ONDANSETRON

1 INDICATIONS AND USAGE Ondansetron oral solution 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 oral solution is also indicated for the prevention of postoperative nausea and/or vomiting. Ondansetron oral solution is a 5-HT3 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 Recommended Dosage The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively. Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting 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 )] .

4 CONTRAINDICATIONS Ondansetron oral solution 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 oral solution 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 ondansetron oral solution 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 oral solution and initiate supportive treatment. If concomitant use of ondansetron oral solution with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. ( 5.3 ) 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 ) 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 oral solution; 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 oral solution. Avoid ondansetron oral solution 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. 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.

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 oral solution and initiate supportive treatment [see Warnings and Precautions ( 5.3 )] . 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.

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 )] 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 PAI Pharma at 1-800-845-8210 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 oral solution. A causal relationship to therapy with ondansetron was unclear in many cases. Prevention of Chemotherapy- I nduced 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 Reported in greater than or equal to 5% of patients treated with ondansetron and at a rate that exceeded placebo. 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%) Less Common Adverse Reactions C entral Nervous System: Extrapyramidal reactions (less than 1% of patients). H epatic: Aspartate transaminase (AST) and/or alanine transaminase (ALT) values exceeded twice the upper limit of normal in approximately 1% to 2% of 723 patients receiving ondansetron and cyclophosphamide-based chemotherapy in US clinical trials. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes is unclear. Liver failure and death has been reported in cancer patients receiving concurrent medications, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Integumentary: Rash (approximately 1% of patients). Other (less than 2%): Anaphylaxis, bronchospasm, tachycardia, angina, hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures. Except for bronchospasm and anaphylaxis, the relationship to ondansetron is unclear. Prevention of Radiation- I nduced 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 Reported in greater than or equal to 5% of patients treated with ondansetron and at a rate that exceeded placebo. 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%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ondansetron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron, transient ECG changes, including QT interval prolongation have been reported. Myocardial ischemia was reported predominately with intravenous administration [see Warnings and Precautions ( 5.4 )] . General Flushing : Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylactic reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron. Hepatobiliary Liver enzyme abnormalities. Lower Respiratory Hiccups. Neurology Oculogyric crisis, appearing alone, as well as with other dystonic reactions. Skin Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Eye Disorders Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.

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). 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.