Ondansetron

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 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 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. 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 a Few patients above 80 kg have been studied. b 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 )] . c For pediatric patients (1 month to 12 years) prevention of nausea and vomiting was only studied in patients who had not received prophylactic ondansetron. Population Recommended Single Dose Administration Instructions Timing of Administration Adults and pediatric patients older than 12 years of age 4 mg a 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 b,c 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). 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 )

Not available.

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/or 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 across a range of dosages. A causal relationship to therapy with Ondansetron was unclear in many cases. Chemotherapy-Induced Nausea and Vomiting Table 2. Adverse Reactions Reported in > 5% of Adult Patients Who Received Ondansetron at a Dosage of Three 0.15-mg/kg Doses 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. 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 a Adverse reactions: Rates of these reactions were not significantly different in the ondansetron and placebo groups. b Patients were receiving multiple concomitant perioperative and postoperative medications. Adverse Reaction a,b Ondansetron Injection 4 mg Intravenous (n = 547) Placebo (n = 547) Headache 92 (17%) 77 (14%) Drowsiness/Sedation 44 (8%) 37 (7%) Injection-site reaction 21 (4%) 18 (3%) Fever 10 (2%) 6 (1%) Cold sensation 9 (2%) 8 (1%) Pruritus 9 (2%) 3 (< 1%) Paresthesia 9 (2%) 2 (< 1%) 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 (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 post-approval use of ondansetron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ondansetron. 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 predominantly with intravenous administration [see Warnings and Precautions ( 5.4 )]. General Flushing: Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylactic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported. A positive lymphocyte transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron. Hepatobiliary Liver enzyme abnormalities have been reported. Liver failure and death have been reported in patients with cancer receiving concurrent medications, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. Local Reactions Pain, redness, and burning at site of injection. Lower Respiratory Hiccups. Neurological Oculogyric crisis, appearing alone, as well as with other dystonic reactions. Transient dizziness during or shortly after intravenous infusion. Skin Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Eye Disorders Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours. Transient blurred vision, in some cases associated with abnormalities of accommodation, has also been reported.