Onzet

ONDANSETRON

2 mg/mL (8 mg/4 mL)
Solution for Injection (I.M./I.V.)

ANTIEMETIC

Category:

Description

The Cathay Drug Co., Inc.

 

FORMULATION

Each mL contains:

Ondansetron ( as hydrochloride Dihydrate), USP ………………………………… 2 mg

 

PRODUCT DESCRIPTION

Ondansetron (ONZET) is a colorless to light yellow, clear solution, seated in a 5 mL glass ampule (easy cut).

 

CLINICAL PHARMACOLOGY

Mechanism of Action

Ondansetron is a selective 5-HT3 receptor antagonist. Chemotherapeutic agents and radiotherapy may cause release of 5-HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5-HT3 receptors. The initiation of this reflex is blocked by ondansetron. Activation of vagal afferents may also cause a release of 5-HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus the effect of ondansetron in the management of the nausea and vomiting induced by chemotherapy and radiotherapy may be due to the antagonism of 5-HT3 receptors on neurons located both in the peripheral and central nervous system. In psychomotor testing, ondansetron does not cause sedation nor impair performance.

 

PHARMACODYNAMICS/PHARMACOKINETICS

Pharmacodynamics

In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or a small intestinal transit time. In another study in six normal male volunteers, a 16 mg dose infused over 5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). However, no thorough QT study has been conducted with ondansetron. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. ondansetron has no effect on plasma prolactin concentrations.

 

In a gender-balanced pharmacodynamic study (n = 50), ondansetron 4 mg administered intravenously or

intramuscularly was dynamically similar in the prevention of nausea and vomiting using the ipecacuanha

model of emesis.

 

 

 

Pharmacokinetics

In normal adult volunteers, the following mean pharmacokinetic data have been determined following a single 0.15 mg/kg intravenous dose.

 

 

Absorption

A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of single 4 mg dose administered as a 5 minute infusion compared to a single intramuscular injection. Systemic exposure as measured by mean AUC were equivalent, with values of 156 (95% CI 136, 180) and 161 (95% CI 137, 190) ng/h/mL for intravenous and intramuscular groups, respectively. Mean peak plasma concentrations were 42.9 (95% CI 33.8, 54.4) ng/mL at 10 minutes after intravenous infusion and 31.9 (95% CI 26.3, 38.6) ng/mL at 41 minutes after intramuscular injection. In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was 264 ng/mL following a single 32 mg dose administered as a 15 minute intravenous infusion.

 

Distribution

Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, over the pharmacologic

concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.

 

Metabolism

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recoveredas the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.

 

Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at

concentrations likely to significantly contribute to the biological activity of ondansetron. The metabolites are observed in the urine.

 

In vitro metabolism studies have shown that ondansetron is a substance for multiple human hepatic

cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron

turnover, CYP3A4 plays a predominant role while formation of the major in vivo metabolites is apparently

mediated by CYP1A2. The role of CYP2D6 in ondansetron in vivo metabolism is relatively minor.

The pharmacokinetics of intravenous ondansetron did not differ between subjects who were poor

metabolisers of CYP2D6 and those who were extensive metabolisers of CYP2D6, further supporting the

limited role of CYP2D6 in ondansetron disposition in vivo.

 

Elimination

In normal volunteers (19 to 39 years old, n = 23), following a single 32 mg dose administered as a 15 minute intravenous infusion, the mean elimination half-life was 4.1 hours. Systemic exposure to 32 mg ondansetron was not proportional to dose as measured by comparing dose-normalized AUC values to an 8 mg dose. This is consistent with a small decrease in systemic clearance with increasing plasma concentrations.

 

In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no difference in the

multidose pharmacokinetics over a 4 day period.

 

Geriatrics

A 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 conclusion in that age group. No dosage adjustment is recommended in the elderly.

 

Pediatrics

In general, surgical and cancer pediatric patients younger than 18 years tend to have a higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher volume of distribution in this age group.

 

In a study of 21 pediatric cancer patients (4 to 18 years of age) who received three intravenous 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 adults.

 

Hepatic Impairment

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 those without hepatic impairment. In patients with severe hepatic (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.

Renal Impairment

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.

 

Non-Clinical Toxicology

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 (approximately 2.5 and 3.8 times the recommended human intravenous dose of 32 mg/day, based on body surface area).

Ondansetron was not mutagenic in standard test for mutagenicity.

Oral administration of ondansetron up to 15 mg/kg per day (approximately 3.8 times the recommended

human intravenous dose, based on body surface area) did not affect fertility or general reproductive

performance of male and female rats.

 

INDICATIONS

Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic cancer Chemotherapy

Ondansetron (Onzet) Injection is indicated for the prevention of nausea and vomiting associated with initial and repeat course of emetogenic cancer chemotherapy, including high-dose cisplastin.

Ondansetron (Onzet) Injection is approved for patients aged 6 months and older.

 

Prevention of Postoperative Nausea and/or Vomiting

Ondansetron (Onzet) Injection is indicated for the prevention of postoperative nausea and/or vomiting. As

with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients in whom nausea and/or vomiting must be avoided postoperatively, Ondansetron (Onzet) Injection is recommended even when the incidence of postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic

Ondansetron (Onzet) Injection and experience nausea and/or vomiting postoperatively, Ondansetron (Onzet) Injection may be given to prevent further episodes.

Ondansetron (Onzet) Injection is approved for patients aged 1 month and older.

 

DOSAGE AND ADMINISTRATION

Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic

Chemotherapy

Ondansetron (Onzet) Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

ADULTS

The recommended adult intravenous dosage of Ondansetron (Onzet) Injection is a single 32-mg dose or

three 0.15-mg/kg doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes before the

start of emetogenic chemotherapy. Efficacy of the 32-mg single dose beyond 24 hours has not been

established. The recommended infusion rate should not be exceeded. 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 4 and 8 hours after the first dose of

Ondansetron Injection.

 

PEDIATRICS

For pediatric patients 6 months through 18 years of age, the intravenous dosage of Ondansetron (Onzet)

Injection is 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 4 and 8 hours after the first dose of Ondansetron (Onzet) Injection. The drug should be infused intravenously over 15 minutes.

 

Prevention of Postoperative Nausea and Vomiting

Ondansetron (Onzet) 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 a precipitate may form.

 

ADULTS

The recommended adult intravenous dosage of Ondansetron (Onzet) Injection is 4 mg undiluted

administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occuring within 2 hours after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron (Onzet) 4 mg, administration of a second intravenous dose of 4 mg ondansetron (Onzet) postoperatively does not provide additional control of nausea and vomiting.

 

PEDIATRICS

For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1-mg/kg dose for patients

weighing 40 kg or less, or a single 4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and

vomiting was only studied in patients who had not received prophylactic Ondansetron (Onzet) Injection or as prescribed by the physician.

 

STABILITY AND HANDLING

After dilution, do not use beyond 24 hours. Although Ondansetron (Onzet) Injection is chemically and

physically stable when diluted as recommended, sterile precautions should be observed because diluents

generally do not contain a preservative.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Precaution: Occasionally, ondansetron (Onzet) precipitates at the stopper/vial interface in vials stored

upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial

vigorously

 

Dosage adjustment for Patients with Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg 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 in these patients.

 

CONTRAINDICATIONS

Ondansetron Injection is contraindicated for patients known to have hypersensitivity (e.g., anaphylaxis) to

this product or any of its components. Anaphylaxis reactions have been reported in patients taking

ondansetron.

 

The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound

hypotension and loss of consciousness when apomorphine was administered with ondansetron.

 

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who

have exhibited hypersensitivity to other selective 5-HT receptor antagonists.

 

Electrocardiographic Changes

Rarely and predominantly with intravenous ondansetron, transient electrocardiogram (ECG) changes

including QT/QTc interval prolongation have been reported.

 

Masking of Progressive Ileus and Gastric Distension

The use of Ondansetron Injection in patients following abdominal surgery or in patients with chemotherapyinduced nausea and vomiting may mask a progressive ileus and gastric distention.

 

Effect on Peristalsis

Ondansetron Injection is not a drug that stimulates gastric or intestinal peristalsis. It should not be used

instead of nasogastric suction.

Keep away from children.

 

USE IN SPECIFIC POPULATION

Pregnancy

Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at intravenous doses up to 4 mg/kg per day (approximately 1 and 2 times the recommended human intravenous dose of 32 mg/day, respectively, based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

 

Nursing Mothers

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

 

Pediatric Use

Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month of age. Little information is available about the use of ondansetron in pediatric cancer patients younger than 6 months of age.

 

The clearance of ondansetron in pediatric patients 1 month to 4 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 a precaution, it is recommended that

patients less than 4 months of age receiving this drug be closely monitored.

 

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 experiences 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 age of 65.

 

Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced and

apparent volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a total daily dose of 8 mg should not be exceeded.

 

Renal Impairment

Although plasma clearance is reduced in patients with severe renal impairment (creatinine clearance < 30

mL/min), no dosage adjustment is recommended.

 

DRUG INTERACTIONS

 

Ondansetron does not appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver . 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.

 

Apomorphine

Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with ondansetron is contradindicated.

 

Phenytoin, Carbamazepine, and Rifampin

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.

 

Tramadol

Although there are no data on pharmacokinetic drug interactions between ondansetron and tramadol, data from two small studies indicate that concomitant use of ondansetron may result in reduced analgesic activity of tramadol. Patients on concomitant ondansetron self administered tramadol more frequently in these studies, leading to an increased cumulative dose in patient controlled administration (PCA) of tramadol.

 

Chemotherapy

In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.

In a crossover study in 76 pediatric patients, intravenous ondansetron did not increase blood levels of high-dose methotrexate.

 

Temazepam

The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of

temazepam.

 

Alfentanil and Atracurium

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.

 

ADVERSE DRUG REACTIONS

Clinical Trials Experience

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

 

The following adverse reactions have been reported in clinical trials of adult patients treated with ondansetron, the active ingredient of intravenous Ondansetron Injection at a dosage of three 0.15-mg/kg

doses or as a single 32-mg dose. A causal relationship to therapy with Ondansetron Injection was unclear in many cases.

 

 

 

 

 

 

 

 

 

 

Chemotherapy-Induced Nausea and Vomiting

Table 2. Adverse Reactions Reported >5% of Adult Patients who Received Ondansetron at a Dosage of Three 0.15 mg/kg Doses or as a Single 32 mg Dose

 

Cardiovascular

Rare cases of angina (chest pain), electrocardiographic alterations, and tachycardia have been reported.

 

Gastrointestinal

Constipation has been reported in 11% of chemotherapy patients receiving multiday ondansetron.

 

Hepatic

In comparative trials in cisplatin chemotherepy 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 occured in some courses, but symptomatic hepatic disease did not occur.

 

Integumentary

Rash has occurred in approximately 1% of patients receiving ondansetron.

 

Neurologica

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.

 

Other

Rare cases of hypokalemia have been reported.

 

Postoperative Nausea and Vomiting

The adverse reactions in Table 2 have been reported in ≥2% of adults receiving ondansetron at a dosage of 4 mg intravenous over 2 to 5 minutes in clinical trials.

 

Pediatric Use

Rates of adverse reactions were similar in both the ondansetron and placebo groups in pediatric patients

receiving ondansetron (a single 0.1-mg/kg dose for pediatric patients weighing 40 kg or less, or 4 mg for

pediatric patients weighing more than 40 kg) administered intravenously over at least 30 seconds. Diarrhea was seen more frequently in patients taking Ondansetron Injection (2%) compared to placebo ( < 1%) in the 1 month to 24 month age group. These patients were receiving multiple concomitant perioperative and postoperative medications.

 

POSTMARKETING EXPERIENCE

The following adverse reactions have been identified during post-approval 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. The reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ondansetron.

 

Cardiovascular

Arrhythmias (including ventricular and supraventricular tachycardia, premature ventriicular 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/QTc interval prolongation have been reported.

 

 

General

Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylatic reactions,

angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported. A positive lymphocyte transform test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron.

 

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.

 

Skin

Urticaria

 

Local Reactions

Pain, redness, and burning at site of injection.

 

Lower Respiratory

Hiccups

 

Neurological

Oculogyric crisis, appearing alone, as well as with other dystonic reactions. Transient dizziness during or shortly after intravenous infusion.

 

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. Transient blurred vision, in some cases associated with abnormalities of accommodation, have also been reported.

 

DRUG ABUSE AND DEPENDENCE

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

 

OVERDOSE

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose.

 

In addition to the adverse reactions listed above, the following events 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) occured in another patient that took 48 mg of ondansetron hydrochloride tablets.

Following infusion of 32 mg over only a 4 minute period, a vasovagal episode with transient second degree heartblock was observed. In all instances, the events resolved completely.

 

STORAGE

Store at temperatures not exceeding 30°C. Protect from light.

 

AVAILABILITY

Ondansetron (ONZET) 2 mg/mL (8mg/4mL) Solution for Injection (IM/IV): 5 mL capacity, 4 mL net content Type I clear and colorless glass ampule (Box of 10 ampules).

 

Manufacturer

TAIWAN BIOTECH CO., LTD.

No. 22, Chieh Shou Road, Taoyuan City, Taiwan

 

Marketing Authorization Holder

THE CATHAY DRUG CO., INC.

2/F Vernida I Condominium, 120 Amorsolo St.

 

Date of revision: July 2018

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