ONDANSETRON

The active ingredient in Ondansetron Tablets, USP is ondansetron hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT 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 H N O•HCl•2H O, representing a molecular weight of 365.9. Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal saline. Each 4 mg ondansetron tablet, USP for oral administration contains ondansetron hydrochloride, USP equivalent to 4 mg of ondansetron. Each 8 mg ondansetron tablet, USP for oral administration contains ondansetron hydrochloride, USP equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, titanium dioxide, triacetin, and iron oxide yellow (8 mg tablet only). Product meets USP Drug Release Test 3. ondansetron structure

• Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m 2 . • Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. • Prevention of 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. • 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 where nausea and/or vomiting must be avoided postoperatively, ondansetron tablets, USP are recommended even where the incidence of postoperative nausea and/or vomiting is low.

DOSAGE & ADMINISTRATION Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy The recommended adult oral dosage of ondansetron tablets, USP is 24 mg given as three 8-mg tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥ 50 mg/m . Multiday, single-dose administration of a 24 mg dosage has not been studied. There is no experience with the use of a 24 mg dosage in pediatric patients. The dosage recommendation is the same as for the general population. Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy The recommended adult oral dosage is one 8-mg ondansetron tablet, USP given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8-mg ondansetron tablet, USP should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4-mg ondansetron tablet, USP or one 4-mg given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4-mg ondansetron tablet, USP should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy. The dosage is the same as for the general population. Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen The recommended oral dosage is one 8-mg ondansetron tablet, USP given 3 times a day. For total body irradiation , one 8-mg ondansetron tablet, USP should be administered 1 to 2 hours before each fraction of radiotherapy administered each day. For single high-dose fraction radiotherapy to the abdomen , one 8-mg ondansetron tablet, USP should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. , one 8-mg ondansetron tablet, USP should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given. There is no experience with the use of ondansetron tablet, USP in the prevention of radiation-induced nausea and vomiting in pediatric patients. The dosage recommendation is the same as for the general population. Postoperative Nausea and Vomiting The recommended dosage is 16 mg given as two 8-mg ondansetron tablets, USP 1 hour before induction of anesthesia. There is no experience with the use of ondansetron tablets, USP in the prevention of postoperative nausea and vomiting in pediatric patients. The dosage is the same as for the general population. Dosage Adjustment for Patients With Impaired Renal Function The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron. Dosage Adjustment for Patients With Impaired Hepatic Function 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. In such patients, a total daily dose of 8 mg should not be exceeded.

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. Ondansetron tablets, USP are contraindicated for patients known to have hypersensitivity to the drug.

The following have been reported as adverse events in clinical trials of patients treated with ondansetron, the active ingredient of ondansetron tablets, USP. A causal relationship to therapy with ondansetron tablets, USP have been unclear in many cases. Chemotherapy-Induced Nausea and Vomiting The adverse events in Table 5 have been reported in ≥ 5% of adult patients receiving a single 24-mg ondansetron tablet, USP in 2 trials. These patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens (cisplatin dose ≥ 50 mg/m ). Event Ondansetron 24 mg q.d.n = 300 Ondansetron 8 mg b.i.d.n = 124 Ondansetron32 mg q.d.n = 117 Headache 33 (11%) 16 (13%) 17 (15%) Diarrhea 13 (4%) 9 (7%) 3 (3%) The adverse events in Table 6 have been reported in ≥ 5% of adults receiving either 8 mg of ondansetron tablets, USP 2 or 3 times a day for 3 days or placebo in 4 trials. These patients were receiving concurrent moderately emetogenic chemotherapy, primarily cyclophosphamide-based regimens. Event Ondansetron 8 mg b.i.d.n = 242 Ondansetron 8 mg t.i.d.n = 415 Placebon = 262 Headache 58 (24%) 113 (27%) 34 (13%) Malaise/fatigue 32 (13%) 37 (9%) 6 (2%) Constipation 22 (9%) 26 (6%) 1 (<1%) Diarrhea 15 (6%) 16 (4%) 10 (4%) Dizziness 13 (5%) 18 (4%) 12 (5%) There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron. In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in approximately 1% to 2% of patients receiving ondansetron tablets, USP. 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 cannot be clearly determined. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Rash has occurred in approximately 1% of patients receiving ondansetron. Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures have been reported. Except for bronchospasm and anaphylaxis, the relationship to ondansetron tablets, USP were unclear. Radiation-Induced Nausea and Vomiting The adverse events reported in patients receiving ondansetron tablets, USP and concurrent radiotherapy were similar to those reported in patients receiving ondansetron tablets, USP and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea. Postoperative Nausea and Vomiting The adverse events in Table 7 have been reported in ≥ 5% of patients receiving ondansetron tablets, USP at a dosage of 16 mg orally in clinical trials. With the exception of headache, rates of these events were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications. Adverse Event Ondansetron 16 mg(n = 550) Placebo(n = 531) Wound problem 152 (28%) 162 (31%) Drowsiness/sedation 112 (20%) 122 (23%) 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%) Bradycardia 32 (6%) 30 (6%) Shiver(s) 28 (5%) 30 (6%) Urinary retention 28 (5%) 18 (3%) Hypotension 27 (5%) 32 (6%) Pruritus 27 (5%) 20 (4%) Observed During Clinical Practice In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of ondansetron tablets, USP. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ondansetron tablets, USP. Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid 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. Liver enzyme abnormalities Hiccups Oculogyric crisis, appearing alone, as well as with other dystonic reactions Urticaria 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.

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (see ). 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. On the basis of available data, no dosage adjustment is recommended for patients on these drugs. Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, concomitant use of apomorphine with ondansetron is contraindicated (see ). In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), 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. Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol. Tumor response to chemotherapy in the P-388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover studying 76 patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate.