PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL-PRINCIPAL DISPLAY PANEL 8 mg (6 Tablet Bottle). NDC10544-575-06Ondansetron USP 8mgRx Only6 Tablets. Label 8mg 6ct.

PEDIATRIC USE SECTION.


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

PHARMACOKINETICS SECTION.


Pharmacokinetics. Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of single mg tablet, is approximately 56%. Ondansetron systemic exposure does not increase proportionately to dose. AUC from 16 mg tablet was 24% greater than predicted from an mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. Bioavailability is also slightly enhanced by the presence of food but unaffected by antacids. Ondansetron is extensively metabolized in humans, with approximately 5% of 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. In vitro metabolism studies have shown that ondansetron is 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. Ondansetron elimination may be affected by cytochrome P-450 inducers. In pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, max, and 1/2 of ondansetron was observed. This resulted in significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended (see PRECAUTIONS: Drug Interactions). In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. Gender differences were shown in the disposition of ondansetron given as single dose. The extent and rate of ondansetrons absorption is greater in women than men. Slower clearance in women, smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables and taken from studies. Table 1. Pharmacokinetics in Normal Volunteers: Single mg Ondansetron Tablet Dose Age-group(years)MeanWeight(kg)nPeak PlasmaConcentration(ng/mL)Time of PeakPlasmaConcentration (h)MeanEliminationHalf-life(h)SystemicPlasmaClearanceL/h/kgAbsoluteBioavailability18-40 F 69 62.7 5 26.2 42.7 1.7 3.1 3.5 0.403 0.354 0.483 0.663 61-74 F 77.5 60.2 6 24.1 52.4 2.1 1.9 4.1 4.9 0.384 0.255 0.585 0.643 >=75 F 78 67.6 6 37 46.1 2.2 2.1 4.5 6.2 0.277 0.249 0.619 0.747 Table 2. Pharmacokinetics in Normal Volunteers: Single 24 mg Ondansetron Tablet Dose Age-group(years)MeanWeight (kg)nPeak PlasmaConcentration(ng/mL)Time of PeakPlasmaConcentration(h)Mean EliminationHalf-life (h)18-43 F 84.1 71.8 8 125.8 194.4 1.9 1.6 4.7 5.8 reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly. In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. 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 resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, total daily dose of mg should not be exceeded. 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 oral mean plasma clearance was reduced by about 50% 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. No reduction in dose or dosing frequency in these patients is warranted. 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. Four and mg doses of either ondansetron oral solution or ondansetron orally disintegrating tablets are bioequivalent to corresponding doses of ondansetron tablets and may be used interchangeably. One 24 mg ondansetron tablet is bioequivalent to and interchangeable with three mg ondansetron tablets. Clinical Trials Chemotherapy-Induced Nausea and Vomiting Highly Emetogenic Chemotherapy In randomized, double-blind, monotherapy trials, single 24 mg ondansetron tablet was superior to relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin >=50 mg/m 2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving cisplatin dose >=50 mg/m in the historical placebo comparator experienced vomiting in the absence of antiemetic therapy. The first trial compared oral doses of ondansetron 24 mg once day, mg twice day, and 32 mg once day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin >=50 mg/m 2. total of 66% of patients in the ondansetron 24 mg once-a-day group, 55% in the ondansetron mg twice-a-day group, and 55% in the ondansetron 32 mg once-a-day group completed the 24-hour study period with emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the treatment groups was shown to be statistically significantly superior to historical placebo control. In the same trial, 56% of patients receiving oral ondansetron 24 mg once day experienced no nausea during the 24-hour study period, compared with 36% of patients in the oral ondansetron mg twice-a-day group P 0.001) and 50% in the oral ondansetron 32 mg once-a-day group. In second trial, efficacy of the oral ondansetron 24 mg once-a-day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin >=50 mg/m 2, was confirmed. Moderately Emetogenic Chemotherapy In double-blind U.S. study in 67 patients, ondansetron tablets mg administered twice day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 3: Table 3. Emetic Episodes: Treatment Response The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent dose hours after the first dose. An mg ondansetron tablet was administered twice day for days after completion of chemotherapy. bMedian undefined since at least 50% of the patients were withdrawn or had more than emetic episodes. Median undefined since at least 50% of patients did not have any emetic episodes. Ondansetron8 mg b.i.d.Ondansetron Tablets PlaceboP Value Number of patients 33 34 Treatment response Emetic episodes to Emetic episodes More than emetic episodes/withdrawn 20 (61%) (18%) (21%) (6%) (24%) 24 (71%) <0.001 <0.001 Median number of emetic episodes Undefined Median time to first emetic episode (h) Undefined 6.5 In double-blind U.S. study in 336 patients, ondansetron tablets mg administered twice day were as effective as ondansetron tablets mg administered times day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 4:Table 4. Emetic Episodes: Treatment Response The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent dose hours after the first dose. An mg ondansetron tablet was administered twice day for days after completion of chemotherapy. The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses and hours after the first dose. An mg ondansetron tablet was administered times day for days after completion of chemotherapy. Median undefined since at least 50% of patients did not have any emetic episodes. Visual analog scale assessment: = no nausea, 100 nausea as bad as it can be. Ondansetron8 mg b.i.d. Ondansetron Tablets 8 mg t.i.d. Ondansetron Tablets Number of patients 165 171 Treatment response Emetic episodes to Emetic episodes More than emetic episodes/withdrawn 101 (61%) 16 (10%) 48 (29%) 99 (58%) 17 (10%) 55 (32%) Median number of emetic episodes 0 Median time to first emetic episode (h) Undefined Undefined Median nausea scores (0 to 100) 6 Re-treatment In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ondansetron tablets mg times daily during subsequent chemotherapy for total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only to emetic episodes occurred in 43 (11%) of the re-treatment courses. Pediatric Studies Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients to 18 years old with cancer who were given variety of cisplatin or noncisplatin regimens. In these foreign trials, the initial dose of ondansetron hydrochloride injection ranged from 0.04 to 0.87 mg/kg for total dose of 2.16 to 12 mg. This was followed by the administration of ondansetron tablets ranging from to 24 mg daily for days. In these studies, 58% of the 170 evaluable patients had complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received ondansetron tablets mg times day to be similar to those in patients 12 to 18 years of age who received ondansetron tablets mg times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, ondansetron tablets were well tolerated in these pediatric patients. Radiation-Induced Nausea and Vomiting Total Body Irradiation In randomized, double-blind study in 20 patients, ondansetron tablets (8 mg given 1.5 hours before each fraction of radiotherapy for days) were 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 days for total of 1,320 cGy. Patients received fractions for days, then fractions on day 4. Single High-Dose Fraction Radiotherapy Ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of >=80 cm to the abdomen. Patients received the first dose of ondansetron tablets (8 mg) or metoclopramide (10 mg) to hours before radiotherapy. If radiotherapy was given in the morning, additional doses of study treatment were given (1 tablet late afternoon and tablet before bedtime). If radiotherapy was given in the afternoon, patients took only further tablet that day before bedtime. Patients continued the oral medication on 3 times day basis for days. Daily Fractionated Radiotherapy Ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in double-blind trial in 135 patients receiving 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over field size of >=100 cm to the abdomen. Patients received the first dose of ondansetron tablets (8 mg) or prochlorperazine (10 mg) to hours before the patient received the first daily radiotherapy fraction, with subsequent doses on 3 times day basis. Patients continued the oral medication on 3 times day basis on each day of radiotherapy. Postoperative Nausea and Vomiting Surgical patients who received ondansetron hour before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; and supplemental isoflurane or enflurane) were evaluated in double-blind studies (1 U.S. study, foreign) involving 865 patients. Ondansetron tablets (16 mg) were significantly more effective than placebo in preventing postoperative nausea and vomiting. The study populations in all trials thus far consisted of women undergoing inpatient surgical procedures. No studies have been performed in males. No controlled clinical study comparing ondansetron tablets to ondansetron hydrochloride injection has been performed.

PRECAUTIONS SECTION.


PRECAUTIONS. General. Ondansetron is not 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 progressive ileus and/or gastric distension. Serotonin Syndrome Advise patients of the possibility of serotonin syndrome with concomitant use of ondansetron hydrochloride 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. 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 Serotonergic Drugs Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) (see WARNINGS). Tramadol Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 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 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 nursing woman. Pediatric Use. Little information is available about dosage in pediatric patients years of age or younger (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION sections for use in pediatric patients to 18 years of age). Geriatric Use. Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in U.S.- 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).

PREGNULLNCY SECTION.


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.

DRUG ABUSE AND DEPENDENCE SECTION.


DRUG ABUSE AND DEPENDENCE. Animal studies have shown that ondansetron is not discriminated as benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies.

ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS. The following have been reported as adverse events in clinical trials of patients treated with ondansetron, the active ingredient of ondansetron hydrochloride. causal relationship to therapy with ondansetron hydrochloride has been unclear in many cases. Chemotherapy-Induced Nausea and Vomiting The adverse events in Table have been reported in >=5% of adult patients receiving single 24 mg ondansetron tablet in trials. These patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens (cisplatin dose >=50 mg/m 2). Table 5. Principal Adverse Events in U.S. Trials: Single Day Therapy With 24 mg Ondansetron Tablets (Highly Emetogenic Chemotherapy) EventOndansetron 24 mg q.d. = 300 Ondansetron mg b.i.d. = 124 Ondansetron 32 mg q.d. = 117 Headache 33 (11%) 16 (13%) 17 (15%) Diarrhea 13 (4%) (7%) (3%) The adverse events in Table have been reported in >=5% of adults receiving either mg of ondansetron tablets or times day for days or placebo in trials. These patients were receiving concurrent moderately emetogenic chemotherapy, primarily cyclophosphamide-based regimens. Table 6. Principal Adverse Events in U.S. Trials: Days of Therapy With mg Ondansetron Tablets (Moderately Emetogenic Chemotherapy) EventOndansetron mg b.i.d. = 242 Ondansetron mg t.i.d. = 415 Placebo = 262 Headache 58 (24%) 113 (27%) 34 (13%) Malaise/fatigue 32 (13%) 37 (9%) (2%) Constipation 22 (9%) 26 (6%) (<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 U.S. 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 hydrochloride 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 have been reported in >=5% of patients receiving ondansetron tablets at 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 EventOndansetron 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 PracticeIn addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of ondansetron hydrochloride. Because they are reported voluntarily from population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to ondansetron hydrochloride. Cardiovascular: Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation 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, Stevens-Johnson syndrome, and toxic epidermal necrolysis 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 few minutes up to 48 hours.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


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.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY. Pharmacodynamics Ondansetron is selective 5-HT receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not dopamine-receptor antagonist. Serotonin receptors of the 5-HT 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 ondansetrons 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-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT receptors and initiate the vomiting reflex. In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with serotonin 5-HT receptor antagonist. 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. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. 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. Pharmacokinetics. Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of single mg tablet, is approximately 56%. Ondansetron systemic exposure does not increase proportionately to dose. AUC from 16 mg tablet was 24% greater than predicted from an mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. Bioavailability is also slightly enhanced by the presence of food but unaffected by antacids. Ondansetron is extensively metabolized in humans, with approximately 5% of 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. In vitro metabolism studies have shown that ondansetron is 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. Ondansetron elimination may be affected by cytochrome P-450 inducers. In pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, max, and 1/2 of ondansetron was observed. This resulted in significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended (see PRECAUTIONS: Drug Interactions). In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. Gender differences were shown in the disposition of ondansetron given as single dose. The extent and rate of ondansetrons absorption is greater in women than men. Slower clearance in women, smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables and taken from studies. Table 1. Pharmacokinetics in Normal Volunteers: Single mg Ondansetron Tablet Dose Age-group(years)MeanWeight(kg)nPeak PlasmaConcentration(ng/mL)Time of PeakPlasmaConcentration (h)MeanEliminationHalf-life(h)SystemicPlasmaClearanceL/h/kgAbsoluteBioavailability18-40 F 69 62.7 5 26.2 42.7 1.7 3.1 3.5 0.403 0.354 0.483 0.663 61-74 F 77.5 60.2 6 24.1 52.4 2.1 1.9 4.1 4.9 0.384 0.255 0.585 0.643 >=75 F 78 67.6 6 37 46.1 2.2 2.1 4.5 6.2 0.277 0.249 0.619 0.747 Table 2. Pharmacokinetics in Normal Volunteers: Single 24 mg Ondansetron Tablet Dose Age-group(years)MeanWeight (kg)nPeak PlasmaConcentration(ng/mL)Time of PeakPlasmaConcentration(h)Mean EliminationHalf-life (h)18-43 F 84.1 71.8 8 125.8 194.4 1.9 1.6 4.7 5.8 reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly. In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. 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 resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, total daily dose of mg should not be exceeded. 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 oral mean plasma clearance was reduced by about 50% 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. No reduction in dose or dosing frequency in these patients is warranted. 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. Four and mg doses of either ondansetron oral solution or ondansetron orally disintegrating tablets are bioequivalent to corresponding doses of ondansetron tablets and may be used interchangeably. One 24 mg ondansetron tablet is bioequivalent to and interchangeable with three mg ondansetron tablets. Clinical Trials Chemotherapy-Induced Nausea and Vomiting Highly Emetogenic Chemotherapy In randomized, double-blind, monotherapy trials, single 24 mg ondansetron tablet was superior to relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin >=50 mg/m 2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving cisplatin dose >=50 mg/m in the historical placebo comparator experienced vomiting in the absence of antiemetic therapy. The first trial compared oral doses of ondansetron 24 mg once day, mg twice day, and 32 mg once day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin >=50 mg/m 2. total of 66% of patients in the ondansetron 24 mg once-a-day group, 55% in the ondansetron mg twice-a-day group, and 55% in the ondansetron 32 mg once-a-day group completed the 24-hour study period with emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the treatment groups was shown to be statistically significantly superior to historical placebo control. In the same trial, 56% of patients receiving oral ondansetron 24 mg once day experienced no nausea during the 24-hour study period, compared with 36% of patients in the oral ondansetron mg twice-a-day group P 0.001) and 50% in the oral ondansetron 32 mg once-a-day group. In second trial, efficacy of the oral ondansetron 24 mg once-a-day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin >=50 mg/m 2, was confirmed. Moderately Emetogenic Chemotherapy In double-blind U.S. study in 67 patients, ondansetron tablets mg administered twice day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 3: Table 3. Emetic Episodes: Treatment Response The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent dose hours after the first dose. An mg ondansetron tablet was administered twice day for days after completion of chemotherapy. bMedian undefined since at least 50% of the patients were withdrawn or had more than emetic episodes. Median undefined since at least 50% of patients did not have any emetic episodes. Ondansetron8 mg b.i.d.Ondansetron Tablets PlaceboP Value Number of patients 33 34 Treatment response Emetic episodes to Emetic episodes More than emetic episodes/withdrawn 20 (61%) (18%) (21%) (6%) (24%) 24 (71%) <0.001 <0.001 Median number of emetic episodes Undefined Median time to first emetic episode (h) Undefined 6.5 In double-blind U.S. study in 336 patients, ondansetron tablets mg administered twice day were as effective as ondansetron tablets mg administered times day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 4:Table 4. Emetic Episodes: Treatment Response The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent dose hours after the first dose. An mg ondansetron tablet was administered twice day for days after completion of chemotherapy. The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses and hours after the first dose. An mg ondansetron tablet was administered times day for days after completion of chemotherapy. Median undefined since at least 50% of patients did not have any emetic episodes. Visual analog scale assessment: = no nausea, 100 nausea as bad as it can be. Ondansetron8 mg b.i.d. Ondansetron Tablets 8 mg t.i.d. Ondansetron Tablets Number of patients 165 171 Treatment response Emetic episodes to Emetic episodes More than emetic episodes/withdrawn 101 (61%) 16 (10%) 48 (29%) 99 (58%) 17 (10%) 55 (32%) Median number of emetic episodes 0 Median time to first emetic episode (h) Undefined Undefined Median nausea scores (0 to 100) 6 Re-treatment In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ondansetron tablets mg times daily during subsequent chemotherapy for total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only to emetic episodes occurred in 43 (11%) of the re-treatment courses. Pediatric Studies Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients to 18 years old with cancer who were given variety of cisplatin or noncisplatin regimens. In these foreign trials, the initial dose of ondansetron hydrochloride injection ranged from 0.04 to 0.87 mg/kg for total dose of 2.16 to 12 mg. This was followed by the administration of ondansetron tablets ranging from to 24 mg daily for days. In these studies, 58% of the 170 evaluable patients had complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received ondansetron tablets mg times day to be similar to those in patients 12 to 18 years of age who received ondansetron tablets mg times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, ondansetron tablets were well tolerated in these pediatric patients. Radiation-Induced Nausea and Vomiting Total Body Irradiation In randomized, double-blind study in 20 patients, ondansetron tablets (8 mg given 1.5 hours before each fraction of radiotherapy for days) were 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 days for total of 1,320 cGy. Patients received fractions for days, then fractions on day 4. Single High-Dose Fraction Radiotherapy Ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of >=80 cm to the abdomen. Patients received the first dose of ondansetron tablets (8 mg) or metoclopramide (10 mg) to hours before radiotherapy. If radiotherapy was given in the morning, additional doses of study treatment were given (1 tablet late afternoon and tablet before bedtime). If radiotherapy was given in the afternoon, patients took only further tablet that day before bedtime. Patients continued the oral medication on 3 times day basis for days. Daily Fractionated Radiotherapy Ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in double-blind trial in 135 patients receiving 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over field size of >=100 cm to the abdomen. Patients received the first dose of ondansetron tablets (8 mg) or prochlorperazine (10 mg) to hours before the patient received the first daily radiotherapy fraction, with subsequent doses on 3 times day basis. Patients continued the oral medication on 3 times day basis on each day of radiotherapy. Postoperative Nausea and Vomiting Surgical patients who received ondansetron hour before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; and supplemental isoflurane or enflurane) were evaluated in double-blind studies (1 U.S. study, foreign) involving 865 patients. Ondansetron tablets (16 mg) were significantly more effective than placebo in preventing postoperative nausea and vomiting. The study populations in all trials thus far consisted of women undergoing inpatient surgical procedures. No studies have been performed in males. No controlled clinical study comparing ondansetron tablets to ondansetron hydrochloride injection has been performed.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS. 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 are contraindicated for patients known to have hypersensitivity to the drug.

DESCRIPTION SECTION.


DESCRIPTION. The active ingredient in ondansetron tablets, USP is ondansetron hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and 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 molecular formula is 18H 19N 3OoHClo2H 2O, representing molecular weight of 365.9. Ondansetron hydrochloride USP (dihydrate) is white to off-white powder that is soluble in water and normal saline. Ondansetron tablets, USP for oral administration contain ondansetron hydrochloride USP (dihydrate) equivalent to mg or mg or 24 mg of ondansetron. Each film-coated tablet also contains the inactive ingredients anhydrous lactose, microcrystalline cellulose, pregelatinized starch (maize), magnesium stearate, triacetin, titanium dioxide and hypromellose. In addition mg tablet also contains iron oxide yellow and 24 mg tablet also contains iron oxide red. Meets USP dissolution test 6. Structure.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION. Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer ChemotherapyThe recommended adult oral dosage of ondansetron tablets is 24 mg given as three mg tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin >=50 mg/m 2. Multiday, single-dose administration of 24 mg dosage has not been studied. Pediatric Use There is no experience with the use of 24 mg dosage in pediatric patients. Geriatric Use 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 mg ondansetron tablet given twice day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent dose hours after the first dose. One mg ondansetron tablet should be administered twice day (every 12 hours) for to days after completion of chemotherapy. Pediatric Use For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients through 11 years of age, the dosage is one mg ondansetron tablet given times day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses and hours after the first dose. One mg ondansetron tablet should be administered times day (every hours) for to days after completion of chemotherapy. Geriatric Use 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 mg ondansetron tablet given times day. For total body irradiation one mg ondansetron tablet should be administered to hours before each fraction of radiotherapy administered each day. For single high-dose fraction radiotherapy to the abdomen one mg ondansetron tablet should be administered to hours before radiotherapy, with subsequent doses every hours after the first dose for to days after completion of radiotherapy. For daily fractionated radiotherapy to the abdomen one mg ondansetron tablet should be administered to hours before radiotherapy, with subsequent doses every hours after the first dose for each day radiotherapy is given. Pediatric Use There is no experience with the use of ondansetron tablets in the prevention of radiation-induced nausea and vomiting in pediatric patients. Geriatric Use The dosage recommendation is the same as for the general population. Postoperative Nausea and Vomiting The recommended dosage is 16 mg given as two mg ondansetron tablets hour before induction of anesthesia. Pediatric Use There is no experience with the use of ondansetron tablets in the prevention of postoperative nausea and vomiting in pediatric patients. Geriatric Use 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 resultant increase in plasma half-life. In such patients, total daily dose of mg should not be exceeded.

DRUG INTERACTIONS SECTION.


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 Serotonergic Drugs Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) (see WARNINGS). Tramadol Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 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 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.

GENERAL PRECAUTIONS SECTION.


General. Ondansetron is not 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 progressive ileus and/or gastric distension. Serotonin Syndrome Advise patients of the possibility of serotonin syndrome with concomitant use of ondansetron hydrochloride 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.

GERIATRIC USE SECTION.


Geriatric Use. Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in U.S.- 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).

HOW SUPPLIED SECTION.


HOW SUPPLIED. Ondansetron Tablets USP, mg are white to off-white, oval shaped, film-coated tablets debossed with on one side and 91 on the other side. Bottles of 30 NDC 65862-187-30 Bottles of 500 NDC 65862-187-05 Bottles of 1000 NDC 65862-187-99 x Unit-dose Tablets NDC 65862-187-03 10 10 Unit-dose Tablets NDC 65862-187-10 Ondansetron Tablets USP, mg are yellow colored, oval shaped, film-coated tablets debossed with on one side and 92 on the other side. Bottles of 30 NDC 65862-188-30 Bottles of 500 NDC 65862-188-05 Bottles of 1000 NDC 65862-188-99 x Unit-dose Tablets NDC 65862-188-03 10 10 Unit-dose Tablets NDC 65862-188-10 Ondansetron Tablets USP, 24 mg are pink colored, oval shaped, film-coated tablets debossed with on one side and 71 on the other side. Unit-dose Packs of Tablet NDC 65862-189-11 Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Protect from light.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE. 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.. 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.

NURSING MOTHERS SECTION.


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 nursing woman.

OVERDOSAGE SECTION.


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 events listed above, the following events have been described in the setting of ondansetron overdose: Sudden blindness (amaurosis) of to minutes duration plus severe constipation occurred in patient that was administered 72 mg of ondansetron intravenously as single dose. Hypotension (and faintness) occurred in patient that took 48 mg of ondansetron tablets. Following infusion of 32 mg over only 4-minute period, 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 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 to days.

REFERENCES SECTION.


REFERENCES. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit Surg. 1973;60:646-649. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321. Arcioni R, della Rocca M, Romano R, et al. Anesth Analg. 2002;94:1553-1557. Manufactured for: Aurobindo Pharma USA, Inc. 2400 Route 130 North Dayton, NJ 08810 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 072, India Revised: 10/2014 Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit Surg. 1973;60:646-649. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321. Arcioni R, della Rocca M, Romano R, et al. Anesth Analg. 2002;94:1553-1557.

TERATOGENIC EFFECTS SECTION.


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.

WARNINGS SECTION.


WARNINGS. Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT receptor antagonists. ECG changes including QT interval prolongation has been seen in patients receiving ondansetron. In addition, postmarketing 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. The development of serotonin syndrome has been reported with 5-HT3 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 hydrochloride alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in 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 hydrochloride and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue ondansetron hydrochloride and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if ondansetron hydrochloride is used concomitantly with other serotonergic drugs (see PRECAUTIONS and OVERDOSAGE).