ONDANSETRON tablet, orally disintegrating

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ONDANSETRON (UNII: 4AF302ESOS) (ONDANSETRON - UNII:4AF302ESOS)
Available from:
RPK Pharmaceuticals, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Ondansetron orally disintegrating tablets are indicated for the prevention of nausea and vomiting associated with: - highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m2 - initial and repeat courses of moderately emetogenic cancer chemotherapy - radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen    Ondansetron orally disintegrating tablets also indicated for the prevention of postoperative nausea and/or vomiting. Ondansetron orally disintegrating tablets are contraindicated in patients: - known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation [see Adverse Reactions (6.2)] - receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness    Risk Summary Available data do not reliably inform the association of ondansetron and adverse fetal outcomes. Published epidemiological studies on
Product summary:
Product: 53002-0591 NDC: 53002-0591-1 3 TABLET, ORALLY DISINTEGRATING in a BLISTER PACK NDC: 53002-0591-2 6 TABLET, ORALLY DISINTEGRATING in a BLISTER PACK NDC: 53002-0591-3 10 TABLET, ORALLY DISINTEGRATING in a BLISTER PACK NDC: 53002-0591-4 30 TABLET, ORALLY DISINTEGRATING in a BLISTER PACK
Authorization status:
Abbreviated New Drug Application
Authorization number:
53002-0591-1, 53002-0591-2, 53002-0591-3, 53002-0591-4

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ONDANSETRON - ondansetron tablet, orally disintegrating

RPK Pharmaceuticals, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ONDANSETRON ORALLY

DISINTEGRATING TABLETS, safely and effectively. See full prescribing information for ONDANSETRON

ORALLY DISINTEGRATING TABLETS.

ONDANSETRON orally disintegrating tablets

Initial U.S. Approval: 1991

INDICATIONS AND USAGE

Ondansetron orally disintegrating tablets are a 5-HT receptor antagonist indicated for the prevention of:

nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal

to 50 mg/m (1)

nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (1)

nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose

fraction to the abdomen, or daily fractions to the abdomen (1)

postoperative nausea and/or vomiting (1)

DOSAGE AND ADMINISTRATION

See full prescribing information for the recommended dosage in adults and pediatrics. (2)

Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg. (2.2, 8.6)

DOSAGE FORMS AND STRENGTHS

4 mg and 8 mg (3)

CONTRAINDICATIONS

Patients known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any components of the formulation. (4)

Concomitant use of apomorphine (4)

WARNINGS AND PRECAUTIONS

Hypersensitivity reactions including anaphylaxis and bronchospasm: Discontinue ondansetron if suspected. Monitor

and treat promptly per standard of care until signs and symptoms resolve. (5.1)

QT interval prolongation and Torsade de Pointes: Avoid in patients with congenital long QT syndrome; monitor with

electrocardiograms (ECGs) if concomitant electrolyte abnormalities, cardiac failure or arrhythmias, or use of other QT

prolonging drugs. (5.2)

Serotonin syndrome: Reported with 5-HT receptor antagonists alone but particularly with concomitant use of

serotonergic drugs. If such symptoms occur, discontinue ondansetron and initiate supportive treatment. If concomitant

use of ondansetron with other serotonergic drugs is clinically warranted, patients should be made aware of a potential

increased risk for serotonin syndrome. (5.3)

Masking of progressive ileus and/or gastric distention following abdominal surgery or chemotherapy-induced nausea

and vomiting: Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal

obstruction. (5.4)

Phenylketonuria: Patients should be informed that ondansetron orally disintegrating tablets contain phenylalanine (a

component of aspartame). Each 4 mg orally disintegrating tablet contains 1.68 mg phenylalanine and 8 mg orally

disintegrating tablet contains 3.37 mg phenylalanine. (5.5)

ADVERSE REACTIONS

The most common adverse reactions in adults for the:

prevention of chemotherapy-induced (greater than or equal to 5%) are: headache, malaise/fatigue, constipation,

diarrhea (6.1)

prevention of radiation-induced nausea and vomiting (greater than or equal to 2%) are: headache, constipation, and

diarrhea (6.1)

prevention of postoperative nausea and vomiting (greater than or equal to 9%) are: headache and hypoxia (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

2.2 Dosage in Hepatic Impairment

2.3 Administration Instructions for Ondansetron Orally Disintegrating Tablets

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

5.2 QT Prolongation

5.3 Serotonin Syndrome

5.4 Masking of Progressive Ileus and Gastric Distension

5.5 Phenylketonuria

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Serotonergic Drugs

7.2 Drugs Affecting Cytochrome P-450 Enzymes

7.3 Tramadol

7.4 Chemotherapy

7.5 Alfentanil and Atracurium

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Prevention of Chemotherapy-Induced Nausea and Vomiting

14.2 Radiation-Induced Nausea and Vomiting

14.3 Postoperative Nausea and Vomiting

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Ondansetron orally disintegrating tablets are indicated for the prevention of nausea and vomiting

associated with:

highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m

initial and repeat courses of moderately emetogenic cancer chemotherapy

radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the

abdomen, or daily fractions to the abdomen

Ondansetron orally disintegrating tablets also indicated for the prevention of postoperative nausea

and/or vomiting.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table

2, respectively.

Corresponding doses of ondansetron tablets, ondansetron orally disintegrating tablets and ondansetron

oral solution may be used interchangeably.

Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting

Indication

Dosage Regimen

Highly Emetogenic

Cancer

Chemotherapy

A single 24 mg dose administered 30 minutes before the start of single-day

highly emetogenic chemotherapy, including cisplatin greater than or equal to 50

mg/m

Moderately

Emetogenic Cancer

Chemotherapy

administered

minutes

before

start

chemotherapy,

with

subsequent 8 mg dose 8 hours after the first dose.

Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after

completion of chemotherapy.

Radiotherapy

For total body irradiation: 8 mg administered 1 to 2 hours before each fraction

of radiotherapy each day.

For single high-dose fraction radiotherapy to the abdomen: 8 mg administered 1

to 2 hours before radiotherapy, with subsequent 8 mg doses every 8 hours after

the first dose for 1 to 2 days after completion of radiotherapy.

For daily fractionated radiotherapy to the abdomen: 8 mg administered 1 to 2

hours before radiotherapy, with subsequent 8 mg doses every 8 hours after the

first dose for each day radiotherapy is given.

Postoperative

16 mg administered 1 hour before induction of anesthesia.

Table 2: Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting

Indication

Dosage Regimen

Moderately

Emetogenic

Cancer

Chemotherapy

12 to 17 years of age: 8 mg administered 30 minutes before the start of chemotherapy,

with a subsequent 8 mg dose 8 hours after the first dose.

Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of

chemotherapy.

4 to 11 years of age: 4 mg administered 30 minutes before the start of chemotherapy,

with a subsequent 4 mg dose 4 and 8 hours after the first dose.

Then

administer

three

times

days

after

completion

chemotherapy.

2.2 Dosage in Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total

daily dose of 8 mg [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.3 Administration Instructions for Ondansetron Orally Disintegrating Tablets

Do not attempt to push ondansetron orally disintegrating tablets through the foil backing. With dry hands,

remove the tablet from the bottle or PEEL BACK the foil backing of 1 blister and GENTLY remove the

tablet. IMMEDIATELY place the ondansetron orally disintegrating tablet on top of the tongue where it

will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary.

3 DOSAGE FORMS AND STRENGTHS

Ondansetron Orally Disintegrating Tablets USP, 4 mg are white to off-white, round tablets

debossed with ‘5’ on one side and ‘E’ on the other side with an embossed circular edge.

Ondansetron Orally Disintegrating Tablets USP, 8 mg are white to off-white, round tablets

debossed with ‘7’ on one side and ‘E’ on the other side with an embossed circular edge.

4 CONTRAINDICATIONS

Ondansetron orally disintegrating tablets are contraindicated in patients:

known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the

formulation [see Adverse Reactions (6.2)]

receiving concomitant apomorphine due to the risk of profound hypotension and loss of

consciousness

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

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

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

reactions occur, discontinue use of ondansetron; treat promptly per standard of care and monitor until

signs and symptoms resolve [see Contraindications (4)].

5.2 QT Prolongation

Electrocardiogram (ECG) changes including QT interval prolongation have been seen in patients

receiving ondansetron. In addition, postmarketing cases of Torsade de Pointes have been reported in

patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. ECG

monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or

hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking other medicinal

products that lead to QT prolongation [see Clinical Pharmacology (12.2)].

5.3 Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT receptor antagonists alone. Most

reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin

reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine

oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the

reported cases were fatal. Serotonin syndrome occurring with overdose of ondansetron alone has also

been reported. The majority of reports of serotonin syndrome related to 5-HT receptor antagonist use

occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and

symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic

instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia),

neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures,

with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be

monitored for the emergence of serotonin syndrome, especially with concomitant use of ondansetron

and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue ondansetron and

initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome,

especially if ondansetron is used concomitantly with other serotonergic drugs [see Drug Interactions

(7.1), Overdosage (10)].

5.4 Masking of Progressive Ileus and Gastric Distension

The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-

induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Monitor for

decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

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

nasogastric suction.

5.5 Phenylketonuria

Phenylketonuric patients should be informed that ondansetron orally disintegrating tablets contain

phenylalanine (a component of aspartame). Each 4 mg orally disintegrating tablet contains 1.68 mg

phenylalanine and 8 mg orally disintegrating tablet contains 3.37 mg phenylalanine.

6 ADVERSE REACTIONS

6.1 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 with rates in the clinical trials of another

drug and may not reflect the rates observed in practice.

The following adverse reactions have been reported in clinical trials of patients treated with

ondansetron, the active ingredient of ondansetron orally disintegrating tablets. A causal relationship to

therapy with ondansetron was unclear in many cases.

Prevention of Chemotherapy-Induced Nausea and Vomiting

The most common adverse reactions reported in greater than or equal to 4% of 300 adults receiving a

single 24 mg dose of ondansetron orally in 2 trials for the prevention of nausea and vomiting associated

with highly emetogenic chemotherapy (cisplatin greater than or equal to 50 mg/m ) were: headache

(11%) and diarrhea (4%).

The most common adverse reactions reported in 4 trials in adults for the prevention of nausea and

vomiting associated with moderately emetogenic chemotherapy (primarily cyclophosphamide-based

regimens) are shown in Table 3.

Table 3: Most Common Adverse Reactions in Adults

for the Prevention of Nausea and Vomiting

Associated with Moderately Emetogenic Chemotherapy [Primarily Cyclophosphamide-based

Regimens ]

Reported in greater than or equal to 5% of patients treated with ondansetron orally disintegrating

tablets and at a rate that exceeded placebo.

Adverse Reaction

Ondansetron Orally

Disintegrating Tablets

8 mg Twice Daily

(n = 242)

Placebo

(n = 262)

Headache

58 (24%)

34 (13%)

Malaise/fatigue

32 (13%)

6 (2%)

Constipation

22 (9%)

1 (<1%)

Diarrhea

15 (6%)

10 (4%)

Less Common Adverse Reactions

Central Nervous System: Extrapyramidal reactions (less than 1% of patients).

Hepatic: Aspartate transaminase (AST) and/or alanine transaminase (ALT) values exceeded twice the

upper limit of normal in approximately 1% to 2% of 723 patients receiving ondansetron and

cyclophosphamide-based chemotherapy in U.S. clinical trials. The increases were transient and did not

appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in

transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role

of cancer chemotherapy in these biochemical changes is unclear.

Liver failure and death has been reported in cancer patients receiving concurrent medications, including

potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is

unclear.

Integumentary: Rash (approximately 1% of patients).

Other (less than 2%): Anaphylaxis, bronchospasm, tachycardia, angina, hypokalemia,

electrocardiographic alterations, vascular occlusive events, and grand mal seizures. Except for

bronchospasm and anaphylaxis, the relationship to ondansetron is unclear.

Prevention of Radiation-Induced Nausea and Vomiting

The most common adverse reactions (greater than or equal to 2%) reported in patients receiving

ondansetron and concurrent radiotherapy were similar to those reported in patients receiving

ondansetron and concurrent chemotherapy and were headache, constipation, and diarrhea.

Prevention of Postoperative Nausea and Vomiting

The most common adverse reactions reported in adults in trial(s) of prevention of postoperative nausea

and vomiting are shown in Table 4. In these trial(s), patients were receiving multiple concomitant

perioperative and postoperative medications in both treatment groups.

a

Table 4: Most Common Adverse Reactions in Adults

for the Prevention of Postoperative

Nausea and Vomiting

Reported in greater than or equal to 5% of patients treated with ondansetron orally disintegrating

tablets and at a rate that exceeded placebo.

Adverse Reaction

Ondansetron Orally

Disintegrating Tablets

16 mg as a Single Dose

(n = 550)

Placebo

(n = 531)

Headache

49 (9%)

27 (5%)

Hypoxia

49 (9%)

35 (7%)

Pyrexia

45 (8%)

34 (6%)

Dizziness

36 (7%)

34 (6%)

Gynecological disorder

36 (7%)

33 (6%)

Anxiety/agitation

33 (6%)

29 (5%)

Urinary retention

28 (5%)

18 (3%)

Pruritus

27 (5%)

20 (4%)

In a crossover study with 25 subjects, headache was reported in 6 subjects administered ondansetron

orally disintegrating tablets with water (24%) as compared with 2 subjects administered ondansetron

orally disintegrating tablets without water (8%).

6.2 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.

Cardiovascular

Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions,

and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart

block, QT/QTc interval prolongation, and ST segment depression), palpitations, and syncope. Rarely

and predominantly with intravenous ondansetron, transient ECG changes including QT interval

prolongation have been reported.

General

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

angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been

reported.

Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients

receiving injectable ondansetron.

Hepatobiliary

Liver enzyme abnormalities.

Lower Respiratory

Hiccups.

a

Neurology

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

Skin

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

Eye Disorders

Cases of transient blindness, predominantly during intravenous administration, have been reported.

These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.

7 DRUG INTERACTIONS

7.1 Serotonergic Drugs

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms)

has been described following the concomitant use of 5-HT receptor antagonists and other

serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and

noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If

symptoms occur, discontinue ondansetron and initiate supportive treatment [see Warnings and Precautions

(5.3)].

7.2 Drugs Affecting Cytochrome P-450 Enzymes

Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme

system of the liver [see Clinical Pharmacology (12.3)]. Because ondansetron is metabolized by hepatic

cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of

these enzymes may change the clearance and, hence, the half-life of ondansetron. In patients treated with

potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), the clearance of ondansetron

was significantly increased and ondansetron blood concentrations were decreased. However, on the

basis of available data, no dosage adjustment for ondansetron is recommended for patients on these

drugs [see Clinical Pharmacology (12.3)].

7.3 Tramadol

Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed,

data from 2 small trials indicate that when used together, ondansetron may increase patient-controlled

administration of tramadol. Monitor patients to ensure adequate pain control when ondansetron is

administered with tramadol.

7.4 Chemotherapy

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

In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase systemic

concentrations of high-dose methotrexate.

7.5 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data do not reliably inform the association of ondansetron and adverse fetal outcomes.

Published epidemiological studies on the association between ondansetron and fetal outcomes have

reported inconsistent findings and have important methodological limitations hindering interpretation

(see Data). Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when

ondansetron was administered during organogenesis at approximately 6 and 24 times the maximum

recommended human oral dose of 24 mg/day, based on body surface area, respectively (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In

the U.S. general population, the estimated background risk of major birth defects and miscarriages in

clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Methodological limitations of the epidemiology studies preclude a reliable evaluation of the potential

risk of adverse fetal outcomes with the use of ondansetron in pregnancy.

Two large retrospective cohort studies of ondansetron use in pregnancy have been published. In one

study with 1,349 infants born to women who reported the use of ondansetron or received an ondansetron

prescription in the first trimester, no increased risk for major congenital malformations was seen in

aggregate analysis. In this same study, however, a sub-analysis for specific malformations reported an

association between ondansetron exposure and cardiovascular defect (odds ratio (OR) 1.62 [95% CI

(1.04, 2.14)]) and cardiac septal defect (OR 2.05 [95% CI (1.19, 3.28)]). The second study examined

1970 women who received ondansetron prescription during pregnancy and reported no association

between ondansetron exposure and major congenital malformations, miscarriage or stillbirth, and infants

of low-birth weight or small for gestational age. Important methodological limitations with these

studies include the uncertainty of whether women who filled a prescription actually took the medication,

the concomitant use of other medications or treatments, and other unadjusted confounders that may

account for the study findings.

A case-control study evaluating associations between several common non-cardiac malformations and

multiple antiemetic drugs reported an association between maternal use of ondansetron and isolated cleft

palate (reported adjusted OR = 2.37 [95% CI (1.18, 4.76)]). However, this association could be a chance

finding, given the large number of drugs-birth defect comparisons in this study. It is unknown whether

ondansetron exposure in utero in the cases of cleft palate occurred during the time of palate formation

(the palate is formed between the 6

and 9

weeks of pregnancy) or whether mothers of infants with

cleft palate used other medications or had other risk factors for cleft palate in the offspring. In addition,

no cases of isolated cleft palate were identified in the aforementioned 2 large retrospective cohort

studies. At this time, there is no clear evidence that ondansetron exposure in early pregnancy can cause

cleft palate.

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of

ondansetron up to 15 mg/kg/day and 30 mg/kg/day, respectively, during the period of organogenesis.

With the exception of a slight decrease in maternal body weight gain in the rabbits, there were no

significant effects of ondansetron on the maternal animals or the development of the offspring. At doses

significant effects of ondansetron on the maternal animals or the development of the offspring. At doses

of 15 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal exposure margin was approximately 6

and 24 times the maximum recommended human oral dose of 24 mg/day, respectively, based on body

surface area.

In a pre- and postnatal developmental toxicity study, pregnant rats received oral doses of ondansetron up

to 15 mg/kg/day from Day 17 of pregnancy to litter Day 21. With the exception of a slight reduction in

maternal body weight gain, there were no effects upon the pregnant rats and the pre- and postnatal

development of their offspring, including reproductive performance of the mated F1 generation. At a

dose of 15 mg/kg/day in rats, the maternal exposure margin was approximately 6 times the maximum

recommended human oral dose of 24 mg/day, based on body surface area.

8.2 Lactation

Risk Summary

It is not known whether ondansetron is present in human milk. There are no data on the effects of

ondansetron on the breastfed infant or the effects on milk production. However, it has been demonstrated

that ondansetron is present in the milk of rats.

The developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for ondansetron and any potential adverse effects on the breast fed infant from ondansetron

or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of orally administered ondansetron have been established in pediatric

patients 4 years and older for the prevention of nausea and vomiting associated with moderately

emetogenic cancer chemotherapy. Use of ondansetron in these age-groups is supported by evidence

from adequate and well- controlled studies of ondansetron in adults with additional data from 3 open-

label, uncontrolled, non-U.S. trials in 182 pediatric patients aged 4 to 18 years with cancer who were

given a variety of cisplatin or noncisplatin regimens [see Dosage and Administration (2.2), Clinical

Studies (14.1)].

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

Injection prescribing information.

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

patients for:

prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy

prevention of nausea and vomiting associated with radiotherapy

prevention of postoperative nausea and/or vomiting

8.5 Geriatric Use

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and

vomiting in U.S.- and foreign-controlled clinical trials, for which there were subgroup analyses, 938

(19%) were aged 65 years and older.

No overall differences in safety or effectiveness were observed between subjects 65 years of age and

older and younger subjects. A reduction in clearance and increase in elimination half-life were seen in

patients older than 75 years compared with younger subjects [see Clinical Pharmacology (12.3)]. There

were an insufficient number of patients older than 75 years of age and older in the clinical trials to

permit safety or efficacy conclusions in this age-group. Other reported clinical experience has not

identified differences in responses between the elderly and younger patients, but greater sensitivity of

some older individuals cannot be ruled out. No dosage adjustment is needed in elderly patients.

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