Ondansetron Hydrochloride

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 are recommended even where the incidence of postoperative nausea and/or vomiting is low.

The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorhpine was administered with ondansetron. Ondansetron tablets are contraindicated for patients known to have hypersensitivity to the drug.

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. ECG changes including QT interval prolongation has been seen in patients receiving ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron hydrochloride 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.

General Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. 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. Drug Interactions Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY, Pharmacokinetics ). 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. Apomorphine 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 CONTRAINDICATIONS ). Phenytoin, Carbamazepine, and Rifampicin 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. 1, 3 Tramadol 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. 4, 5 Chemotherapy 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 study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. Use in Surgical Patients: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam. 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/day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg/day did not affect fertility or general reproductive performance of male and female rats. Pregnancy Teratogenic Effects Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman. Pediatric Use Little information is available about dosage in pediatric patients 4 years of age or younger (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION sections for use in pediatric patients 4 to 18 years of age) 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 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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 (see CLINICAL PHARMACOLOGY ).

The following have been reported as adverse events in clinical trials of patients treated with ondansetron, the active ingredient of ondansetron tablets. A causal relationship to therapy with ondansetron tablets 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 in 2 trials. These patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens (cisplatin dose ≥ 50 mg/m 2 ). Table 5. Principal Adverse Events in US Trials: Single Day Therapy With 24-mg Ondansetron hydrochloride tablets (Highly Emetogenic Chemotherapy) Event Ondansetron 24 mg q.d. n = 300 Ondansetron 8 mg b.i.d. n = 124 Ondansetron 32 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 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. Table 6. Principal Adverse Events in US Trials: 3 Days of Therapy With 8 mg Ondansetron tablets (Moderately Emetogenic Chemotherapy) Event Ondansetron 8 mg b.i.d. n = 242 Ondansetron 8 mg t.i.d. n = 415 Placebo n = 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%) Central Nervous System There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron. Hepatic 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. 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. Integumentary Rash has occurred in approximately 1% of patients receiving ondansetron. Other 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 was unclear. Radiation-Induced Nausea and Vomiting The adverse events reported in patients receiving ondansetron tablets and concurrent radiotherapy were similar to those reported in patients receiving ondansetron tablets 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 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. Table 7. Frequency of Adverse Events From Controlled Studies With Ondansetron tablets (Postoperative Nausea and Vomiting) 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. 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. Cardiovascular Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prlongation have been reported. General 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. Hepatobiliary Liver enzyme abnormalities Lower Respiratory Hiccups Neurology Oculogyric crisis, appearing alone, as well as with other dystonic reactions Skin Urticaria Special Senses 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.

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY, Pharmacokinetics ). 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. Apomorphine 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 CONTRAINDICATIONS ). Phenytoin, Carbamazepine, and Rifampicin 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. 1, 3 Tramadol 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. 4, 5 Chemotherapy 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 study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. Use in Surgical Patients: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.

Teratogenic Effects Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman.

Little information is available about dosage in pediatric patients 4 years of age or younger (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION sections for use in pediatric patients 4 to 18 years of age)

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 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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 (see CLINICAL PHARMACOLOGY ).