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 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 • 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 [ see Warnings and Precautions ( Error! Hyperlink reference not valid. ) ]. Myocardial Ischemia 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 )] . 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 ) ]. Administration of Ondansetron Orally Disintegrating Tablets Instruct patients not to remove ondansetron orally disintegrating tablets from the blister until just prior to dosing. • Do not attempt to push ondansetron orally disintegrating tablets through the foil backing. • With dry hands, 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. Manufactured by: Glenmark Pharmaceuticals Limited India Manufactured for: Glenmark Pharmaceuticals Inc., USA Mahwah, NJ 07430 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com November 2021 logo

1 INDICATIONS AND USAGE Ondansetron Injection is a 5-HT 3 receptor antagonist indicated for the prevention of: • nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy. ( 1.1 ) • postoperative nausea and/or vomiting. ( 1.2 ) 1.1 Prevention of Nausea and Vomiting Associated With Initial and Repeat Courses of Emetogenic Cancer Chemotherapy 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. 1.2 Prevention of Postoperative Nausea and/or Vomiting 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.

2 DOSAGE AND ADMINISTRATION Prevention of Nausea and Vomiting Associated With Initial and Repeat Courses of Emetogenic Cancer Chemotherapy ( 2.1 ): • 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. • Adults and pediatric patients 6 months of age and older: The recommended dosage is 0.15 mg/kg per dose for 3 doses (maximum of 16 mg per dose), infused intravenously over 15 minutes. • Administer the first dose 30 minutes before the start of chemotherapy and subsequent doses 4 and 8 hours after the first dose. Prevention of Postoperative Nausea and/or Vomiting ( 2.2 ) : • Dilution of Ondansetron Injection is not required before administration to adult and pediatric patients. • See full prescribing information for the recommended dosage and administration instructions for adult and pediatric patients 1 month of age and older. Patients With Severe Hepatic Impairment ( 2.3 ) : • Do not exceed a total daily dose of 8 mg. 2.1 Prevention of Nausea and Vomiting Associated With Initial and Repeat Courses of Emetogenic Chemotherapy 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.

g/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. 2.2 Prevention of Postoperative Nausea and/or Vomiting 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 Population Recommended Single Dose Administration Instructions Timing of Administration Adults and pediatric patients older than 12 years of age 4 mg 1 May be administered intravenously or intramuscularly: Intravenously: infuse undiluted syringe contents (4 mg) over at least 30 seconds and preferably longer (over 2 to 5 minutes). Intramuscularly: inject undiluted syringe contents (4 mg) Administer immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery 2,3 Pediatric patients 1 month to 12 years and more than 40 kg 4 mg Infuse intravenously over at least 30 seconds and preferably longer (over 2 to 5 minutes). Pediatric patients 1 month to 12 years and 40 kg or less 0.1 mg/kg Infuse intravenously over at least 30 seconds and preferably longer (over 2 to 5 minutes). 1. Few patients above 80 kg have been studied. 2. Administration of a second intravenous dose of 4 mg ondansetron postoperatively in adult patients who received a 4 mg prophylactic dose does not provide additional control of nausea and vomiting [see Clinical Studies (14.3) ]. 3. For pediatric patients (1 month to 12 years) prevention of nausea and vomiting was only studied in patients who had not received prophylactic ondansetron. 2.3 Dosage Adjustment for Patients With Hepatic Impairment 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)] .

4 CONTRAINDICATIONS Ondansetron Injection is contraindicated for patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Anaphylactic reactions have been reported in patients taking ondansetron [see Adverse Reactions (6.2) ] . The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron. • Patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. ( 4 ) • Concomitant use of apomorphine. ( 4 , 7.2 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Hypersensitivity reactions, including anaphylaxis and bronchospasm have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. ( 5.1 ) QT Prolongation and Torsade de Pointes : QT prolongation occurs in a dose-dependent manner. Cases of Torsade de Pointes have been reported. Avoid Ondansetron Injection in patients with congenital long QT syndrome. ( 5.2 ) Serotonin Syndrome : Serotonin syndrome has been reported with 5-HT 3 receptor agonists alone but particularly with concomitant use of serotonergic drugs. ( 5.3 ) Myocardial Ischemia: Do not exceed the recommended infusion rate and monitor patients during and after administration. ( 2.1 , 2.2 , 5.4 ) Masking of Progressive Ileus and/or Gastric Distension Following Abdominal Surgery or Chemotherapy-Induced Nausea and Vomiting : Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. ( 5.5 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. 5.2 QT Prolongation 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. 5.3 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of Ondansetron Injection alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of Ondansetron Injection and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Ondansetron Injection and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Ondansetron Injection is used concomitantly with other serotonergic drugs [see Drug Interactions (7.5) , Overdosage (10) ] .

f 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) ] . 5.4 Myocardial Ischemia 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) ] . 5.5 Masking of Progressive Ileus and Gastric Distension 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 distension. 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] QT Prolongation [see Warnings and Precautions (5.2) ] Serotonin Syndrome [see Warnings and Precautions (5.3) ] Myocardial Ischemia [see Warnings and Precautions (5.4) ] Masking of Progressive Ileus and Gastric Distension [see Warnings and Precautions (5.5) ] Chemotherapy-Induced Nausea and Vomiting : · The most common adverse reactions (≥7%) in adults are diarrhea, headache, and fever. ( 6.1 ) Postoperative Nausea and Vomiting : · The most common adverse reaction (≥10%) which occurs at a higher frequency compared with placebo in adults is headache. ( 6.1 ) · The most common adverse reaction (≥2%) which occurs at a higher frequency compared with placebo in pediatric patients aged 1 to 24 months is diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 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 Adverse Reaction Number of Adult Patients With Reaction Ondansetron Injection 0.15 mg/kg x 3 (n = 419) Metoclopramide (n = 156) Placebo (n = 34) Diarrhea 16% 44% 18% Headache 17% 7% 15% Fever 8% 5% 3% 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.

dansetron 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 Adverse Reaction 1,2 Ondansetron Injection 4 mg Intravenous (n = 547) Placebo (n = 547) Headache 92 (17%) 77 (14%) Drowsiness/Sedation 44 (8%) 37 (7%) Injection-site reaction 21 (4%) 18 (3%) Fever 10 (2%) 6 (1%) Cold sensation 9 (2%) 8 (1%) Pruritus 9 (2%) 3 (< 1%) Paresthesia 9 (2%) 2 (< 1%) 1. Adverse reactions: Rates of these reactions were not significantly different in the ondansetron and placebo groups. 2. 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. 6.2 Postmarketing Experience 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.

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.

<table width="90%" cellspacing="0" cellpadding="0"><colgroup><col width="26%"/><col width="30%"/><col width="24%"/><col width="19%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" rowspan="2" align="center" valign="top"><content styleCode="bold"> Adverse Reaction</content></td><td styleCode="Rrule" colspan="3" align="center" valign="top"><content styleCode="bold">Number of Adult Patients With Reaction</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"><content styleCode="bold">Ondansetron Injection</content> <content styleCode="bold">0.15 mg/kg x 3</content> <content styleCode="bold">(n = 419)</content></td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold"> Metoclopramide</content> <content styleCode="bold">(n = 156)</content></td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold"> Placebo</content> <content styleCode="bold">(n = 34)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Diarrhea</td><td styleCode="Rrule" align="center" valign="top">16%</td><td styleCode="Rrule" align="center" valign="top">44%</td><td styleCode="Rrule" align="center" valign="top">18%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Headache</td><td styleCode="Rrule" align="center" valign="top">17%</td><td styleCode="Rrule" align="center" valign="top">7%</td><td styleCode="Rrule" align="center" valign="top">15%</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Fever</td><td styleCode="Rrule" align="center" valign="top">8%</td><td styleCode="Rrule" align="center" valign="top">5%</td><td styleCode="Rrule" align="center" valign="top">3%</td></tr></tbody></table>

p">7%</td><td styleCode="Rrule" align="center" valign="top">15%</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Fever</td><td styleCode="Rrule" align="center" valign="top">8%</td><td styleCode="Rrule" align="center" valign="top">5%</td><td styleCode="Rrule" align="center" valign="top">3%</td></tr></tbody></table> <table cellspacing="0" cellpadding="0"><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="center" valign="middle"> <content styleCode="bold">Adverse Reaction</content><content styleCode="italics">^1,2</content></td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Ondansetron Injection 4 mg Intravenous (n = 547)</content></td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Placebo (n = 547)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Headache</td><td styleCode="Rrule" align="center" valign="middle"> 92 (17%)</td><td styleCode="Rrule" align="center" valign="middle"> 77 (14%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Drowsiness/Sedation</td><td styleCode="Rrule" align="center" valign="middle"> 44 (8%)</td><td styleCode="Rrule" align="center" valign="middle"> 37 (7%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Injection-site reaction</td><td styleCode="Rrule" align="center" valign="middle"> 21 (4%)</td><td styleCode="Rrule" align="center" valign="middle"> 18 (3%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Fever</td><td styleCode="Rrule" align="center" valign="middle"> 10 (2%)</td><td styleCode="Rrule" align="center" valign="middle"> 6 (1%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Cold sensation</td><td styleCode="Rrule" align="center" valign="middle"> 9 (2%)</td><td styleCode="Rrule" align="center" valign="middle"> 8 (1%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="middle"> Pruritus</td><td styleCode="Rrule" align="center" valign="middle"> 9 (2%)</td><td styleCode="Rrule" align="center" valign="middle"> 3 (&lt; 1%)</td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="middle"> Paresthesia</td><td styleCode="Rrule" align="center" valign="middle"> 9 (2%)</td><td styleCode="Rrule" align="center" valign="middle"> 2 (&lt; 1%)</td></tr></tbody></table>

7 DRUG INTERACTIONS 7.1 Drugs Affecting Cytochrome P-450 Enzymes 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. 7.2 Apomorphine 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) ] . 7.3 Phenytoin, Carbamazepine, and Rifampin 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) ] . 7.4 Tramadol 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. 7.5 Serotonergic Drugs Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including SSRIs and SNRIs [see Warnings and Precautions (5.3) ] . 7.6 Chemotherapy 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. 7.7 Temazepam The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam. 7.8 Alfentanil and Atracurium 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 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. 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 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]).

up 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. 8.2 Lactation 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 the 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. 8.4 Pediatric Use Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month [see Clinical Studies (14.2) ] .

gle-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. 8.4 Pediatric Use Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month [see Clinical Studies (14.2) ] . Little information is available about the use of ondansetron in pediatric cancer patients younger than 6 months [see Clinical Studies (14.1) , Dosage and Administration (2) ] . The clearance of ondansetron in pediatric patients aged 1 month to 4 months is slower and the half-life is ~2.5-fold longer than patients who are aged > 4 to 24 months. As a precaution, it is recommended that patients younger than 4 months receiving this drug be closely monitored [see Clinical Pharmacology (12.3) ] . 8.5 Geriatric Use Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting US- and foreign-controlled clinical trials, 862 were aged 65 years and older. No overall differences in safety or effectiveness were observed between subjects 65 years and older and younger subjects. A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects [see Clinical Pharmacology (12.3) ] . There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age-group. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65. 8.6 Hepatic Impairment In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life [see Clinical Pharmacology (12.3) ] . In such patients, a total daily dose of 8 mg should not be exceeded [see Dosage and Administration (2.3) ] . 8.7 Renal Impairment Although plasma clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), no dosage adjustment is recommended [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy 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 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. 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 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).

ssociations 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.

8.4 Pediatric Use Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month [see Clinical Studies (14.2) ] . Little information is available about the use of ondansetron in pediatric cancer patients younger than 6 months [see Clinical Studies (14.1) , Dosage and Administration (2) ] . The clearance of ondansetron in pediatric patients aged 1 month to 4 months is slower and the half-life is ~2.5-fold longer than patients who are aged > 4 to 24 months. As a precaution, it is recommended that patients younger than 4 months receiving this drug be closely monitored [see Clinical Pharmacology (12.3) ] .

8.5 Geriatric Use Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting US- and foreign-controlled clinical trials, 862 were aged 65 years and older. No overall differences in safety or effectiveness were observed between subjects 65 years and older and younger subjects. A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects [see Clinical Pharmacology (12.3) ] . There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age-group. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65.

10 OVERDOSAGE There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose. In addition to the adverse reactions listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of ondansetron hydrochloride tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely. Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg/kg) in young children. Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure. Patients required supportive care, including intubation in some cases, with complete recovery without sequelae within 1 to 2 days.

11 DESCRIPTION The active ingredient of Ondansetron Injection, USP is ondansetron hydrochloride, a selective blocking agent of the serotonin 5-HT 3 receptor type. Its chemical name is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula: The empirical formula is C 18 H 19 N 3 O•HCl•2H 2 O, 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; 9.0 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for Injection. 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 hydrochloride chemical structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ondansetron is a selective 5-HT 3 receptor antagonist. While ondansetron’s mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist. 12.2 Pharmacodynamics 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. 12.3 Pharmacokinetics 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 Age-group (years) n Peak Plasma Concentration (ng/mL) Mean Elimination Half-life (h) Plasma Clearance (L/h/kg) 19-40 11 102 3.5 0.381 61-74 12 106 4.7 0.319 ≥ 75 11 170 5.5 0.262 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.

ributes 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 Subjects and Age-group N CL (L/h/kg) Vd ss (L/kg) t ½ (h) Geometric Mean Mean Pediatric Cancer Patients 4 to 18 years N = 21 0.599 1.9 2.8 Population PK Patients 1 1 month to 48 months N = 115 0.582 3.65 4.9 1. 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.

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 Subjects and Age-group N CL (L/h/kg) Vd ss (L/kg) t ½ (h) Geometric Mean Mean Pediatric Surgery Patients 3 to 12 years N = 21 0.439 1.65 2.9 Pediatric Surgery Patients 5 to 24 months N = 22 0.581 2.3 2.9 Pediatric Surgery Patients 1 month to 4 months N = 19 0.401 3.5 6.7 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 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 ½ 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 t ½ 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) ].

12.2 Pharmacodynamics 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.

12.3 Pharmacokinetics 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 Age-group (years) n Peak Plasma Concentration (ng/mL) Mean Elimination Half-life (h) Plasma Clearance (L/h/kg) 19-40 11 102 3.5 0.381 61-74 12 106 4.7 0.319 ≥ 75 11 170 5.5 0.262 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.

e 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 Subjects and Age-group N CL (L/h/kg) Vd ss (L/kg) t ½ (h) Geometric Mean Mean Pediatric Cancer Patients 4 to 18 years N = 21 0.599 1.9 2.8 Population PK Patients 1 1 month to 48 months N = 115 0.582 3.65 4.9 1. 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 Subjects and Age-group N CL (L/h/kg) Vd ss (L/kg) t ½ (h) Geometric Mean Mean Pediatric Surgery Patients 3 to 12 years N = 21 0.439 1.65 2.9 Pediatric Surgery Patients 5 to 24 months N = 22 0.581 2.3 2.9 Pediatric Surgery Patients 1 month to 4 months N = 19 0.401 3.5 6.7 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.

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 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 ½ 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 t ½ 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) ].

<table width="98%" cellspacing="0" cellpadding="0"><colgroup><col width="15.1%"/><col width="10.06%"/><col width="25.96%"/><col width="30.98%"/><col width="17.9%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="center" valign="bottom"><content styleCode="bold">Age-group</content> <content styleCode="bold">(years)</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">n</content></td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Peak Plasma</content> <content styleCode="bold">Concentration</content> <content styleCode="bold">(ng/mL)</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Mean Elimination </content> <content styleCode="bold">Half-life (h)</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Plasma Clearance</content> <content styleCode="bold">(L/h/kg)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle">19-40</td><td styleCode="Rrule" align="center" valign="middle">11</td><td styleCode="Rrule" align="center" valign="middle">102</td><td styleCode="Rrule" align="center" valign="middle">3.5</td><td styleCode="Rrule" align="center" valign="middle">0.381</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle">61-74</td><td styleCode="Rrule" align="center" valign="middle">12</td><td styleCode="Rrule" align="center" valign="middle">106</td><td styleCode="Rrule" align="center" valign="middle">4.7</td><td styleCode="Rrule" align="center" valign="middle">0.319</td></tr><tr><td styleCode="Lrule Rrule" align="center" valign="middle">&#x2265; 75</td><td styleCode="Rrule" align="center" valign="middle">11</td><td styleCode="Rrule" align="center" valign="middle">170</td><td styleCode="Rrule" align="center" valign="middle">5.5</td><td styleCode="Rrule" align="center" valign="middle">0.262</td></tr></tbody></table>

Rrule" align="center" valign="middle">&#x2265; 75</td><td styleCode="Rrule" align="center" valign="middle">11</td><td styleCode="Rrule" align="center" valign="middle">170</td><td styleCode="Rrule" align="center" valign="middle">5.5</td><td styleCode="Rrule" align="center" valign="middle">0.262</td></tr></tbody></table> <table width="98%" cellspacing="0" cellpadding="0"><colgroup><col width="43.92%"/><col width="13.52%"/><col width="16.06%"/><col width="13.52%"/><col width="12.98%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" rowspan="2" valign="bottom"><content styleCode="bold">Subjects and Age-group </content></td><td styleCode="Rrule" rowspan="2" align="center" valign="bottom"><content styleCode="bold">N </content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">CL</content> <content styleCode="bold">(L/h/kg) </content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Vd_ss</content> <content styleCode="bold">(L/kg) </content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">t</content><content styleCode="bold">_&#xBD;</content> <content styleCode="bold"> (h) </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold">Geometric Mean </content></td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Mean </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom">Pediatric Cancer Patients 4 to 18 years</td><td styleCode="Rrule" align="center" valign="top">N = 21</td><td styleCode="Rrule" align="center" valign="top">0.599</td><td styleCode="Rrule" align="center" valign="top">1.9</td><td styleCode="Rrule" align="center" valign="top">2.8</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Population PK Patients<content styleCode="italics">¹</content> 1 month to 48 months</td><td styleCode="Rrule" align="center" valign="top">N = 115</td><td styleCode="Rrule" align="center" valign="top">0.582</td><td styleCode="Rrule" align="center" valign="top">3.65</td><td styleCode="Rrule" align="center" valign="top">4.9</td></tr></tbody></table>

e="italics">¹</content> 1 month to 48 months</td><td styleCode="Rrule" align="center" valign="top">N = 115</td><td styleCode="Rrule" align="center" valign="top">0.582</td><td styleCode="Rrule" align="center" valign="top">3.65</td><td styleCode="Rrule" align="center" valign="top">4.9</td></tr></tbody></table> <table width="97%" cellspacing="0" cellpadding="0"><colgroup><col width="44.38%"/><col width="13.64%"/><col width="16.2%"/><col width="13.66%"/><col width="12.14%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" rowspan="2" valign="bottom"><content styleCode="bold">Subjects and Age-group </content></td><td styleCode="Rrule" rowspan="2" align="center" valign="bottom"><content styleCode="bold">N </content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">CL</content> <content styleCode="bold">(L/h/kg) </content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Vd_ss</content> <content styleCode="bold">(L/kg) </content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">t_&#xBD;</content> <content styleCode="bold">(h) </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">Geometric Mean </content></td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Mean </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom">Pediatric Surgery Patients 3 to 12 years</td><td styleCode="Rrule" align="center" valign="top">N = 21</td><td styleCode="Rrule" align="center" valign="top">0.439</td><td styleCode="Rrule" align="center" valign="top">1.65</td><td styleCode="Rrule" align="center" valign="top">2.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom">Pediatric Surgery Patients 5 to 24 months</td><td styleCode="Rrule" align="center" valign="top">N = 22</td><td styleCode="Rrule" align="center" valign="top">0.581</td><td styleCode="Rrule" align="center" valign="top">2.3</td><td styleCode="Rrule" align="center" valign="top">2.9</td></tr><tr><td styleCode="Lrule Rrule" valign="bottom">Pediatric Surgery Patients 1 month to 4 months</td><td styleCode="Rrule" align="center" valign="top">N = 19</td><td styleCode="Rrule" align="center" valign="top">0.401</td><td styleCode="Rrule" align="center" valign="top">3.5</td><td styleCode="Rrule" align="center" valign="top">6.7</td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

14 CLINICAL STUDIES The clinical efficacy of ondansetron hydrochloride, the active ingredient of Ondansetron Injection, was assessed in clinical trials as described below. 14.1 Chemotherapy-Induced Nausea and Vomiting 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 Therapy 1 in Adults Ondansetron Injection (0.15 mg/kg x 3) Placebo P -v alue 2 Number of patients 14 14 Treatment response 0 Emetic episodes 1-2 Emetic episodes 3-5 Emetic episodes More than 5 emetic episodes/rescued 2 (14%) 8 (57%) 2 (14%) 2 (14%) 0 (0%) 0 (0%) 1 (7%) 13 (93%) 0.001 Median number of emetic episodes 1.5 Undefined 3 Median time to first emetic episode (h) 11.6 2.8 0.001 Median nausea scores (0-100) 4 3 59 0.034 Global satisfaction with control of nausea and vomiting (0-100) 5 96 10.5 0.009 1. Chemotherapy was high dose (100 and 120 mg/m 2 ; Ondansetron Injection n = 6, placebo n = 5) or moderate dose (50 and 80 mg/m 2 ; 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. 2. Efficacy based on "all-patients-treated" analysis. 3. Median undefined since at least 50% of the patients were rescued or had more than five emetic episodes. 4. Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be. 5. 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/m 2 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.

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/m 2 ) Single-day Therapy 1 in Adults Ondansetron Injection 0.15 mg/kg x 3 Metoclopramide 2 mg/kg x 6 P- value Number of patients in efficacy population 136 138 Treatment response 0 Emetic episodes 1-2 Emetic episodes 3-5 Emetic episodes More than 5 emetic episodes/rescued 54 (40%) 34 (25%) 19 (14%) 29 (21%) 41 (30%) 30 (22%) 18 (13%) 49 (36%) Comparison of treatments with respect to 0 Emetic episodes More than 5 emetic episodes/rescued 54/136 29/136 41/138 49/138 0.083 0.009 Median number of emetic episodes 1 2 0.005 Median time to first emetic episode (h) 20.5 4.3 < 0.001 Global satisfaction with control of nausea and vomiting (0-100) 2 85 63 0.001 Acute dystonic reactions 0 8 0.005 Akathisia 0 10 0.002 1. 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. 2. 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/m 2 ) 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 Therapy 1 in Adults Ondansetron Injection (0.15 mg/kg x 3) Placebo P- value 2 Number of patients 10 10 Treatment response 0 Emetic episodes 1-2 Emetic episodes 3-5 Emetic episodes More than 5 emetic episodes/rescued 7 (70%) 0 (0%) 2 (20%) 1 (10%) 0 (0%) 2 (20%) 4 (40%) 4 (40%) 0.001 0.131 Median number of emetic episodes 0 4 0.008 Median time to first emetic episode (h) Undefined 3 8.79 Median nausea scores (0-100) 4 0 60 0.001 Global satisfaction with control of nausea and vomiting (0-100) 5 100 52 0.008 1. 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. 2. Efficacy based on "all-patients-treated" analysis. 3. Median undefined since at least 50% of patients did not have any emetic episodes. 4. Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be. 5. 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/m 2 ) 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.

n-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. 14.2 Prevention of Postoperative Nausea and/or Vomiting 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 Ondansetron 4 mg Intravenous Placebo P- value Study 1 Emetic episodes: Number of patients Treatment response over 24-h postoperative period 0 Emetic episodes 1 Emetic episode More than 1 emetic episode/rescued 136 103 (76%) 13 (10%) 20 (15%) 139 64 (46%) 17 (12%) 58 (42%) < 0.001 Nausea assessments: Number of patients No nausea over 24-h postoperative period 134 56 (42%) 136 39 (29%) Study 2 Emetic episodes: Number of patients Treatment response over 24-h postoperative period 0 Emetic episodes 1 Emetic episode More than 1 emetic episode/rescued 136 85 (63%) 16 (12%) 35 (26%) 143 63 (44%) 29 (20%) 51 (36%) 0.002 Nausea assessments: Number of patients No nausea over 24-h postoperative period 125 48 (38%) 133 42 (32%) The populations in Table 10 consisted mainly of females undergoing laparoscopic procedures. In a placebo-controlled trial conducted in 468 males undergoing outpatient procedures, a single 4-mg intravenous ondansetron dose prevented postoperative vomiting over a 24-hour period in 79% of males receiving drug compared with 63% of males receiving placebo ( P < 0.001). Two other placebo-controlled trials were conducted in 2,792 patients undergoing major abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg intravenous ondansetron dose for prevention of postoperative nausea and vomiting over a 24-hour period.

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 1049 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 NNausea and/or Vomiting in Pediatric Patients Aged 2 to 12 Years Treatment Response Over 24 Hours Ondansetron n (%) Placebo n (%) P- value Study 1 Number of patients 0 Emetic episodes Failure 1 205 140 (68%) 65 (32%) 210 82 (39%) 128 (61%) ≤ 0.001 Study 2 Number of patients 0 Emetic episodes Failure 1 112 68 (61%) 44 (39%) 110 38 (35%) 72 (65%) ≤ 0.001 Study 3 Number of patients 0 Emetic episodes Failure 1 206 123 (60%) 83 (40%) 206 96 (47%) 110 (53%) ≤ 0.01 Nausea assessments 2 Number of patients None 185 119 (64%) 191 99 (52%) ≤ 0.01 1. Failure was one or more emetic episodes, rescued, or withdrawn. 2. 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. 14.3 Prevention of Further Postoperative Nausea and/or Vomiting 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.

d/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 Ondansetron 4 mg Intravenous Placebo P- value Study 1 Emetic episodes: Number of patients Treatment response 24 h after study drug 0 Emetic episodes 1 Emetic episode More than 1 emetic episode/rescued Median time to first emetic episode (min) 1 104 49 (47%) 12 (12%) 43 (41%) 55.0 117 19 (16%) 9 (8%) 89 (76%) 43.0 < 0.001 Nausea assessments: Number of patients Mean nausea score over 24-h postoperative period 2 98 1.7 102 3.1 Study 2 Emetic episodes: Number of patients Treatment response 24 h after study drug 0 Emetic episodes 1 Emetic episode More than 1 emetic episode/rescued Median time to first emetic episode (min) 1 112 49 (44%) 14 (13%) 49 (44%) 60.5 108 28 (26%) 3 (3%) 77 (71%) 34.0 0.006 Nausea assessments: Number of patients Mean nausea score over 24-h postoperative period 2 105 1.9 85 2.9 1. After administration of study drug. 2. 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 Treatment Response Over 24 Hours Ondansetron n (%) Placebo n (%) P- value Number of patients 0 Emetic episodes Failure 1 180 96 (53%) 84 (47%) 171 29 (17%) 142 (83%) ≤ 0.001 1. Failure was one or more emetic episodes, rescued, or withdrawn.

<table width="100%" cellspacing="0" cellpadding="0"><colgroup><col width="43.2%"/><col width="23.5%"/><col width="19.64%"/><col width="13.66%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="center" valign="middle"/><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Ondansetron Injection</content> <content styleCode="bold">(0.15 mg/kg x 3)</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Placebo</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold"><content styleCode="italics">P</content>-v</content><content styleCode="bold">alue<content styleCode="italics">²</content></content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Number of patients</td><td styleCode="Rrule" align="center" valign="middle">14</td><td styleCode="Rrule" align="center" valign="middle">14</td><td styleCode="Rrule" align="center" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><paragraph>Treatment response</paragraph><paragraph> 0 Emetic episodes 1-2 Emetic episodes 3-5 Emetic episodes More than 5 emetic episodes/rescued</paragraph></td><td styleCode="Rrule" align="center" valign="bottom"><paragraph/><paragraph>2 (14%)</paragraph><paragraph>8 (57%) 2 (14%) 2 (14%)</paragraph></td><td styleCode="Rrule" align="center" valign="bottom"><paragraph/><paragraph>0 (0%) 0 (0%) 1 (7%) 13 (93%)</paragraph></td><td styleCode="Rrule" align="center" valign="bottom"><paragraph/><paragraph/><paragraph>0.001</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Median number of emetic episodes</td><td styleCode="Rrule" align="center" valign="middle">1.5</td><td styleCode="Rrule" align="center" valign="middle">Undefined<content styleCode="italics">³</content></td><td styleCode="Rrule" align="center" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Median time to first emetic episode (h)</td><td styleCode="Rrule" align="center" valign="middle">11.6</td><td styleCode="Rrule" align="center" valign="middle">2.8</td><td styleCode="Rrule" align="center" valign="middle">0.001</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Median nausea scores (0-100)<content styleCode="italics">⁴</content></td><td styleCode="Rrule" align="center" valign="middle">3</td><td styleCode="Rrule" align="center" valign="middle">59</td><td styleCode="Rrule" align="center" valign="middle">0.034</td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Global satisfaction with control of nausea and vomiting (0-100)<content styleCode="italics">⁵</content></td><td styleCode="Rrule" align="center" valign="bottom">96</td><td styleCode="Rrule" align="center" valign="bottom">10.5</td><td styleCode="Rrule" align="center" valign="bottom">0.009</td></tr></tbody></table>

l satisfaction with control of nausea and vomiting (0-100)<content styleCode="italics">⁵</content></td><td styleCode="Rrule" align="center" valign="bottom">96</td><td styleCode="Rrule" align="center" valign="bottom">10.5</td><td styleCode="Rrule" align="center" valign="bottom">0.009</td></tr></tbody></table> <table width="100%" cellspacing="0" cellpadding="0"><colgroup><col width="44.36%"/><col width="20.26%"/><col width="23.16%"/><col width="12.22%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="center" valign="middle"/><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Ondansetron Injection</content> <content styleCode="bold">0.15 mg/kg x 3</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Metoclopramide</content> <content styleCode="bold">2 mg/kg x 6</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold"><content styleCode="italics">P-</content></content><content styleCode="bold">value</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom">Number of patients in efficacy population</td><td styleCode="Rrule" align="center" valign="middle">136</td><td styleCode="Rrule" align="center" valign="middle">138</td><td styleCode="Rrule" align="center" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><paragraph>Treatment response</paragraph><paragraph> 0 Emetic episodes 1-2 Emetic episodes 3-5 Emetic episodes More than 5 emetic episodes/rescued</paragraph></td><td styleCode="Rrule" align="center" valign="bottom"><paragraph/><paragraph>54 (40%)</paragraph><paragraph>34 (25%) 19 (14%) 29 (21%)</paragraph></td><td styleCode="Rrule" align="center" valign="bottom"><paragraph/><paragraph>41 (30%) 30 (22%) 18 (13%) 49 (36%)</paragraph></td><td styleCode="Rrule" align="center" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Comparison of treatments with respect to 0 Emetic episodes More than 5 emetic episodes/rescued</td><td styleCode="Rrule" align="center" valign="bottom"><paragraph/><paragraph>54/136 29/136</paragraph></td><td styleCode="Rrule" align="center" valign="bottom"> 41/138 49/138</td><td styleCode="Rrule" align="center" valign="bottom"> 0.083 0.009</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Median number of emetic episodes</td><td styleCode="Rrule" align="center" valign="middle">1</td><td styleCode="Rrule" align="center" valign="middle">2</td><td styleCode="Rrule" align="center" valign="middle">0.005</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Median time to first emetic episode (h)</td><td styleCode="Rrule" align="center" valign="middle">20.5</td><td styleCode="Rrule" align="center" valign="middle">4.3</td><td styleCode="Rrule" align="center" valign="middle">&lt; 0.001</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Global satisfaction with control of nausea and vomiting (0-100)<content styleCode="italics">²</content></td><td styleCode="Rrule" align="center" valign="bottom">85</td><td styleCode="Rrule" align="center" valign="bottom">63</td><td styleCode="Rrule" align="center" valign="bottom">0.001</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Acute dystonic reactions</td><td styleCode="Rrule" align="center" valign="middle">0</td><td styleCode="Rrule" align="center" valign="middle">8</td><td styleCode="Rrule" align="center" valign="middle">0.005</td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Akathisia</td><td styleCode="Rrule" align="center" valign="middle">0</td><td styleCode="Rrule" align="center" valign="middle">10</td><td styleCode="Rrule" align=

rule" align="center" valign="middle">8</td><td styleCode="Rrule" align="center" valign="middle">0.005</td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Akathisia</td><td styleCode="Rrule" align="center" valign="middle">0</td><td styleCode="Rrule" align="center" valign="middle">10</td><td styleCode="Rrule" align= "center" valign="middle">0.002</td></tr></tbody></table>

rule" align="center" valign="middle">8</td><td styleCode="Rrule" align="center" valign="middle">0.005</td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Akathisia</td><td styleCode="Rrule" align="center" valign="middle">0</td><td styleCode="Rrule" align="center" valign="middle">10</td><td styleCode="Rrule" align= "center" valign="middle">0.002</td></tr></tbody></table> <table width="100%" cellspacing="0" cellpadding="0"><colgroup><col width="44%"/><col width="24%"/><col width="16%"/><col width="14%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="center" valign="top"/><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Ondansetron Injection</content> <content styleCode="bold">(0.15 mg/kg x 3)</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Placebo</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold"><content styleCode="italics">P-</content></content><content styleCode="bold">value<content styleCode="italics">²</content></content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Number of patients</td><td styleCode="Rrule" align="center" valign="middle">10</td><td styleCode="Rrule" align="center" valign="middle">10</td><td styleCode="Rrule" align="center" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Treatment response 0 Emetic episodes 1-2 Emetic episodes 3-5 Emetic episodes More than 5 emetic episodes/rescued</td><td styleCode="Rrule" align="center" valign="bottom">7 (70%) 0 (0%) 2 (20%) 1 (10%)</td><td styleCode="Rrule" align="center" valign="bottom"> 0 (0%) 2 (20%) 4 (40%) 4 (40%)</td><td styleCode="Rrule" align="center" valign="bottom"> 0.001 0.131</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Median number of emetic episodes</td><td styleCode="Rrule" align="center" valign="middle">0</td><td styleCode="Rrule" align="center" valign="middle">4</td><td styleCode="Rrule" align="center" valign="middle">0.008</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Median time to first emetic episode (h)</td><td styleCode="Rrule" align="center" valign="middle">Undefined<content styleCode="italics">³</content></td><td styleCode="Rrule" align="center" valign="middle">8.79</td><td styleCode="Rrule" align="center" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Median nausea scores (0-100)<content styleCode="italics">⁴</content></td><td styleCode="Rrule" align="center" valign="middle">0</td><td styleCode="Rrule" align="center" valign="middle">60</td><td styleCode="Rrule" align="center" valign="middle">0.001</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Global satisfaction with control of nausea and vomiting (0-100)<content styleCode="italics">⁵</content></td><td styleCode="Rrule" align="center" valign="bottom">100</td><td styleCode="Rrule" align="center" valign="bottom">52</td><td styleCode="Rrule" align="center" valign="bottom">0.008</td></tr></tbody></table>

al satisfaction with control of nausea and vomiting (0-100)<content styleCode="italics">⁵</content></td><td styleCode="Rrule" align="center" valign="bottom">100</td><td styleCode="Rrule" align="center" valign="bottom">52</td><td styleCode="Rrule" align="center" valign="bottom">0.008</td></tr></tbody></table> <table width="837.9px" cellspacing="0" cellpadding="0"><colgroup><col width="45.7142857142857%"/><col width="23.1746031746032%"/><col width="17.6190476190476%"/><col width="13.4920634920635%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" valign="top"/><td styleCode="Rrule" align="center" valign="top"> <content styleCode="bold">Ondansetron </content><content styleCode="bold">4 mg</content> <content styleCode="bold">Intravenous</content></td><td styleCode="Rrule" align="center" valign="bottom"> <content styleCode="bold">Placebo</content></td><td styleCode="Rrule" align="center" valign="bottom"> <content styleCode="bold"><content styleCode="italics">P-</content></content><content styleCode="bold">value</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Study 1</content></td><td styleCode="Rrule" valign="top"/><td styleCode="Rrule" valign="top"/><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Emetic episodes: Number of patients Treatment response over 24-h postoperative period 0 Emetic episodes 1 Emetic episode More than 1 emetic episode/rescued</td><td styleCode="Rrule" align="center" valign="bottom"> 136 103 (76%) 13 (10%) 20 (15%)</td><td styleCode="Rrule" align="center" valign="bottom"> 139 64 (46%) 17 (12%) 58 (42%)</td><td styleCode="Rrule" align="center" valign="bottom"> &lt; 0.001</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Nausea assessments: Number of patients No nausea over 24-h postoperative period</td><td styleCode="Rrule" align="center" valign="bottom"> 134 56 (42%)</td><td styleCode="Rrule" align="center" valign="bottom"> 136 39 (29%)</td><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Study 2</content></td><td styleCode="Rrule" valign="top"/><td styleCode="Rrule" valign="top"/><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Emetic episodes: Number of patients Treatment response over 24-h postoperative period 0 Emetic episodes 1 Emetic episode More than 1 emetic episode/rescued</td><td styleCode="Rrule" align="center" valign="bottom"> 136 85 (63%) 16 (12%) 35 (26%)</td><td styleCode="Rrule" align="center" valign="bottom"> 143 63 (44%) 29 (20%) 51 (36%)</td><td styleCode="Rrule" align="center" valign="bottom"> 0.002</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Nausea assessments: Number of patients No nausea over 24-h postoperative period</td><td styleCode="Rrule" align="center" valign="bottom"><paragraph>125</paragraph><paragraph>48 (38%)</paragraph></td><td styleCode="Rrule" align="center" valign="bottom"> 133 42 (32%)</td><td styleCode="Rrule" valign="top"/></tr></tbody></table>

assessments: Number of patients No nausea over 24-h postoperative period</td><td styleCode="Rrule" align="center" valign="bottom"><paragraph>125</paragraph><paragraph>48 (38%)</paragraph></td><td styleCode="Rrule" align="center" valign="bottom"> 133 42 (32%)</td><td styleCode="Rrule" valign="top"/></tr></tbody></table> <table width="97%" cellspacing="0" cellpadding="0"><colgroup><col width="43%"/><col width="22%"/><col width="22%"/><col width="11%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="center" valign="bottom"> Treatment Response Over 24 Hours</td><td styleCode="Rrule" align="center" valign="bottom"> <content styleCode="bold"> Ondansetron n </content><content styleCode="bold">(%)</content></td><td styleCode="Rrule" align="center" valign="bottom"> <content styleCode="bold">Placebo </content><content styleCode="bold">n (%)</content></td><td styleCode="Rrule" align="center" valign="bottom"> <content styleCode="bold"><content styleCode="italics">P-</content></content><content styleCode="bold">value</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> <content styleCode="bold">Study 1</content></td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Number of patients 0 Emetic episodes Failure<content styleCode="italics">¹</content></td><td styleCode="Rrule" align="center" valign="middle"><paragraph> 205 140 (68%)</paragraph><paragraph>65 (32%)</paragraph></td><td styleCode="Rrule" align="center" valign="middle"> 210 82 (39%) 128 (61%)</td><td styleCode="Rrule" align="center" valign="top"> &#x2264; 0.001</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> <content styleCode="bold">Study 2</content></td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Number of patients 0 Emetic episodes Failure<content styleCode="italics">¹</content></td><td styleCode="Rrule" align="center" valign="middle"> 112 68 (61%) 44 (39%)</td><td styleCode="Rrule" align="center" valign="middle"> 110 38 (35%) 72 (65%)</td><td styleCode="Rrule" align="center" valign="top"> &#x2264; 0.001</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Study 3</content></td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Number of patients 0 Emetic episodes Failure<content styleCode="italics">¹</content></td><td styleCode="Rrule" align="center" valign="middle"> 206 123 (60%) 83 (40%)</td><td styleCode="Rrule" align="center" valign="middle"> 206 96 (47%) 110 (53%)</td><td styleCode="Rrule" align="center" valign="middle"> &#x2264; 0.01</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Nausea assessments<content styleCode="italics">²</content> Number of patients None</td><td styleCode="Rrule" align="center" valign="top"> 185 119 (64%)</td><td styleCode="Rrule" align="center" valign="top"> 191 99 (52%)</td><td styleCode="Rrule" align="center" valign="top"> &#x2264; 0.01</td></tr></tbody></table>

a assessments<content styleCode="italics">²</content> Number of patients None</td><td styleCode="Rrule" align="center" valign="top"> 185 119 (64%)</td><td styleCode="Rrule" align="center" valign="top"> 191 99 (52%)</td><td styleCode="Rrule" align="center" valign="top"> &#x2264; 0.01</td></tr></tbody></table> <table width="98%" cellspacing="0" cellpadding="0"><colgroup><col width="55.76%"/><col width="18.86%"/><col width="14.58%"/><col width="10.8%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" align="center" valign="middle"/><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Ondansetron 4 mg Intravenous</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold">Placebo</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold"><content styleCode="italics">P-</content></content><content styleCode="bold">value</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Study 1</content></td><td styleCode="Rrule" align="center" valign="middle"/><td styleCode="Rrule" align="center" valign="middle"/><td styleCode="Rrule" align="center" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom">Emetic episodes: Number of patients Treatment response 24 h after study drug 0 Emetic episodes 1 Emetic episode More than 1 emetic episode/rescued Median time to first emetic episode (min)<content styleCode="italics">¹</content></td><td styleCode="Rrule" align="center" valign="bottom">104 49 (47%) 12 (12%) 43 (41%) 55.0</td><td styleCode="Rrule" align="center" valign="bottom"> 117 19 (16%) 9 (8%) 89 (76%) 43.0</td><td styleCode="Rrule" align="center" valign="top"> &lt; 0.001</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Nausea assessments: Number of patients Mean nausea score over 24-h postoperative period<content styleCode="italics">²</content></td><td styleCode="Rrule" align="center" valign="bottom"> 98 1.7</td><td styleCode="Rrule" align="center" valign="bottom"> 102 3.1</td><td styleCode="Rrule" align="center" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Study 2</content></td><td styleCode="Rrule" align="center" valign="middle"/><td styleCode="Rrule" align="center" valign="middle"/><td styleCode="Rrule" align="center" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Emetic episodes: Number of patients Treatment response 24 h after study drug 0 Emetic episodes 1 Emetic episode More than 1 emetic episode/rescued Median time to first emetic episode (min)<content styleCode="italics">¹</content></td><td styleCode="Rrule" align="center" valign="bottom">112 49 (44%) 14 (13%) 49 (44%) 60.5</td><td styleCode="Rrule" align="center" valign="bottom"> 108 28 (26%) 3 (3%) 77 (71%) 34.0</td><td styleCode="Rrule" align="center" valign="top"> 0.006</td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Nausea assessments: Number of patients Mean nausea score over 24-h postoperative period<content styleCode="italics">²</content></td><td styleCode="Rrule" align="center" valign="top"> 105 1.9</td><td styleCode="Rrule" align="center" valign="top"> 85 2.9</td><td styleCode="Rrule" align="center" valign="middle"/></tr></tbody></table>

ber of patients Mean nausea score over 24-h postoperative period<content styleCode="italics">²</content></td><td styleCode="Rrule" align="center" valign="top"> 105 1.9</td><td styleCode="Rrule" align="center" valign="top"> 85 2.9</td><td styleCode="Rrule" align="center" valign="middle"/></tr></tbody></table> <table width="97%" cellspacing="0" cellpadding="0"><colgroup><col width="28.6%"/><col width="22.28%"/><col width="29.76%"/><col width="19.36%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Treatment Response Over 24 Hours</content></td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Ondansetron</content> <content styleCode="bold">n (%)</content></td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">n (%)</content></td><td styleCode="Rrule" align="center" valign="bottom"><content styleCode="bold"><content styleCode="italics">P-</content></content><content styleCode="bold">value</content></td></tr><tr><td styleCode="Lrule Rrule" valign="top">Number of patients 0 Emetic episodes Failure<content styleCode="italics">¹</content></td><td styleCode="Rrule" align="center" valign="top">180 96 (53%) 84 (47%)</td><td styleCode="Rrule" align="center" valign="top">171 29 (17%) 142 (83%)</td><td styleCode="Rrule" align="center" valign="top"> &#x2264; 0.001</td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Inform patients that Ondansetron Injection may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. The patient should report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems [see Warnings and Precautions (5.1) ] . QT Prolongation Patients should be informed that Ondansetron Injection may cause serious cardiac arrhythmias, such as QT prolongation. Patients should be instructed to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode. Patients should be informed that the chances of developing severe cardiac arrhythmias, such as QT prolongation and Torsade de Pointes are higher in the following people: • 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; • 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) ] . Drug Interactions: •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 [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) ] . Masking of Progressive Ileus and Gastric Distension Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that Ondansetron Injection may mask signs and symptoms of bowel obstruction. Instruct patients to immediately report any signs or symptoms consistent with a potential bowel obstruction to their healthcare provider [see Warnings and Precautions (5.5) ]. Manufactured by: Qilu Pharmaceutical (Hainan) Co., Ltd. Haikou, 570314, China Manufactured for: Apotex Corp Weston,Florida USA 33326 34120001211D