These Highlights Do Not Include All The Information Needed To Use Ondansetron Oral Solution Safely And Effectively. See Full Prescribing Information For Ondansetron Oral Solution.

Prevention of Chemotherapy-Induced Nausea and Vomiting: The most common adverse reactions reported in greater than or equal to 4% of 300 adults receiving a single 24-mg dose of ondansetron orally in 2 trials for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (cisplatin greater than or equal to 50 mg/m²) were: headache (11%) and diarrhea (4%).

The most common adverse reactions reported in 4 trials in adults for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (primarily cyclophosphamide-based regimens) are shown in Table 3.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light.

The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively. Corresponding doses of ondansetron tablets, orally disintegrating tablets and oral solution may be used interchangeably.

Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small trials indicate that when used together, ondansetron may increase patient-controlled administration of tramadol. Monitor patients to ensure adequate pain control when ondansetron is administered with tramadol.

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy.

In addition to the adverse reactions listed above, the following adverse reactions have been described in the setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of ondansetron tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the adverse reactions resolved completely.

Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg per 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 1 to 2 days.

The active ingredient in ondansetron oral solution, USP is ondansetron hydrochloride, USP as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT₃ receptor type. Chemically it is 4H-carbazol-4-one, 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-, monohydrochloride, (±)-, dihydrate. It has the following structural formula:

The empirical formula is C₁₈H₁₉N₃O∙HCl∙2H₂O, representing a molecular weight of 365.9 g/mol.

Ondansetron hydrochloride, USP (dihydrate) is a white to off-white powder that is soluble in water and normal saline.

Each 5 mL of ondansetron oral solution, USP contains 5 mg of ondansetron hydrochloride, USP (dihydrate) equivalent to 4 mg of ondansetron (base) and the following inactive ingredients: anhydrous citric acid, glycerin, purified water, saccharin sodium, sodium citrate, sodium benzoate and strawberry flavor.

Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.

In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase systemic concentrations of high-dose methotrexate.

The safety and effectiveness of orally administered ondansetron have been established in pediatric patients 4 years and older for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Use of ondansetron in these age-groups is supported by evidence from adequate and well-controlled studies of ondansetron in adults with additional data from 3 open-label, uncontrolled, non-US trials in 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens [see Dosage and Administration (2.2), Clinical Studies (14.1)].

Additional information on the use of ondansetron in pediatric patients may be found in ondansetron injection prescribing information.

The safety and effectiveness of orally administered ondansetron have not been established in pediatric patients for:

• prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy.
• prevention of nausea and vomiting associated with radiotherapy.
• prevention of postoperative nausea and/or vomiting.

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 (19%) were aged 65 years and older.

No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger subjects. A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects [see Clinical Pharmacology (12.3)]. There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age group. 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. No dosage adjustment is needed in elderly patients.

Ondansetron is contraindicated in patients:

• known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation [see Adverse Reactions (6.2)].
• receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness.

Electrocardiogram (ECG) changes, including QT interval prolongation have been seen in patients receiving ondansetron. In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking other medicinal products that lead to QT prolongation [see Clinical Pharmacology (12.2)].

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)]

No dosage adjustment is recommended for patients with any degree of renal impairment (mild, moderate, or severe). There is no experience beyond first-day administration of ondansetron [see Clinical Pharmacology (12.3)].

In healthy subjects, 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 healthy subjects. Ondansetron has no effect on plasma-prolactin concentrations.

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 alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT₃ receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ondansetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue ondansetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if ondansetron is used concomitantly with other serotonergic drugs [see Drug Interactions (7.1), Overdosage (10)].

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 SSRIs and SNRIs. Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ondansetron and initiate supportive treatment [see Warnings and Precautions (5.3)].

No dosage adjustment is needed in patients with mild or moderate hepatic impairment.

In patients with severe hepatic impairment, clearance is reduced and the apparent volume of distribution is increased, resulting in a significant increase in the half-life of ondansetron. Therefore, do not exceed a total daily dose of 8 mg in patients with severe hepatic impairment (Child-Pugh score of 10 or greater) [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Ondansetron is indicated for the prevention of nausea and vomiting associated with:

• highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m².
• initial and repeat courses of moderately emetogenic cancer chemotherapy.
• radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen.

Ondansetron is also indicated for the prevention of postoperative nausea and/or vomiting.

Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm appears to be the most common underlying cause. Therefore, monitor or advise patients for signs or symptoms of myocardial ischemia after oral administration of ondansetron [see Adverse Reactions (6.2)].

Ondansetron is a selective 5-HT₃ receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT₃ 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 ondansetron's 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-hydroxyindoleacetic acid (5-HIAA) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT₃ receptors and initiate the vomiting reflex.

• Hypersensitivity Reactions Including Anaphylaxis and Bronchospasm: Discontinue ondansetron if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve. (5.1)
• QT Interval Prolongation and Torsade de Pointes: Avoid ondansetron in patients with congenital long QT syndrome; monitor with electrocardiograms (ECGs) if concomitant electrolyte abnormalities, cardiac failure or arrhythmias, or use of other QT prolonging drugs. (5.2)
• Serotonin Syndrome: Reported with 5-HT₃ receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue ondansetron and initiate supportive treatment. If concomitant use of ondansetron with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. (5.3)
• Myocardial Ischemia: Monitor or advise patients for signs and symptoms of myocardial ischemia after oral administration. (5.4)
• Masking of Progressive Ileus and/or Gastric Distention Following Abdominal Surgery or Chemotherapy-induced Nausea and Vomiting: Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. (5.5)

• See full prescribing information for the recommended dosage in adults and pediatrics. (2)
• Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg. (2.2, 8.6)

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

Ondansetron Oral Solution, USP 4 mg/5 mL, is a clear, colorless solution.

The following adverse reactions have been identified during postapproval use of ondansetron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron, transient ECG changes, including QT interval prolongation have been reported.

Myocardial ischemia was reported predominately with intravenous administration [see Warnings and Precautions (5.4)].

General: Flushing: Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylactic reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported.

Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron.

Hepatobiliary: Liver enzyme abnormalities.

Lower Respiratory: Hiccups.

Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions.

Skin: Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Eye Disorders: Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.

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.

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT₃ receptor antagonists. If hypersensitivity reactions occur, discontinue use of ondansetron; treat promptly per standard of care and monitor until signs and symptoms resolve [see Contraindications (4)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions have been reported in clinical trials of patients treated with ondansetron, the active ingredient of ondansetron. A causal relationship to therapy with ondansetron was unclear in many cases.

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total daily dose of 8 mg [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

NDC 68094-763-59

PrecisionDose™

ONDANSETRON

Oral Solution, USP

4 mg/5 mL

Pkg: Precision Dose, Inc., S. Beloit, IL 61080

In two placebo-controlled, double-blind trials (one conducted in the US and the other outside the US) in 865 females undergoing inpatient surgical procedures, ondansetron 16 mg as a single dose or placebo was administered one hour before the induction of general balanced anesthesia (barbiturate, opioid, nitrous oxide, neuromuscular blockade, and supplemental isoflurane or enflurane), ondansetron tablets was significantly more effective than placebo in preventing postoperative nausea and vomiting.

No trials have been performed in males.

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver [see Clinical Pharmacology (12.3)]. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs [see Clinical Pharmacology (12.3)].

The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 mg/kg per day and 30 mg/kg per day, respectively (approximately 4 and 6 times the maximum recommended human oral dose of 24 mg per day, based on BSA).

Ondansetron was not mutagenic in standard tests for mutagenicity.

Oral administration of ondansetron up to 15 mg/kg per day (approximately 6 times the maximum recommended human oral dose of 24 mg per day, based on BSA) did not affect fertility or general reproductive performance of male and female rats.

Prevention of Chemotherapy-Induced Nausea and Vomiting: The most common adverse reactions reported in greater than or equal to 4% of 300 adults receiving a single 24-mg dose of ondansetron orally in 2 trials for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (cisplatin greater than or equal to 50 mg/m²) were: headache (11%) and diarrhea (4%).

The most common adverse reactions reported in 4 trials in adults for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (primarily cyclophosphamide-based regimens) are shown in Table 3.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light.

The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively. Corresponding doses of ondansetron tablets, orally disintegrating tablets and oral solution may be used interchangeably.

Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small trials indicate that when used together, ondansetron may increase patient-controlled administration of tramadol. Monitor patients to ensure adequate pain control when ondansetron is administered with tramadol.

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy.

In addition to the adverse reactions listed above, the following adverse reactions have been described in the setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of ondansetron tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the adverse reactions resolved completely.

Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg per 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 1 to 2 days.

The active ingredient in ondansetron oral solution, USP is ondansetron hydrochloride, USP as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT₃ receptor type. Chemically it is 4H-carbazol-4-one, 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-, monohydrochloride, (±)-, dihydrate. It has the following structural formula:

The empirical formula is C₁₈H₁₉N₃O∙HCl∙2H₂O, representing a molecular weight of 365.9 g/mol.

Ondansetron hydrochloride, USP (dihydrate) is a white to off-white powder that is soluble in water and normal saline.

Each 5 mL of ondansetron oral solution, USP contains 5 mg of ondansetron hydrochloride, USP (dihydrate) equivalent to 4 mg of ondansetron (base) and the following inactive ingredients: anhydrous citric acid, glycerin, purified water, saccharin sodium, sodium citrate, sodium benzoate and strawberry flavor.

Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.

In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase systemic concentrations of high-dose methotrexate.

The safety and effectiveness of orally administered ondansetron have been established in pediatric patients 4 years and older for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Use of ondansetron in these age-groups is supported by evidence from adequate and well-controlled studies of ondansetron in adults with additional data from 3 open-label, uncontrolled, non-US trials in 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens [see Dosage and Administration (2.2), Clinical Studies (14.1)].

Additional information on the use of ondansetron in pediatric patients may be found in ondansetron injection prescribing information.

The safety and effectiveness of orally administered ondansetron have not been established in pediatric patients for:

• prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy.
• prevention of nausea and vomiting associated with radiotherapy.
• prevention of postoperative nausea and/or vomiting.

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 (19%) were aged 65 years and older.

No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger subjects. A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects [see Clinical Pharmacology (12.3)]. There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age group. 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. No dosage adjustment is needed in elderly patients.

Ondansetron is contraindicated in patients:

• known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation [see Adverse Reactions (6.2)].
• receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness.

Electrocardiogram (ECG) changes, including QT interval prolongation have been seen in patients receiving ondansetron. In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking other medicinal products that lead to QT prolongation [see Clinical Pharmacology (12.2)].

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)]

No dosage adjustment is recommended for patients with any degree of renal impairment (mild, moderate, or severe). There is no experience beyond first-day administration of ondansetron [see Clinical Pharmacology (12.3)].

In healthy subjects, 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 healthy subjects. Ondansetron has no effect on plasma-prolactin concentrations.

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 alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT₃ receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ondansetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue ondansetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if ondansetron is used concomitantly with other serotonergic drugs [see Drug Interactions (7.1), Overdosage (10)].

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 SSRIs and SNRIs. Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ondansetron and initiate supportive treatment [see Warnings and Precautions (5.3)].

No dosage adjustment is needed in patients with mild or moderate hepatic impairment.

In patients with severe hepatic impairment, clearance is reduced and the apparent volume of distribution is increased, resulting in a significant increase in the half-life of ondansetron. Therefore, do not exceed a total daily dose of 8 mg in patients with severe hepatic impairment (Child-Pugh score of 10 or greater) [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Ondansetron is indicated for the prevention of nausea and vomiting associated with:

• highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m².
• initial and repeat courses of moderately emetogenic cancer chemotherapy.
• radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen.

Ondansetron is also indicated for the prevention of postoperative nausea and/or vomiting.

Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm appears to be the most common underlying cause. Therefore, monitor or advise patients for signs or symptoms of myocardial ischemia after oral administration of ondansetron [see Adverse Reactions (6.2)].

Ondansetron is a selective 5-HT₃ receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT₃ 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 ondansetron's 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-hydroxyindoleacetic acid (5-HIAA) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT₃ receptors and initiate the vomiting reflex.

• Hypersensitivity Reactions Including Anaphylaxis and Bronchospasm: Discontinue ondansetron if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve. (5.1)
• QT Interval Prolongation and Torsade de Pointes: Avoid ondansetron in patients with congenital long QT syndrome; monitor with electrocardiograms (ECGs) if concomitant electrolyte abnormalities, cardiac failure or arrhythmias, or use of other QT prolonging drugs. (5.2)
• Serotonin Syndrome: Reported with 5-HT₃ receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue ondansetron and initiate supportive treatment. If concomitant use of ondansetron with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. (5.3)
• Myocardial Ischemia: Monitor or advise patients for signs and symptoms of myocardial ischemia after oral administration. (5.4)
• Masking of Progressive Ileus and/or Gastric Distention Following Abdominal Surgery or Chemotherapy-induced Nausea and Vomiting: Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. (5.5)

• See full prescribing information for the recommended dosage in adults and pediatrics. (2)
• Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg. (2.2, 8.6)

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

Ondansetron Oral Solution, USP 4 mg/5 mL, is a clear, colorless solution.

The following adverse reactions have been identified during postapproval use of ondansetron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron, transient ECG changes, including QT interval prolongation have been reported.

Myocardial ischemia was reported predominately with intravenous administration [see Warnings and Precautions (5.4)].

General: Flushing: Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylactic reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported.

Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron.

Hepatobiliary: Liver enzyme abnormalities.

Lower Respiratory: Hiccups.

Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions.

Skin: Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Eye Disorders: Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.

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.

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT₃ receptor antagonists. If hypersensitivity reactions occur, discontinue use of ondansetron; treat promptly per standard of care and monitor until signs and symptoms resolve [see Contraindications (4)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions have been reported in clinical trials of patients treated with ondansetron, the active ingredient of ondansetron. A causal relationship to therapy with ondansetron was unclear in many cases.

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total daily dose of 8 mg [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

NDC 68094-763-59

PrecisionDose™

ONDANSETRON

Oral Solution, USP

4 mg/5 mL

Pkg: Precision Dose, Inc., S. Beloit, IL 61080

In two placebo-controlled, double-blind trials (one conducted in the US and the other outside the US) in 865 females undergoing inpatient surgical procedures, ondansetron 16 mg as a single dose or placebo was administered one hour before the induction of general balanced anesthesia (barbiturate, opioid, nitrous oxide, neuromuscular blockade, and supplemental isoflurane or enflurane), ondansetron tablets was significantly more effective than placebo in preventing postoperative nausea and vomiting.

No trials have been performed in males.

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver [see Clinical Pharmacology (12.3)]. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs [see Clinical Pharmacology (12.3)].

The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 mg/kg per day and 30 mg/kg per day, respectively (approximately 4 and 6 times the maximum recommended human oral dose of 24 mg per day, based on BSA).

Ondansetron was not mutagenic in standard tests for mutagenicity.

Oral administration of ondansetron up to 15 mg/kg per day (approximately 6 times the maximum recommended human oral dose of 24 mg per day, based on BSA) did not affect fertility or general reproductive performance of male and female rats.