INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose beyond 24 hours in these patients has not been established.. Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose beyond 24 hours in these patients has not been established.

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.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table have been reported in adults receiving ondansetron at dosage of three 0.15-mg/kg doses or as single 32-mg dose in clinical trials. These patients were receiving concomitant chemotherapy, primarily cisplatin, and I.V. fluids. Most were receiving diuretic.Table 7. Principal Adverse Events in Comparative Trials in Adults Number of Adult Patients With Event Ondansetron Injection, USP 0.15mg/kg 3 = 419 Ondansetron Injection, USP 32mg 1 = 220 Metoclopramide = 156 Placebo = 34 Diarrhea 16% 8% 44% 18% Headache 17% 25% 7% 15% Fever 8% 7% 5% 3% Akathisia 0% 0% 6% 0% Acute dystonic reactions 0% 0% 5% 0%See NeurologicalThe following have been reported during controlled clinical trials:Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations, hypotension, and tachycardia have been reported. In many cases, the relationship to ondansetron injection was unclear.Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients receiving multiday ondansetron.Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been reported to exceed twice the upper limit of normal in approximately 5% of patients. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur.Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron.Neurological: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron injection, and rare cases of grand mal seizure. The relationship to ondansetron injection was unclear.Other: Rare cases of hypokalemia have been reported. The relationship to ondansetron injection was unclear.Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of intravenous formulations of ondansetron injection. 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 injection.Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT interval prolongation and ST segment depression), palpitations, and syncope.General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported.Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death have been reported in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.Local Reactions: Pain, redness, and burning at site of injection.Lower Respiratory: HiccupsNeurological: Oculogyric crisis, appearing alone, as well as with other dystonic reactions.Skin: UrticariaSpecial Senses: Transient dizziness during or shortly after I.V. infusion.Eye Disorders: Transient blurred vision, in some cases associated with abnormalities of accommodation. 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 per day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg per day did not affect fertility or general reproductive performance of male and female rats.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Pharmacodynamics: Ondansetron is selective 5-HT3 receptor antagonist. While ondansetrons mechanism of action has not been fully characterized, it is not 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 ondansetrons antiemetic action in chemotherapy-induced nausea and vomiting 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 vomiting. The released serotonin may stimulate the vagal afferents through the 5-HT3 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-HT3 receptor antagonist.In normal volunteers, single I.V. 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. In another study in six normal male volunteers, 16-mg dose infused over minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.In gender-balanced pharmacodynamic study (n 56), ondansetron mg administered intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting using the ipecacuanha model of emesis.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 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 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, Cmax, and T1/2 of ondansetron was observed.1 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.In normal adult volunteers, the following mean pharmacokinetic data have been determined following single 0.15-mg/kg I.V. dose.Table 1. Pharmacokinetics in Normal Adult Volunteers Age-group (years) Peak Plasma Concentration (ng/mL) Mean Elimination Half-life (h) Plasma Clearance (L/h/kg) 19 40 11 102 3.5 0.381 61 74 12 106 4.7 0.319 >= 75 11 170 5.5 0.262A 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-Pugh2 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 mean plasma clearance was reduced by about 41% 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.In adult cancer patients, the mean elimination half-life was hours, and there was no difference in the multidose pharmacokinetics over 4-day period. In study of 21 pediatric cancer patients (4 to 18 years of age) who received three I.V. doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar to those of adults. Patients to 12 years of age generally showed higher clearance and somewhat larger volume of distribution than adults. Most pediatric patients younger than 15 years of age with cancer had shorter (2.4 hours) ondansetron plasma half-life than patients older than 15 years of age. It is not known whether these differences in ondansetron plasma half-life may result in differences in efficacy between adults and some young pediatric patients (see CLINICAL TRIALS: Pediatric Studies).Pharmacokinetic information for pediatric cancer patients months to 48 months of age is approved for GlaxoSmithKline Corporations ondansetron injection. However, due to GlaxoSmithKlines marketing exclusivity rights, this drug product is not labeled for use in this subpopulation of pediatric patients.In study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery requiring anesthesia for duration of 45 minutes to hours, single I.V. dose of ondansetron, mg (3 to years) or mg (8 to 12 years), was administered immediately prior to anesthesia induction. Mean weight-normalized clearance and volume of distribution values in these pediatric surgical patients were similar to those previously reported for young adults. Mean terminal half-life was slightly reduced in pediatric patients (range, 2.5 to hours) in comparison with adults (range, to 3.5 hours).Table 2. Pharmacokinetics in Pediatric Surgery Patients Month to 12 Years of AgeSubjects and Age Group CL (L/h/kg) SS (L/kg) 1 /2 (h) Geometric Mean MeanPediatric Surgery Patients to 12 years of Age = 21 0.439 1.65 2.9Pediatric Surgery Patients to 24 months of Age = 22 0.581 2.3 2.9Pediatric Surgery Patients month to months of Age = 19 0.401 3.5 6.7In general, surgical and cancer pediatric patients younger than 18 years tend to have higher ondansetron clearance compared to adults leading to shorter half-life in most pediatric patients. In patients month to months of age, longer half-life was observed due to the higher volume of distribution in this age group.Pharmacokinetic information for pediatric surgical patients month to 24 months of age is approved for GlaxoSmithKline Corporations ondansetron injection. However, due to GlaxoSmithKlines marketing exclusivity rights, this drug product is not labeled for use in this subpopulation of pediatric patients.In normal volunteers (19 to 39 years old, = 23), the peak plasma concentration was 264 ng/mL following single 32-mg dose administered as 15-minute I.V. infusion. The mean elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not proportional to dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent with small decrease in systemic clearance with increasing plasma concentrations.A study was performed in normal volunteers (n 56) to evaluate the pharmacokinetics of single 4-mg dose administered as 5-minute infusion compared to single intramuscular injection. Systemic exposure as measured by mean AUC was equivalent, with values of 156 [95% CI 136, 180] and 161 [95% CI 137, 190] ngoh/mL for I.V. and I.M. groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after I.V. infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at 41 minutes after I.M. injection. The mean elimination half-life was not affected by route of administration.Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with binding constant over the pharmacologic concentration range (10 to 500 ng/mL). Circulating drug also distributes into erythrocytes.A positive lymphoblast transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Ondansetron in % Dextrose Injection is contraindicated for patients known to have hypersensitivity to the drug.

DESCRIPTION SECTION.

DESCRIPTION. The active ingredient in Ondansetron in % Dextrose Injection is ondansetron hydrochloride (HCl), the racemic form of ondansetron and selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (+-) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula:The empirical formula is C18H19N3O.HCl.2H2O, representing molecular weight of 365.9.Ondansetron HCl is white to off-white powder that is soluble in water and normal saline.Sterile, Premixed Solution for Intravenous Administration in Single-Dose, Flexible Plastic Containers: Each 50 mL contains ondansetron 32 mg (as the hydrochloride dihydrate); dextrose 2500 mg; and citric acid 26 mg and sodium citrate 11.5 mg as buffers in Water for Injection, USP.It contains no preservatives. The osmolarity of this solution is 270 mOsm/L (approx.), and the pH is to 4.The flexible plastic container is fabricated from specially formulated, plastic film. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out certain chemical components in very small amounts before the expiration period is attained. However, the safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers.. Ondansetron structural formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Prevention of Chemotherapy-Induced Nausea and Vomiting:. Adult Dosing: The recommended I.V. dosage of ondansetron injection for adults is single 32-mg dose or three 0.15-mg/kg doses. single 32-mg dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. The recommended infusion rate should not be exceeded (see OVERDOSAGE). With the three-dose (0.15-mg/kg) regimen, the first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered and hours after the first dose of ondansetron injection.Ondansetron injection should not be mixed with solutions for which physical and chemical compatibility has not been established. In particular, this applies to alkaline solutions as precipitate may form.Flexible Plastic Container: REQUIRES NO DILUTION. Ondansetron in % Dextrose Injection, 32 mg in 50 mL.. Pediatric Dosing: On the basis of the available information (see CLINICAL TRIALS: Pediatric Studies and CLINICAL PHARMACOLOGY: Pharmacokinetics), the dosage in pediatric cancer patients to 18 years of age should be three 0.15-mg/kg doses. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy, subsequent doses (0.15 mg/kg) are administered and hours after the first dose of Ondansetron in % Dextrose Injection. The drug should be infused intravenously over 15 minutes. Little information is available about dosage in pediatric cancer patients younger than months of age.Dosing information for pediatric cancer patients months to 48 months of age is approved for GlaxoSmithKline Corporations ondansetron injection. However, due to GlaxoSmithKlines marketing exclusivity rights, this drug product is not labeled for use in this subpopulation of pediatric patients.Flexible Plastic Container: REQUIRES NO DILUTION. Ondansetron in % Dextrose Injection, 32 mg in 50 mL.. Geriatric Dosing: The dosage recommendation 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-Pugh2 score of 10 or greater), single maximal daily dose of mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron.Ondansetron in % Dextrose Injection in Flexible Plastic Containers: Instructions for Use: To Open: Tear outer wrap at notch and remove solution container. Check for minute leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.Preparation for Administration: Use aseptic technique.1. Close flow control clamp of administration set.2. Remove cover from outlet port at bottom of container.3. Insert piercing pin of administration set into port with twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.4. Suspend container from hanger.5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Ondansetron in % Dextrose Injection.6. Open flow control clamp to expel air from set. Close clamp.7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.8. Perform venipuncture.9. Regulate rate of administration with flow control clamp.Caution: Ondansetron in % Dextrose Injection in flexible plastic containers is to be administered by I.V. drip infusion only. Ondansetron in % Dextrose Injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as precipitate may form. If used with primary I.V. fluid system, the primary solution should be discontinued during ondansetron in % Dextrose Injection. Do not administer unless solution is clear and container is undamaged.Warning: Do not use flexible plastic container in series connections.Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

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.

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 limited available data, no dosage adjustment is recommended for patients on these drugs.

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 distention.Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.

GERIATRIC USE SECTION.

Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 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 in % Dextrose Injection, 32 mg/50 mL, in 5% Dextrose, contains no preservatives and is supplied as sterile, premixed solution for I.V. administration in single-dose, flexible plastic containers (NDC 0143-9771-06) (case of 6).Store between 20 and 25C (68 and 77F). [See USP Controlled Room Temperature] Protect from light. Avoid excessive heat. Protect from freezing.

OVERDOSAGE SECTION.

OVERDOSAGE. There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual doses as large as 150 mg and total daily dosages (three doses) as large as 252 mg have been administered intravenously 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 one patient that was administered 72 mg of ondansetron intravenously as single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. Ondansetron in 5% Dextrose Injection 32 mg/50 mL. Ondansetron in 5% Dextrose Injection 32 mg/50 mL.

PEDIATRIC USE SECTION.

Pediatric Use: Little information is available about the use of ondansetron in pediatric surgical patients younger than month of age. Little information is available about the use of ondansetron in pediatric cancer patients younger than months of age. The clearance of ondansetron in pediatric patients month to months of age is slower and the half-life is ~2.5 fold longer than patients who are >4 to 24 months of age. As precaution, it is recommended that patients less than months of age receiving this drug be closely monitored. (See CLINICAL PHARMACOLOGY: Pharmacokinetics).The frequency and type of adverse events reported in pediatric patients receiving ondansetron were similar to those in patients receiving placebo.

PHARMACODYNAMICS SECTION.

Pharmacodynamics: Ondansetron is selective 5-HT3 receptor antagonist. While ondansetrons mechanism of action has not been fully characterized, it is not 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 ondansetrons antiemetic action in chemotherapy-induced nausea and vomiting 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 vomiting. The released serotonin may stimulate the vagal afferents through the 5-HT3 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-HT3 receptor antagonist.In normal volunteers, single I.V. 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. In another study in six normal male volunteers, 16-mg dose infused over minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.In gender-balanced pharmacodynamic study (n 56), ondansetron mg administered intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting using the ipecacuanha model of emesis.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 SECTION.

Pharmacokinetics: 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 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, Cmax, and T1/2 of ondansetron was observed.1 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.In normal adult volunteers, the following mean pharmacokinetic data have been determined following single 0.15-mg/kg I.V. dose.Table 1. Pharmacokinetics in Normal Adult Volunteers Age-group (years) Peak Plasma Concentration (ng/mL) Mean Elimination Half-life (h) Plasma Clearance (L/h/kg) 19 40 11 102 3.5 0.381 61 74 12 106 4.7 0.319 >= 75 11 170 5.5 0.262A 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-Pugh2 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 mean plasma clearance was reduced by about 41% 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.In adult cancer patients, the mean elimination half-life was hours, and there was no difference in the multidose pharmacokinetics over 4-day period. In study of 21 pediatric cancer patients (4 to 18 years of age) who received three I.V. doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar to those of adults. Patients to 12 years of age generally showed higher clearance and somewhat larger volume of distribution than adults. Most pediatric patients younger than 15 years of age with cancer had shorter (2.4 hours) ondansetron plasma half-life than patients older than 15 years of age. It is not known whether these differences in ondansetron plasma half-life may result in differences in efficacy between adults and some young pediatric patients (see CLINICAL TRIALS: Pediatric Studies).Pharmacokinetic information for pediatric cancer patients months to 48 months of age is approved for GlaxoSmithKline Corporations ondansetron injection. However, due to GlaxoSmithKlines marketing exclusivity rights, this drug product is not labeled for use in this subpopulation of pediatric patients.In study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery requiring anesthesia for duration of 45 minutes to hours, single I.V. dose of ondansetron, mg (3 to years) or mg (8 to 12 years), was administered immediately prior to anesthesia induction. Mean weight-normalized clearance and volume of distribution values in these pediatric surgical patients were similar to those previously reported for young adults. Mean terminal half-life was slightly reduced in pediatric patients (range, 2.5 to hours) in comparison with adults (range, to 3.5 hours).Table 2. Pharmacokinetics in Pediatric Surgery Patients Month to 12 Years of AgeSubjects and Age Group CL (L/h/kg) SS (L/kg) 1 /2 (h) Geometric Mean MeanPediatric Surgery Patients to 12 years of Age = 21 0.439 1.65 2.9Pediatric Surgery Patients to 24 months of Age = 22 0.581 2.3 2.9Pediatric Surgery Patients month to months of Age = 19 0.401 3.5 6.7In general, surgical and cancer pediatric patients younger than 18 years tend to have higher ondansetron clearance compared to adults leading to shorter half-life in most pediatric patients. In patients month to months of age, longer half-life was observed due to the higher volume of distribution in this age group.Pharmacokinetic information for pediatric surgical patients month to 24 months of age is approved for GlaxoSmithKline Corporations ondansetron injection. However, due to GlaxoSmithKlines marketing exclusivity rights, this drug product is not labeled for use in this subpopulation of pediatric patients.In normal volunteers (19 to 39 years old, = 23), the peak plasma concentration was 264 ng/mL following single 32-mg dose administered as 15-minute I.V. infusion. The mean elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not proportional to dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent with small decrease in systemic clearance with increasing plasma concentrations.A study was performed in normal volunteers (n 56) to evaluate the pharmacokinetics of single 4-mg dose administered as 5-minute infusion compared to single intramuscular injection. Systemic exposure as measured by mean AUC was equivalent, with values of 156 [95% CI 136, 180] and 161 [95% CI 137, 190] ngoh/mL for I.V. and I.M. groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after I.V. infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at 41 minutes after I.M. injection. The mean elimination half-life was not affected by route of administration.Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with binding constant over the pharmacologic concentration range (10 to 500 ng/mL). Circulating drug also distributes into erythrocytes.A positive lymphoblast transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron.

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 distention.Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.. 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 limited available data, no dosage adjustment is recommended for patients on these drugs.. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 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 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.. 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 per day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg per 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 I.V. doses up to mg/kg per day 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 the use of ondansetron in pediatric surgical patients younger than month of age. Little information is available about the use of ondansetron in pediatric cancer patients younger than months of age. The clearance of ondansetron in pediatric patients month to months of age is slower and the half-life is ~2.5 fold longer than patients who are >4 to 24 months of age. As precaution, it is recommended that patients less than months of age receiving this drug be closely monitored. (See CLINICAL PHARMACOLOGY: Pharmacokinetics).The frequency and type of adverse events reported in pediatric patients receiving ondansetron were similar to those in patients receiving placebo. Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 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).

PREGNANCY SECTION.

Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at I.V. doses up to mg/kg per day 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.

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. BritJSurg. 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.Rx OnlyManufactured by:Claris Lifesciences Ltd. IndiaDistributed by:West-ward InjectablesEatontown, NJ 07724. 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. BritJSurg. 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.

SPL UNCLASSIFIED SECTION.

PRESCRIBING INFORMATION.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at I.V. doses up to mg/kg per day 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-HT3 receptor antagonists.