ONDANSETRON HCL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-All oral dosage forms are considered interchangeable.
-All oral dosage forms may be administered without regard to meals.
-Antacids do not interfere with ondansetron absorption.
Oral Solid Formulations
Oral disintegrating tablets (ODT):
-DO NOT attempt to push ODT tablets through foil backing. With dry hands, peel back the foil of 1 blister and remove the tablet just prior to dosing.
-Place tablet on the tongue; it will dissolve in seconds. Once dissolved, the patient may swallow with saliva. Administration with liquid is not necessary.
-Wash hands after administration.

Oral Liquid Formulations
-Oral solution: Measure dose with a calibrated oral syringe or other calibrated container.

Other Oral Formulations
Oral soluble film (Zuplenz):
-With dry hands, fold the pouch along the dotted line to expose the tear notch. While still folded, tear the pouch carefully along the edge and remove the oral soluble film just prior to dosing.
-Place the film on the tongue; it will dissolve in 4 to 20 seconds. Once dissolved, the patient may swallow with saliva. Administration with liquid is not necessary.
-When administering oral soluble films successively to reach a desired dose (i.e., 16 mg given as two 8 mg films) allow each film to dissolve completely before administering the next one.
-Wash hands after administration.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
IV Push
-Doses up to 4 mg may be administered undiluted (2 mg/mL) over at least 30 seconds and preferably over a period of 2 to 5 minutes.

Intermittent IV Infusion
-For doses more than 4 mg and for chemotherapy-induced nausea and vomiting (CINV), dilute ondansetron in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.-For patients 6 months to 1 year of age and/or 10 kg or less: Doses may be diluted in 10 to 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection, depending on the fluid needs of the individual patient.

-Infuse IV over 15 minutes.
-Storage: Dilution is stable for 48 hours at room temperature.

Intramuscular Administration
-In adult patients, a 4 mg undiluted dose of ondansetron may be administered intramuscularly as a single injection.

Diarrhea (2-16%) and constipation (6-11%) were among the most frequently reported adverse events in patients receiving ondansetron during clinical trials for chemotherapy-induced nausea and vomiting (CINV) with moderate-high emetogenic agents. Hiccups have been reported during post-marketing experience with ondansetron.

Urinary retention (5%) and gynecological disorder (7%) have been reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV) during clinical trials.

Headache (9-27%) was the most frequently reported adverse event during clinical trials of ondansetron and appeared to be more common in patients receiving the drug for chemotherapy-induced nausea and vomiting (CINV). Preliminary observations in a small number of subjects suggest a higher incidence of headache when ondansetron orally disintegrating tablets are taken with water, when compared to without water. Other neurologic side effects reported include drowsiness (8-20%), malaise and fatigue (9-13%), anxiety or agitation (6%), paresthesias (2%), and dizziness (4-7%). Transient dizziness associated with intravenous infusion has been reported post-marketing. Rarely, extrapyramidal reactions, including oculogyric crisis appearing alone or with other types of dystonic reaction, have been reported with ondansetron use. In one case, extrapyramidal reactions were confirmed by rechallenge. In addition, there have been rare reports of grand mal seizures in patients receiving ondansetron, although a casual relationship has not been established.

Elevated hepatic enzymes were reported in patients receiving either cisplatin- or cyclophosphamide-based chemotherapy during ondansetron clinical trials. The elevation did not appear to be related to ondansetron dose or duration of therapy. The enzyme levels exceeded twice the upper limit of normal (ULN) in approximately 5% of chemotherapy patients receiving intravenous (IV) ondansetron, and 1-2% of patients receiving oral therapy, but the increases were transient in nature and did not cause symptomatic hepatic disease. Repeat exposure showed similar elevations in some instances. In addition, hepatic failure and death have been reported in patients with cancer receiving concomitant medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics; the etiology of the hepatic failure is unclear.

Rare cases of hypokalemia have been reported following treatment with ondansetron in oncology patients; the relationship to ondansetron is unclear. It may be prudent to monitor serum electrolytes in select patients, as hypokalemia is a risk factor for electrocardiogram (ECG) changes.

Ondansetron causes QT prolongation in a dose-dependent manner; cases of torsade de pointes have been reported. Single IV doses should not exceed 16 mg. Patients at risk for developing torsade de pointes include those with underlying heart conditions, such as congenital long QT syndrome, those who are predisposed to hypokalemia and hypomagnesemia, and those taking other medications that lead to QT prolongation. ECG monitoring is recommended in patients with electrolyte imbalance, heart failure, significant bradycardia, and in patients taking other medications that can lead to QT prolongation.

In addition to QT prolongation, other cardiovascular adverse events reported during clinical trials with ondansetron include angina, chest pain (unspecified), ECG alterations (including second-degree AV block, QT prolongation, and ST-T wave changes), hypotension (5%), and sinus tachycardia. Bradycardia (6% vs. 6% placebo) was reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV). Syncope, palpitations, and arrhythmias, including ventricular tachycardia and supraventricular tachycardia (SVT), bradycardia, premature ventricular contractions (PVCs), atrial fibrillation, and acute myocardial ischemia have been reported during postmarketing use of ondansetron. In some cases, predominantly during intravenous administration, the symptoms of myocardial ischemia appeared immediately after administration but resolved with prompt treatment. Coronary vasospasm (coronary artery spasm) appears to be the most common cause of the ischemia. To minimize the risk of these adverse events in patients receiving intravenous treatment, do not exceed the recommended ondansetron infusion rate and monitor patients for signs and symptoms of myocardial ischemia during and after administration. In patients receiving oral therapy, monitor or advise patients of these symptoms.

Several reports of anaphylactoid reactions have been associated with serotonin (5-HT3) receptor antagonists, such as ondansetron. Manifestations of anaphylactoid reactions have included angioedema, bronchospasm, dyspnea, hypotension, laryngeal edema, stridor, and/or urticaria. Laryngospasm, shock, cardiac arrest, and respiratory arrest have been reported during allergic reactions in patients receiving injectable ondansetron. Rash (unspecified) (1%), pruritus (2-5%), and flushing have been reported in clinical trials with both oral and injectable formulations. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with post-marketing use of ondansetron.

An injection site reaction (4%) was reported in patients receiving ondansetron injection intravenously over 2 to 5 minutes during clinical trials for post-operative nausea/vomiting (PONV); symptoms included pain, erythema, and burning at the site.

Visual impairment has occurred with ondansetron use. Cases of transient blindness, predominantly during intravenous (IV) administration, have been reported; resolution occurred within minutes up to 48 hours. Sudden blindness (amaurosis) of 2-3 minute duration occurred in one patient who was administered ondansetron 72 mg IV as a single dose. In another case, transient blindness was reported in a patient who received ondansetron 4mg as a post-operative rapid IV bolus dose. The mechanism by which ondansetron may cause visual impairment is not well understood. Clinicians in the latter case suggest that it may be related to the rate of administration. Transient blurred vision, in some cases associated with accommodation disorder, has also been reported during post-marketing experience.

Fever (2-8%) and shivers or chills (2-5%) were reported in patients receiving ondansetron during clinical trials. Wound problems (28% vs. 31% placebo) were reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV).

Serotonin syndrome has been reported with 5-HT3 receptor antagonists, such as ondansetron, during concurrent use of other medications known to increase CNS or peripheral serotonin concentrations or during overdose. Some of the reported cases were fatal; most occurred in a post-anesthesia care unit or infusion center. If serotonin syndrome becomes evident during treatment, discontinue ondansetron and any other serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome includes a range of signs and symptoms that can include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or seizures. Cases consistent with serotonin syndrome have been reported in pediatric patients after inadvertent overdose of oral ondansetron (estimated ingestion > 5 mg/kg). Symptoms reported in these cases included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizures. Patients required supportive care, including intubation in some cases, with complete recovery in 1-2 days.

Concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when the agents were given together.

Ondansetron is extensively metabolized in the liver and should be used with caution in patients with hepatic disease, hepatitis, or elevated hepatic enzymes because of possible increased plasma levels, reduced clearance, and subsequent toxicity.

Ondansetron should not be used in patients with a known ondansetron hypersensitivity. Use with caution in patients with known granisetron hypersensitivity, palonosetron hypersensitivity, dolasetron hypersensitivity, or sensitivity to related drugs. Cross-sensitivity is possible between these agents; there have been several reports of anaphylactic/anaphylactoid reactions associated with the use of drugs in this class. Antagonism at serotonin (5-HT) receptors, and the subsequent increased concentrations of serotonin, may increase the risk of developing bronchospasm and/or vasoconstriction.

Ondansetron orally disintegrating tablets (ODT) contain phenylalanine and should be used with caution in patients with phenylketonuria.

The use of ondansetron may mask the symptoms of adynamic ileus, GI obstruction, or gastric distention after abdominal surgery or in patients with chemotherapy-induced nausea and vomiting. Ondansetron is not a drug that stimulates gastric or intestinal peristalsis; it should not be used instead of nasogastric suction.

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 (coronary vasospasm) appears to be the most common underlying cause. Therefore, monitor for or advise patients of signs or symptoms of myocardial ischemia during use of ondansetron. Ondansetron increases the risk of developing QT prolongation in a dose-dependent manner, which can lead to abnormal and potentially fatal heart rhythms, including torsade de pointes. Due to the increased risk of QT prolongation seen with intravenous (IV) doses of 32 mg, single IV doses should not exceed 16 mg. Avoid ondansetron in patients with congenital long QT syndrome. Electrocardiogram (ECG) monitoring and cautious use is recommended in patients with hypokalemia, hypomagnesemia, heart failure, significant bradycardia, or in patients receiving other medications known to prolong the QT interval. Use ondansetron with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Description: Ondansetron is an oral and parenteral serotonin (5-HT3) receptor antagonist. It is used as an antiemetic agent for the prevention and treatment of nausea and vomiting during chemotherapy, radiation therapy, and surgery. In the pediatric population, ondansetron is also used off-label for cyclic vomiting syndrome and gastroenteritis-induced vomiting. Ondansetron is a safe and highly effective antiemetic compared to older, traditional antiemetics (e.g., metoclopramide, droperidol); however, there is a risk of dose-dependent QT-prolongation and torsade de points. When administered at optimal doses, ondansetron and other 5HT3 receptor antagonists (e.g., granisetron) are equally effective. The guidelines recommend that children receiving moderate to high-emetic-risk agents should be offered a 2-drug combination of a 5-HT3 receptor antagonist and dexamethasone; aprepitant is also added to the 2-drug combination with high-emetic-risk agents. The Society for Ambulatory Anesthesia (SAMBA) guidelines recommend the use of a 5-HT3 receptor antagonist as the first choice for prophylaxis of postoperative nausea and vomiting in children. The intravenous formulation of ondansetron is FDA approved for use in pediatric patients as young as 1 month; the oral formulations are approved in pediatric patients 4 years of age and older.

For chemotherapy-induced nausea/vomiting prophylaxis (CINV prophylaxis) and radiation-induced nausea/vomiting prophylaxis* (RINV prophylaxis*):
Intravenous dosage:
Infants 6 months and older, Children, and Adolescents: 0.15 mg/kg IV infused over 15 minutes beginning 30 minutes prior to the initiation of chemotherapy and repeat 4 and 8 hours later (3 doses total). Max: 16 mg/dose. The American Society of Clinical Oncology (ASCO) recommends 0.15 mg/kg/dose (Max: 8 mg) twice daily during chemotherapy and for 2 days after completion, or give 1 to 2 hours before each fraction of radiation and for 1 day after completion for highly emetogenic therapy. Alternatively, ondansetron has been administered every 8 hours and continued for 1 to 5 days after completion of therapy. A single dose of 0.6 mg/kg IV was as effective as standard therapy (0.15 mg/kg/dose up to 8 mg every 4 hours for 4 doses) in a prospective, double-blind study in chemotherapy-naive pediatric oncology patients; however, the maximum dose in the study was 32 mg, which is no longer recommended because of dose-dependent QT prolongation.
Oral dosage:
Infants* and Children less than 4 years* with a body surface area less than 0.3 meter-squared: 1 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy or 1 to 2 hours prior to radiation. May be continued for 1 to 5 days after completion of therapy.
Infants* and Children less than 4 years* with a body surface area 0.3 to 0.6 meter-squared: 2 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy or 1 to 2 hours prior to radiation. May be continued for 1 to 5 days after completion of therapy.
Infants* and Children less than 4 years* with a body surface area 0.6 to 1 meter-squared: 3 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy or 1 to 2 hours prior to radiation. May be continued for 1 to 5 days after completion of therapy.
Infants* and Children less than 4 years* with a body surface area more than 1 meter-squared: 4 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy or 1 to 2 hours prior to radiation. May be continued for 1 to 5 days after completion of therapy.
Children 4 to 11 years: 4 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy, with subsequent doses 4 and 8 hours after the initial dose. Further doses may be given every 8 hours for 1 to 2 days after completion of therapy. For radiation, give the first dose 1 to 2 hours prior to therapy. Further doses may be given every 8 hours for 1 to 5 days after completion of therapy. Alternatively, a single 12 mg PO dose may be given prior to chemotherapy.
Children and Adolescents 12 years and older: 8 mg PO twice daily. Give the first dose 30 minutes prior to chemotherapy with a subsequent dose 8 hours after the initial dose. Further doses may be given every 12 hours for 1 to 2 days after completion of therapy. For radiation, give the first dose 1 to 2 hours prior to therapy. Further doses may be given every 8 to 12 hours for 1 to 5 days after completion of therapy. Alternatively, a single 24 mg PO dose may be given prior to chemotherapy.

For the short-term treatment of nausea/vomiting associated with acute gastroenteritis*:
Intravenous dosage:
Infants, Children, and Adolescents: 0.15 mg/kg/dose (Max: 8 mg/dose) IV as a single dose has been used along with oral or IV rehydration. Although routine use of antiemetics is not recommended, some studies have shown that single IV doses of ondansetron are safe and effective for reducing vomiting and increasing patients' ability to tolerate oral rehydration.
Oral dosage:
Infants and Children 6 months and older and weighing 8 to 15 kg: 2 mg PO as a single dose along with oral or IV rehydration. Alternatively, 0.2 mg/kg/dose PO every 8 hours for 3 doses has also been studied. Although routine use of antiemetics is not recommended for acute gastroenteritis, studies have shown that single and multiple oral doses of ondansetron are safe and effective for reducing vomiting and increasing patients' ability to tolerate oral rehydration.
Children weighing 15 to 30 kg: 4 mg PO as a single dose along with oral or IV rehydration. Alternatively, 0.2 mg/kg/dose PO every 8 hours for 3 doses has also been studied. Although routine use of antiemetics is not recommended for acute gastroenteritis in guidelines, some studies have found that single and multiple oral doses of ondansetron are safe and effective for reducing vomiting and increasing patients' ability to tolerate oral rehydration.
Children and Adolescents weighing more than 30 kg: 6 to 8 mg PO as a single dose along with oral or IV rehydration. Alternatively, 0.2 mg/kg/dose PO every 8 hours for 3 doses has also been studied. Although routine use of antiemetics is not recommended for acute gastroenteritis, some studies have found that single and multiple oral doses of ondansetron are safe and effective for reducing vomiting and increasing patients' ability to tolerate oral rehydration.

For the treatment of cyclic vomiting syndrome*:
Intravenous dosage:
Infants and Children < 2 years: Safety and efficacy have not been established. A diagnosis of cyclic vomiting syndrome is difficult in this age range.
Children >= 2 years and Adolescents: 0.3-0.4 mg/kg/dose IV infusion every 4-6 hours as needed. Infuse over 15 minutes. Max: 16 mg/dose.

For post-operative nausea/vomiting (PONV) prophylaxis:
Intravenous dosage:
Infants and Children weighing 40 kg or less: 0.05 to 0.1 mg/kg IV as single dose injected over 2 to 5 minutes, immediately prior to or following anesthesia induction, or once postoperatively if patient experiences nausea/vomiting shortly after surgery. Max: 4 mg/dose. Administration of a second IV dose postoperatively in response to inadequate control is generally not effective; use of an antiemetic from another pharmacologic class should be considered.
Children and Adolescents weighing more than 40 kg: 4 mg IV as single dose injected over 2 to 5 minutes, immediately prior to or following anesthesia induction, or once postoperatively if patient experiences nausea/vomiting shortly after surgery. Max: 4 mg/dose. Administration of a second IV dose postoperatively in response to inadequate control is generally not effective; use of an antiemetic from another pharmacologic class should be considered.
Intramuscular dosage:
Adolescents: 4 mg IM as single dose injected immediately prior to or following anesthesia induction, or once postoperatively if patient experiences nausea/vomiting shortly after surgery. Max: 4 mg/dose. Administration of a second dose postoperatively in response to inadequate control is generally not effective; use of an antiemetic from another pharmacologic class should be considered.
Oral dosage:
Infants*, Children*, and Adolescents*: 0.15 mg/kg PO as a single dose, immediately prior to or after anesthesia induction, or once postoperatively if patient experiences nausea/vomiting shortly after surgery. Max: 8 mg/dose. Administration of a second dose postoperatively in response to inadequate control is generally not effective; use of an antiemetic from another pharmacologic class should be considered.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
1-5 months: 0.1 mg/kg IV (single dose). Safety and efficacy have not been established for PO formulation.
>= 6 months: 0.15 mg/kg/dose IV (Max: 16 mg/dose). Safety and efficacy have not been established for PO formulation.
-Children
< 4 years: 0.15 mg/kg/dose IV (Max: 16 mg/dose). Safety and efficacy have not been established for PO formulation.
4-11 years: 0.15 mg/kg/dose IV (Max: 16 mg/dose). 12 mg/day PO.
>= 12 years: 0.15 mg/kg/dose IV (Max: 16 mg/dose). 16 mg/day PO.
-Adolescents
0.15 mg/kg/dose IV (Max: 16 mg/dose). 16 mg/day PO.

Patients with Hepatic Impairment Dosing
Though there are no specific pediatric recommendations, the manufacturer recommends ondansetron dosage should not exceed 8 mg/day in adult patients with severe hepatic impairment (Child-Pugh score >= 10). In such patients, plasma clearance is reduced, resulting in a dramatically prolonged elimination half-life.

Patients with Renal Impairment Dosing
No dosage adjustments are recommended. A small percentage (5%) of ondansetron is renally cleared. In patients with severe renal impairment (CrCl < 30 ml/min) the mean plasma clearance is reduced; however, the reduction is not consistent with an increase in half-life.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Ondansetron is a 5-HT3 receptor antagonist. Although other neurotransmitters are involved, serotonin plays an important role in the emetogenic pathways associated with chemotherapy- and radiation-induced nausea and vomiting. During the early or acute phase, the primary site of emetogenesis in chemotherapy-induced nausea and vomiting (CINV) is thought to be the gut wall. Chemotherapy is cytotoxic to enterochromaffin cells in the small intestine. Enterochromaffin cell death leads to serotonin release and therefore increased serotonin binding on nerve endings, leading to sensory input that contributes to emesis. Peripherally, ondansetron preferentially blocks the serotonin 5-hydroxytryptamine, type 3 (5-HT3) receptors at the peripheral vagal nerve terminals in the intestines, blocking the signal transmission to the central nervous system and antagonizing the effects of serotonin. Ondansetron is also a weak antagonist of the 5-HT1B, 5-HT1C, alpha-adrenergic, and opioid mu receptors; the clinical implications of these actions is uncertain. It has no activity at dopamine receptors.

Much like chemotherapy-induced nausea and vomiting (CINV), postoperative nausea and vomiting (PONV) is not controlled by a single neurotransmitter, but serotonin is believed to play a major role. The process of postoperative nausea and vomiting is coordinated by the vomiting center in the central nervous system. Stimulation can be initiated centrally in areas such as the cerebral cortex and otic or vestibular nerves, or peripherally in areas such as the oropharynx, mediastinum, gastrointestinal track, renal pelvis, peritoneum, or genitalia. Stretching and inflammation that occur during or after surgery may trigger chemical stimulation that lead to nausea and vomiting. Centrally, ondansetron blocks the 5-HT3 receptor site at the chemoreceptor trigger zone, stopping the vomiting reflex produced by the vomiting center. Because of multiple neurochemical receptor sites involved during surgery, combination antiemetic therapy with drugs of different mechanisms is often necessary.

Pharmacokinetics: Ondansetron is administered orally and parenterally. It is approximately 70-76% bound to plasma protein; circulating drug also distributes into erythrocytes. Systemic exposure does not increase proportionately to the dose. Ondansetron undergoes extensive metabolism, mainly by hydroxylation, followed by glucuronide or sulfate conjugation. In vitro studies indicate that ondansetron is metabolized by hepatic cytochrome P450 (CYP450) drug-metabolizing enzymes, including CYP1A2, CYP2D6, and CYP3A4; with CYP3A4 playing the largest role. Because multiple enzymes are involved in the metabolism of ondansetron, inhibition or loss of any one enzyme may not affect the overall rate of metabolism. CYP450 inducers will likely increase ondansetron elimination. The inactive metabolites are eliminated in the urine.

The mean elimination half-life in adults is 4 hours. In general, pediatric patients have a higher ondansetron clearance compared to adult patients, resulting in a shorter half-life. In a study of 21 pediatric cancer patients 4-18 years of age, patients older than 15 years exhibited pharmacokinetic parameters similar to adults. In the same study, mean Vd for the total population was 1.9 L/kg, resulting in an elimination half-life of 2.8 hours and a clearance of 0.599 L/kg/h. A pharmacokinetic study of postoperative children 3-12 years of age given a single dose of 2 or 4 mg IV, demonstrated a Vd of 1.65 L/kg, an elimination half-life of 2.5-3.5 hours, and a clearance of 0.439 L/kg/hour. Another surgical study in infants and children 5-24 months receiving 0.1-0.2 mg/kg ondansetron as a single dose demonstrated a Vd of 2.3 L/kg and an elimination half-life of 2.9 hours; clearance was 0.581 L/kg/hour. Notably, during the same study, infants 1-4 months of age had a higher Vd (3.5 L/kg), a longer half-life (6.7 hours), and slower clearance (0.401 L/kg/hour) compared to older infants and children.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP1A2, CYP2D6, and P-glycoprotein (P-gp)
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic CYP450 drug-metabolizing enzymes (i.e., CYP1A2, CYP2D6, and CYP3A4), with CYP3A4 metabolism predominating. 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. However, the effect of multiple enzyme inhibitors (e.g., combination of drugs that inhibits 2 or 3 of the involved CYP enzymes) is not known. Ondansetron elimination has been shown to be increased when the drug is coadministered with CYP3A4-inducing medications (e.g., carbamazepine and phenytoin). On the basis of currently available data, no dosage adjustment is recommended for patients receiving CYP-interacting drugs. Ondansetron is also a substrate of P-glycoprotein.


-Route-Specific Pharmacokinetics
Oral Route
After oral administration, ondansetron is well absorbed from the gastrointestinal tract and undergoes first-pass metabolism. After a dose of a single 8 mg tablet, mean oral bioavailability in healthy adult subjects is 56%. The AUC from a 16-mg tablet is 24% greater than predicted from an 8-mg tablet dose, indicating reduced first-pass metabolism at higher oral doses. Food slightly enhances tablet bioavailability, but antacids have no effect. Of note, 4- and 8-mg oral ondansetron tablets, orally disintegrating tablets (ODT), and oral solution are bioequivalent. After a single 8 mg dose of ondansetron oral soluble film in adult patients, peak plasma concentrations are achieved in 1.3 hours, and mean Cmax is 37.28 ng/mL and the mean AUC is 225 ng x hour/mL. The Cmax and AUC of the oral soluble film is comparable to that of the same dose of ondansetron ODT. Water does not affect the exposure of ondansetron oral soluble film administration. Administration of the oral soluble film with a high-fat meal delays the Tmax by approximately 1 hour, but the AUC is unaffected.

Intravenous Route
In adults, a single 4-mg dose administered as a 5 minute intravenous (IV) infusion demonstrated a mean AUC of 156 ng x h/ml. Mean peak plasma concentrations were 42.9 ng/ml at 10 minutes after IV infusion. During a pharmacokinetic study in patients age 1-48 months, simulations showed that a dose of ondansetron 0.1 mg/kg in infants less than 6 months produced exposure similar to a 0.15 mg/kg dose in older infants and young children. In the studied population, a dose of 0.1 mg/kg demonstrated an AUC of 150 ng x hour/ml and a Cmax of 76.6 ng/ml, while a dose of 0.2 mg/kg demonstrated an AUC of 313 ng x hour/ml and a Cmax of 169 ng/ml. In infants and children 6-48 months given 3 doses of 0.15 mg/kg/dose, an AUC of 630 ng x hour/ml and a Cmax of 77.8 ng/ml was observed. A pharmacokinetic study of healthy children age 3-11 years receiving ondansetron 2 or 4 mg demonstrated an AUC of 202.8 and 278.8 ng x hour/ml, respectively.


-Special Populations
Hepatic Impairment
In adult patients with mild to moderate hepatic impairment, ondansetron clearance is reduced two-fold and mean half-life is increased to 11.6 hours, compared to 3-5.7 hours in patients without hepatic impairment. In adult patients with severe hepatic impairment, clearance is reduced two-fold to three-fold and volume of distribution is increased, resulting in an increase in elimination half-life to 20 hours.

Renal Impairment
A small percentage (5%) of ondansetron is renally cleared. In patients with severe renal impairment (creatinine clearance < 30 ml/min) the mean plasma clearance is reduced by approximately 40%; however, the reduction is variable and is not consistent with an increase in half-life.