AURO-ONDANSETRON INJECTION SOLUTION

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Active ingredient:
ONDANSETRON (ONDANSETRON HYDROCHLORIDE DIHYDRATE)
Available from:
AURO PHARMA INC
ATC code:
A04AA01
INN (International Name):
ONDANSETRON
Dosage:
2MG
Pharmaceutical form:
SOLUTION
Composition:
ONDANSETRON (ONDANSETRON HYDROCHLORIDE DIHYDRATE) 2MG
Administration route:
INTRAVENOUS
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
5-HT3 RECEPTOR ANTAGONISTS
Product summary:
Active ingredient group (AIG) number: 0131120004; AHFS: 56:22.20
Authorization status:
APPROVED
Authorization number:
02491532
Authorization date:
2019-08-14

Documents in other languages

Page 1 of 29

PRODUCT MONOGRAPH

Pr

Auro-Ondansetron Injection

Ondansetron Injection BP

Ondansetron (as ondansetron hydrochloride dihydrate)

Sterile Solution for Intravenous Injection

2 mg / mL

Antiemetic

(5-HT

receptor antagonist)

Auro Pharma Inc.

3700 Steeles Avenue West, Suite # 402

Woodbridge, Ontario, L4L 8K8

CANADA

Submission Control No: 214616

Date of Preparation:

August 13, 2019

Page 2 of 29

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ......................................................... 3

SUMMARY PRODUCT INFORMATION ........................................................................ 3

INDICATIONS AND CLINICAL USE .............................................................................. 3

CONTRAINDICATIONS .................................................................................................. 4

WARNINGS AND PRECAUTIONS .................................................................................. 4

ADVERSE REACTIONS .................................................................................................... 6

DRUG INTERACTIONS ................................................................................................... 8

DOSAGE AND ADMINISTRATION ............................................................................. 10

ACTION AND CLINICAL PHARMACOLOGY ............................................................ 14

STORAGE AND STABILITY ......................................................................................... 18

DOSAGE FORMS, COMPOSITION AND PACKAGING ............................................. 19

PART II: SCIENTIFIC INFORMATION .............................................................................. 20

PHARMACEUTICAL INFORMATION ......................................................................... 20

CLINICAL TRIALS ......................................................................................................... 21

DETAILED PHARMACOLOGY .................................................................................... 21

MICROBIOLOGY ........................................................................................................... 23

TOXICOLOGY ................................................................................................................ 23

REFERENCES ................................................................................................................. 26

PART III: CONSUMER INFORMATION ............................................................................. 28

Page 3 of 29

Pr

Auro-Ondansetron Injection

Ondansetron Injection BP

Ondansetron (as ondansetron hydrochloride dihydrate)

2 mg / mL

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

All Nonmedicinal Ingredients

Intravenous

Injection / 2 mg / mL

ondansetron

(as hydrochloride dihydrate)

Preservative free formulation: Citric acid

monohydrate, sodium chloride, sodium citrate

(dihydrate), Nitrogen and water for injection.

Preservative-containing formulation: Citric

acid monohydrate, sodium chloride,

sodium citrate (dihydrate), methyl paraben (as

preservative), propyl paraben (as preservative),

nitrogen and water for injection.

INDICATIONS AND CLINICAL USE

Adults

Auro-Ondansetron Injection is indicated for:

the prevention of nausea and vomiting associated with emetogenic chemotherapy,

including high dose cisplatin, and radiotherapy.

the prevention and treatment of post-operative nausea and vomiting.

Pediatrics (4-18 years of age)

Post-Chemotherapy Induced Nausea and Vomiting

Ondansetron hydrochloride was effective and well tolerated when given to children 4-12 years of

age (see

DOSAGE AND ADMINISTRATION). Auro-Ondansetron Injection is not indicated for

the treatment of children 3 years of age or younger.

Post-Radiotherapy Induced Nausea and Vomiting

Auro-Ondansetron Injection is not indicated for use in any age group of this population.

Post-Operative Nausea and Vomiting

Auro-Ondansetron Injection is not indicated for use in any age group of this population.

Geriatrics (> 65 years of age)

Post-Chemotherapy and Radiotherapy Induced Nausea and Vomiting

Efficacy and tolerance of ondansetron hydrochloride were similar to that observed in younger

Page 4 of 29

adults (see

DOSAGE AND ADMINISTRATION).

Post-Operative Nausea and Vomiting

Clinical experience in the use of ondansetron hydrochloride in the prevention and treatment

of post- operative nausea and vomiting is limited and is not indicated for use in this population.

CONTRAINDICATIONS

Auro-Ondansetron Injection is contraindicated in patients

with a history of

hypersensitivity to the drug or any components of its formulations. For a complete

listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the

product monograph.

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

Immune

Cross-reactive hypersensitivity has been reported between different 5-HT

antagonists. Patients who

have experienced hypersensitivity reactions to one 5-HT

antagonist have experienced more severe

reactions upon being challenged with another drug of the same class. The use of a different 5-HT

receptor antagonist is not recommended as a replacement in cases in which a patient has

experienced even a mild hypersensitivity type reaction to another 5-HT

antagonist.

Cardiovascular

QTc Interval Prolongation: Ondansetron prolongs the QT interval (see ACTION AND

CLINICAL PHARMACOLOGY, Electrocardiography). The magnitude of QTc prolongation will

depend on the dose and the infusion rate. In addition, post-marketing cases of torsade de pointes

have been reported in patients using ondansetron. Torsade de pointes is a polymorphic ventricular

tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc

prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the

patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress

to ventricular fibrillation and sudden cardiac death.

Avoid ondansetron in patients with congenital long QT syndrome. Ondansetron should be

administered with caution to patients who have or may develop prolongation of QTc, including

congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to

either QT prolongation or electrolyte abnormalities (see DRUG INTERACTIONS). Hypokalaemia,

hypocalcaemia and hypomagnesemia should be corrected prior to ondansetron administration.

Additional risk factors for torsade de pointes in the general population include, but are

limited to, the following:

female gender;

age 65 years or older;

baseline prolongation of the QT/QTc interval;

presence of genetic variants affecting cardiac ion channels or regulatory proteins;

Page 5 of 29

family history of sudden cardiac death at <50 years;

cardiac disease (e.g., myocardial ischemia or infarction, left ventricular

hypertrophy, cardiomyopathy, conduction system disease);

history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent

conversion from atrial fibrillation);

bradycardia (<50 beats per minute);

acute neurological events (e.g., intracranial or subarachnoid haemorrhage, stroke,

intracranial trauma);

nutritional deficits (e.g., eating disorders, extreme diets);

diabetes mellitus;

autonomic neuropathy.

Auro-Ondansetron Injection is not effective in preventing

motion-induced nausea and

vomiting.

Neurologic

Serotonin syndrome/Neuroleptic Malignant Syndrome: Cases of life-threatening

serotonin syndrome or neuroleptic malignant syndrome-like events have been reported

with

5-HT

receptor antagonist antiemetics, including ondansetron hydrochloride, when given in

combination with other serotonergic and/or neuroleptic drugs. Serotonin

syndrome

symptoms may include mental status changes (e.g. agitation, hallucinations,

coma),

autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),

neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal

symptoms (e.g. nausea, vomiting, diarrhoea). As these syndromes may result in

potentially

life-threatening conditions, treatment should be discontinued if such events

occur and

supportive symptomatic treatment should be initiated. If concomitant treatment

of ondansetron

hydrochloride with a drug affecting the serotonergic neurotransmitter

system is clinically

warranted, careful observation of the patient is advised, particularly

during treatment

initiation and dose increases (see DRUG INTERACTIONS).

Hepatic/Biliary/Pancreatic

There is no experience in patients who are clinically jaundiced. The clearance of an 8 mg

intravenous dose of ondansetron hydrochloride was significantly reduced and the serum half-

life significantly prolonged in subjects with severe impairment of hepatic function. In patients

with moderate or severe impairment of hepatic function, reductions in dosage are therefore

recommended and a total daily dose of 8 mg should not be exceeded. This may be given as a

single intravenous or oral dose.

Ondansetron does not itself appear to induce or inhibit the cytochrome P

drug-

metabolizing enzyme system of the liver. Because ondansetron is metabolised by hepatic

cytochrome P

drug-metabolizing enzymes, inducers or inhibitors of these enzymes may

change the clearance and, hence, the half-life of ondansetron. On the basis of available

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

Gastrointestinal

As ondansetron is known to increase large bowel transit time, patients with signs of subacute

intestinal obstruction should be monitored following administration.

Page 6 of 29

Reproduction

Pregnancy status should be verified for females of reproductive potential prior to starting

treatment with Auro-Ondansetron Injection.

Females of reproductive potential should be advised that it is possible that

Auro-Ondansetron

Injection can cause harm to the developing foetus. Sexually active

females of reproductive

potential are recommended to use effective contraception

(methods that result in less than 1%

pregnancy rates) when using Auro-Ondansetron Injection and for two days after stopping treatment

with Auro-Ondansetron Injection.

Special Populations

Pregnant Women: The safety of ondansetron for use in human pregnancy has not been

established. Ondansetron is not teratogenic in animals. However, as animal studies are not always

predictive of human response, the use of ondansetron in pregnancy is not recommended.

Safety data of ondansetron in pregnancy are limited and findings from available

pharmacoepidemiologic studies are inconsistent.

Post-marketing reports describe cases of congenital malformations with use of ondansetron during

pregnancy; however, the reports are insufficient to establish a causal relationship.

Nursing Women: Ondansetron is excreted in the milk of lactating rats. It is not known if it is

excreted in human milk, however, nursing is not recommended during treatment with ondansetron.

Pediatrics (< 3 years of age): Insufficient information is available to provide dosage

recommendations for children 3 years of age or younger.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates.

Ondansetron hydrochloride has been administered to over 2500 patients worldwide in controlled

clinical trials and has been well tolerated.

The most frequent adverse events reported in controlled clinical trials were headache (11%) and

constipation (4%). Other adverse events include sensations of flushing or warmth (< 1%).

Cardiovascular:

There have been rare reports of tachycardia, angina (chest pain), bradycardia, hypotension,

syncope and electrocardiographic alterations.

Page 7 of 29

Central Nervous System:

There have been rare reports of seizures. Movement disorders and dyskinesia have been reported

in two large clinical trials of ondansetron at a rate of 0.1 – 0.3%.

Dermatological:

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

Eye Disorder:

Rare cases of transient visual disturbances (e.g. blurred vision) have been reported during or

shortly after intravenous administration of ondansetron, particularly at rates equal to or greater

than 30 mg in 15 minutes.

Hypersensitivity:

Rare cases of immediate hypersensitivity reactions sometimes severe, including anaphylaxis,

bronchospasm, urticaria and angioedema have been reported.

Local Reactions:

Pain, redness and burning at the site of injection have been reported.

Metabolic:

There were transient increases of SGOT and SGPT of over twice the upper limit of normal in

approximately 5% of patients. These increases did not appear to be related to dose or duration of

therapy. There have been reports of liver failure and death in patients with cancer receiving

concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics.

The etiology of the liver failure is unclear. There have been rare reports of hypokalaemia.

Other:

There have been reports of abdominal pain, weakness and xerostomia.

Post-Market Adverse Drug Reactions

Over 250 million patient treatment days of ondansetron hydrochloride have been supplied since the

launch of the product worldwide. The following events have been spontaneously reported during

post-approval use of ondansetron hydrochloride, although the link to ondansetron cannot always be

clearly established.

The adverse event profiles in children and adolescents were comparable to that seen in adults.

Immune Disorders:

Rare cases of hypersensitivity reactions, sometimes severe (e.g., laryngeal oedema, stridor,

laryngospasm and cardiopulmonary arrest) have also been reported.

Cardiovascular Disorders:

There have been rare reports (< 0.01%) of myocardial infarction, myocardial ischemia, angina,

chest pain with or without ST segment depression, arrhythmias (including ventricular or

supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation),

electrocardiographic alterations (including second degree heart block), palpitations and syncope.

Rarely and predominantly with intravenous ondansetron, transient ECG changes including QTc

interval prolongation, Torsade de Pointes, ventricular fibrillation, cardiac arrest, and sudden death

Page 8 of 29

have been reported (see WARNINGS AND PRECAUTIONS, Cardiovascular).

Eye Disorder:

There have been very rare cases of transient blindness following ondansetron treatment,

generally

within the recommended dosing range and predominantly during intravenous

administration.

The majority of blindness cases reported resolved within 20 minutes. Although most

patients

had received chemotherapeutic agents, including cisplatin a few cases of transient blindness

occurred following ondansetron administration for the treatment of post-operative nausea or

vomiting and in the absence of cisplatin treatment. Some cases

of transient blindness were reported

as cortical in origin.

Hepatobiliary Disorders:

Occasional asymptomatic increases in liver function tests have been reported.

Nervous System Disorders:

Transient episodes of dizziness (< 0.1%) have been reported predominantly during or upon

completion of IV infusion of ondansetron.

Uncommon reports (< 1%) suggestive of extrapyramidal reactions including oculogyric

crisis/dystonic reactions (e.g. oro-facial dyskinesia, opisthotonos, tremor, etc.),

movement

disorders and dyskinesia have been reported without definitive evidence of persistent clinical

sequelae.

Serotonin syndrome and neuroleptic malignant syndrome-like events have been reported

with 5-

receptor antagonist antiemetics, including ondansetron hydrochloride, when given in

combination with other serotonergic and/or neuroleptic drugs (see

WARNINGS AND

PRECAUTIONS, Neurologic).

Respiratory, Thoracic and Mediastinal Disorders:

There have also been rare reports of hiccups.

Skin and Subcutaneous Tissue Disorders:

Very rare reports have been received for bullous skin and mucosal reactions, including

fatal

cases. These reports include toxic skin eruptions, such as Stevens-Johnson syndrome and toxic

epidermal necrolysis, and have occurred in patients taking other medications that can be

associated with bullous skin and mucosal reactions.

DRUG INTERACTIONS

Serious Drug Interactions

Apomorphine (see CONTRAINDICATIONS)

Drug-Drug Interactions

Specific studies have shown that there are no pharmacokinetic interactions when

ondansetron is

administered with alcohol, temazepam, furosemide, tramadol or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P

enzymes: CYP3A4, CYP2D6

Page 9 of 29

and CYP1A2. Despite the multiplicity of metabolic enzymes capable of metabolising ondansetron

which can compensate for an increase or decrease in enzyme

activity, it was found that patients

treated with inducers of CYP3A4 (i.e. phenytoin,

carbamazepine, and rifampicin)

demonstrated an increase in oral clearance of ondansetron and a decrease in ondansetron

blood concentrations. No effect in

ondansetron clearance secondary to enzyme inhibition or

reduced activity (e.g. CYP2D6 genetic deficiency) has been identified to date.

QTc-Prolonging Drugs: The concomitant use of ondansetron hydrochloride with another QTc-

prolonging drug should be carefully considered to determine that the therapeutic benefit

outweighs

the potential risk. Drugs that have been associated with QTc interval

prolongation and/or torsade

de pointes include, but are not limited to, the examples in the

following list.

Chemical/pharmacological classes are listed if some, although not

necessarily all, class members

have been implicated in QTc prolongation and/or torsade

de pointes:

Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide);

Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone);

Class 1C antiarrhythmics (e.g., flecainide, propafenone);

antiemetics (e.g., dolasetron, droperidol, chlorpromazine, prochlorperazine);

tyrosine kinase inhibitors (e.g., vandetanib, sunitinib, nilotinib, lapatinib);

antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, ziprasidone);

antidepressants (e.g., citalopram, fluoxetine, venlafaxine, tricyclic/tetracyclic

antidepressants e.g., amitriptyline, imipramine, maprotiline);

opioids (e.g., methadone);

domperidone

macrolide

antibiotics

analogues

(e.g.,

erythromycin,

clarithromycin,

telithromycin, tacrolimus);

quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin);

antimalarials (e.g., quinine, chloroquine);

azole antifungals (e.g., ketoconazole, fluconazole, voriconazole);

histone deacetylase inhibitors (e.g., vorinostat);

beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).

Drugs that Cause Electrolyte Abnormalities: The use of ondansetron hydrochloride with drugs

that can

disrupt electrolyte levels should be avoided. Such drugs include, but not limited to, the

following:

loop, thiazide, and related diuretics;

laxatives and enemas;

amphotericin B;

high dose corticosteroids.

The above lists of potentially interacting drugs are not comprehensive. Current

information

sources should be consulted for newly approved drugs that prolong the QTc

interval or cause

electrolyte disturbances, as well as for older drugs for which these

effects have recently been

established.

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic

effect of

tramadol.

Apomorphine: Based on reports of profound hypotension and loss of consciousness when

ondansetron was administered with apomorphine hydrochloride, concomitant use with

Page 10 of 29

apomorphine is contraindicated (see CONTRAINDICATIONS).

Serotonergic Drugs: As with other serotonergic agents, serotonin syndrome, a

potentially life-

threatening condition, may occur with 5-HT

receptor antagonist

antiemetic treatment when

given in combination with other agents that may affect the

serotonergic neurotransmitter system

[including triptans, SSRIs, SNRIs, lithium,

sibutramine, fentanyl and its analogues,

dextromethorphan, tramadol, tapentadol,

meperidine, methadone and pertazocine or St. John’s

Wort (Hypericum perforatum)] and

with drugs which impair metabolism of serotonin (such as

MAOIs, including linezolid

(an antibiotic which is a reversible non-selective MAOI) and

methylene blue) (see

WARNINGS AND PRECAUTIONS, Neurologic).

DOSAGE AND ADMINISTRATION

Dosing Considerations

Auro-Ondansetron Injection has a dose dependent QTc prolongation effect. For IV

administration, the

effect is expected to be greater with a faster rate of infusion. Using the

minimum

effective dose and a slow rate of infusion should always be favoured.

Recommended Dose And Dosage Adjustment

Chemotherapy Induced Nausea and Vomiting:

Use in Adults:

Highly Emetogenic Chemotherapy (e.g. regimens containing cisplatin)

Initial Dose for Prevention of Emesis during the First 24 h Following Chemotherapy:

Auro-Ondansetron Injection should be given as an initial

dose prior to chemotherapy, followed

by a dosage regimen tailored to the anticipated

severity of emetic response caused by different

cancer treatments. The usual dose is

Auro-Ondansetron Injection 8 mg infused intravenously over

15 minutes given at least 30 minutes prior to

chemotherapy. A maximum initial dose of Auro-

Ondansetron Injection 16 mg IV infused over 15 minutes

may be used. A single IV dose greater

than 16 mg should not be given due to the dose dependent risk of QTc prolongation. The QTc

prolongation effect of Ondansetron Injection IV is also expected to be greater if the drug is

administered rapidly. Do not administer more rapidly

than the recommended 15-minute infusion

(see WARNINGS AND PRECAUTIONS, General, QTc Interval Prolongation; DRUG

INTERACTIONS, Drug-Drug Interactions,

QTc-Prolonging Drugs; ACTIONS AND CLINICAL

PHARMACOLOGY, Electrocardiography).

IV doses greater than 8 mg and up to a maximum of 16 mg must be diluted in 50 mL to

100 mL

of 0.9% Sodium Chloride Injection or 5% Dextrose Injection before

administration and infused

over not less than 15 minutes. IV doses of 8 mg or less do not need to be diluted and may be

administered as an IV injection over 15 minutes.

The efficacy of Auro-Ondansetron Injection in highly emetogenic chemotherapy may be enhanced

by the

addition of a single intravenous dose of dexamethasone sodium phosphate 20 mg

administered prior to chemotherapy.

Post-chemotherapy:

Page 11 of 29

Two additional doses of Auro-Ondansetron Injection 8 mg IV (15-minute infusions) may be given

4 and 8 hours after the initial dose of Auro-Ondansetron Injection.

After the first 24 hours, ondansetron 8 mg may be taken orally every 8 hours

for up to

5 days.

Note: Auro-Ondansetron Injection is only available as a solution for injection.

Less Emetogenic Chemotherapy (e.g. regimens containing cyclophosphamide,

doxorubicin,

epirubicin, fluorouracil and carboplatin)

Initial Dose:

Auro-Ondansetron Injection 8 mg infused intravenously over 15 minutes, given at least 30 minutes

prior to

chemotherapy; or ondansetron 8 mg orally 1 to 2 hours prior to chemotherapy. Note: Auro-

Ondansetron Injection is only available as a solution for injection.

Post-chemotherapy:

Ondansetron 8 mg orally twice daily for up to 5 days.

Note: Auro-Ondansetron Injection is only available as a solution for injection.

Use in Children:

Clinical experience of ondansetron hydrochloride for the treatment of Post-Chemotherapy Induced

Nausea

and Vomiting in children is currently limited, however, ondansetron hydrochloride was

effective and well

tolerated when given to children 4-12 years of age.

Auro-Ondansetron Injection

should be given

intravenously at a dose of 3-5 mg/m

over 15 minutes at least 30 minutes before

chemotherapy. For children 3 years of age and younger, there is insufficient information

available

to make dosage recommendations, therefore, Auro-Ondansetron Injection is not indicated for the

treatment of children 3 years of age or younger (see INDICATIONS AND CLINICAL USE).

Use in Elderly:

IV Formulation:

In patients 65 years of age or older, all IV doses should be diluted in 50 mL to 100 mL of 0.9%

Sodium Chloride Injection or 5% Dextrose Injection.

In patients 65 to 74 years of age, the initial IV dose of Auro-Ondansetron Injection 8 mg or 16 mg,

infused

over 15 minutes, may be followed by two doses of 8 mg infused over 15 minutes and

given no less than 4 hours apart. When the initial dose is 16 mg, there is a predicted

increase

of the risk for a slight QTcF interval prolongation above 10 ms (from baseline)

for about 10 min.

ECG monitoring may be considered.

In patients 75 years of age or older, the initial IV dose of Auro-Ondansetron Injection should not

exceed

8 mg infused over 15 minutes. The initial dose of 8 mg may be followed by two doses of 8

mg, infused over 15 minutes and given no less than 4 hours apart. For the third dose, there is a

predicted increase of the risk for a slight QTcF interval prolongation above

10 ms (from

baseline) for about 10 min. ECG monitoring may be considered.

i The efficacy of twice daily dosage regimens for the treatment of post-chemotherapy emesis has been established only

in adult patients receiving less emetogenic chemotherapy. The appropriateness of twice versus three times daily dosage

regimens for other patient groups should be based on an assessment of the needs and responsiveness of the individual

patient.

Page 12 of 29

Post-Operative Nausea and Vomiting:

Use in Adults:

For prevention of post-operative nausea and vomiting ondansetron may be administered as a single

dose of 16 mg given orally one hour prior to anaesthesia. Note: Auro-Ondansetron Injection is

only available as a solution for injection.

Alternatively, a single

dose of 4 mg, undiluted may be injected intravenously preferably over 2-5

minutes, and

not less than 30 seconds, at induction of anaesthesia.

For the treatment of established post-operative nausea and vomiting, a single dose of 4 mg,

undiluted injected intravenously preferably over 2-5 minutes, and not less than

30 seconds, is

recommended.

Use in Children:

There is no experience in the use of ondansetron hydrochloride in the prevention and treatment of

post- operative nausea and vomiting in children

Auro-Ondansetron Injection

is not indicated for

this use in

children (see INDICATIONS AND CLINICAL USE).

Use in Elderly:

There is limited experience in the use of ondansetron hydrochloride in the prevention and

treatment of post-operative nausea and vomiting in the elderly

Auro-Ondansetron Injection

is not

indicated for this use in the elderly (see INDICATIONS AND CLINICAL USE).

Patients with Renal/Hepatic Impairment:

Use in Patients with Impaired Renal Function:

No alteration of daily dosage, frequency of dosing, or route of administration is required.

Use in Patients with Impaired Hepatic Function:

The clearance of an 8 mg intravenous dose of ondansetron hydrochloride was significantly

reduced and

the serum half-life significantly prolonged in subjects with severe impairment of

hepatic

function. In patients with moderate or severe impairment of hepatic function, reductions

dosage are therefore recommended and a total daily dose of 8 mg should not be

exceeded.

This may be given as a single intravenous or oral dose.

No studies have been conducted to date in patients with jaundice.

Patients with Poor Sparteine/Debrisoquine Metabolism:

The elimination half-life and plasma levels of a single 8 mg intravenous dose of ondansetron did

not differ between subjects classified as poor and extensive metabolisers

of sparteine and

debrisoquine. No alteration of daily dosage or frequency of dosing is

recommended for patients

known to be poor metabolisers of sparteine and debrisoquine.

Administration

Administration of Intravenous Infusion Solutions

Compatibility with Intravenous Solutions:

Auro-Ondansetron Injection should only be mixed with the infusion solutions recommended

below:

Page 13 of 29

Auro-Ondansetron Injection (Preservative-Free - 2 mL and 4 mL Vials):

0.9% w/v Sodium Chloride Injection;

5% w/v Dextrose Injection;

10% w/v Mannitol Injection;

Ringers Injection;

0.3% w/v Potassium Chloride and 0.9% w/v Sodium Chloride Injection;

0.3% w/v Potassium Chloride and 5% w/v Dextrose Injection.

Auro-Ondansetron Injection (Preservative - 20 mL Vials):

5% w/v Dextrose Injection

0.9% w/v Sodium Chloride Injection

5% w/v Dextrose and 0.9% w/v Sodium Chloride Injection

5% w/v Dextrose and 0.45% w/v Sodium Chloride Injection

3% w/v Sodium Chloride Injection

Parenteral drug products should be inspected visually for clarity, particulate matter, precipitate and

discoloration prior to administration, whenever solution and container permit. Solutions showing

haziness, particulate matter, precipitate or discoloration or leakage should not be used. Discard

unused portion.

Compatibility with Other Drugs:

Auro-Ondansetron Injection should not be administered in the same syringe or infusion with any

other medication with the exception of dexamethasone (see below).

The following drugs may be administered via the Y-site of the administration set, for

ondansetron concentrations of 16 to 160 µg/mL. If the concentrations of cytotoxic drugs required

are higher than indicated below, they should be administered through a separate

intravenous line.

Cisplatin - concentrations up to 0.48 mg/mL administered over 1 to 8 hours.

Dexamethasone - admixtures containing 8 mg of ondansetron and 20 mg of dexamethasone

phosphate, in 50 mL of 5% dextrose infusion fluid stored in 50 mL

polyvinyl chloride

infusion bags, have been shown to be physically and chemically stable

for up to two days at room

temperature or up to seven days at 2 – 8 ºC. In addition, these

same admixtures have demonstrated

compatibility with Continu-Flo

administration sets.

In a clinical study (Cunningham et al, 1989) ondansetron (standard dosing regimen) was given to

patients receiving cisplatin or non-cisplatin chemotherapy. Eight patients who continued to

experience nausea and vomiting were given dexamethasone in addition to

ondansetron. In every

case, there was an improvement in the control of emesis and all

patients preferred the combination

of ondansetron and dexamethasone.

5-Fluorouracil - concentrations up to 0.8 mg/mL, administered at rates of at least 20 mL/hour.

Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-fluorouracil

infusion may contain up to 0.045% w/v magnesium chloride.

Carboplatin - concentrations of 0.18 mg/mL - 9.9 mg/mL, administered over

10 – 60 minutes.

Page 14 of 29

Ceftazidime - bolus IV doses, over approximately 5 minutes, of 250 – 2000 mg

reconstituted with Water for Injections BP.

Cyclophosphamide - bolus IV doses over approximately 5 minutes, of 100 – 1000 mg,

reconstituted with Water for Injections BP 5 mL per 100 mg cyclophosphamide.

Doxorubicin and Epirubicin - bolus IV doses, over approximately 5 minutes, of 10-100 mg as a

2 mg/mL solution. Lyophilized powder presentations can be reconstituted with 0.9% Sodium

Chloride Injection USP.

Etoposide - concentrations of 0.144 mg/mL - 0.25 mg/mL, administered over 30 – 60 minutes.

OVERDOSAGE

For management of a suspected drug overdose contact your regional Poison Control Centre

immediately.

At present there is little information concerning over dosage with ondansetron. Individual

doses of

84 mg and 145 mg and total daily doses as large as 252 mg have been

administered with only

mild side effects. There is no specific antidote for ondansetron,

therefore, in cases of suspected

over dosage, symptomatic and supportive therapy should

be given as appropriate.

The use of Ipecac to treat over dosage with ondansetron is not recommended as patients

unlikely to respond due to the antiemetic action of ondansetron itself.

“Sudden blindness” (amaurosis) of 2 to 3 minutes duration plus severe constipation

occurred

in one patient that was administered 72 mg of ondansetron intravenously as a

single dose.

Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron.

Following infusion of 32 mg over only a 4-minute period, a vasovagal

episode with transient

second-degree heart block was observed. Neuromuscular

abnormalities, autonomic instability,

somnolence, and a brief generalized tonic-clonic

seizure (which resolved after a dose of

benzodiazepine) were observed in a 12 months’ old infant who ingested seven or eight 8-mg

ondansetron tablets (approximately forty times the recommended 0.1-0.15 mg/kg dose for a

paediatric patient). In all instances,

the events resolved completely.

Ondansetron prolongs QT interval in a dose-dependent fashion (see ACTION AND

CLINCAL PHARMACOLOGY, Pharmacodynamics). ECG monitoring is recommended

in cases

of overdose.

Cases consistent with serotonin syndrome have been reported in young children

following oral

overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Ondansetron hydrochloride is a selective antagonist of the

serotonin receptor subtype, 5-HT

. Its

precise mode of action in the control of chemotherapy induced nausea and vomiting is not known.

Page 15 of 29

Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin

(5-HT)

from enterochromaffin cells of the small intestine, presumably initiating a

vomiting reflex through

stimulation of 5-HT

receptors located on vagal afferents.

Ondansetron may block the initiation of

this reflex. Activation of vagal afferents may also cause a central release of serotonin from the

chemoreceptor trigger zone of the area

postrema, located on the floor of the fourth ventricle.

Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT

receptors on neurons located in either the peripheral or central nervous systems, or both.

The mechanisms of ondansetron's antiemetic action in post-operative nausea and

vomiting

are not known.

Pharmacodynamics

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

cytochrome P

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 metabolising ondansetron, it is likely that

inhibition or loss of one

enzyme (e.g. CYP2D6 enzyme deficiency) will be compensated

by others and may result in little

change in overall rates of ondansetron clearance.

Electrocardiography

The effect of ondansetron on the QTc interval was evaluated in a double blind,

randomized,

placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and

women. Ondansetron was tested at single doses of 8 mg and 32 mg infused intravenously over 15

minutes. At the highest tested dose of 32 mg, prolongation

of the Fridericia-corrected QTc interval

(QT/RR

0.33

=QTcF) was observed from 15 min to

4 h after the start of the 15 min infusion, with a

maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction

of 19.6 (21.5) msec at 20 min. At the lower tested dose of 8 mg, QTc prolongation was observed

from 15 min to 1h after the start of the 15 minute infusion, with a maximum mean (upper limit of

90% CI) difference in QTcF from placebo after baseline-correction of 5.8 (7.8) msec at 15 min.

The magnitude of QTc prolongation with ondansetron is expected to be greater if the

infusion

rate is faster than 15 minutes. The 32 mg intravenous dose of ondansetron must

not be

administered.

No treatment-related effects on the QRS duration or the PR interval were observed at

either the

8 or 32 mg dose.

Page 16 of 29

LS Mean Difference (90% CI) in QTcF Interval Between Treatment and Placebo

Over Time

An ECG assessment study has not been performed for orally administered ondansetron. On the basis

of pharmacokinetic-pharmacodynamic modelling, an 8 mg oral dose of ondansetron is predicted to

cause a mean QTcF increase of 0.7 ms (90% CI -2.1, 3.3) at

steady-state, assuming a mean

maximal plasma concentration of 24.7 ng/mL (95% CI 21.1, 29.0).

The magnitude of QTc prolongation at the recommended 5 mg/m

dose in paediatrics has not been

studied, but pharmacokinetic-pharmacodynamic modelling predicts a mean increase of 6.6 ms

(90% CI 2.8, 10.7) at maximal plasma concentrations.

Pharmacokinetics

Pharmacokinetic studies in human volunteers showed peak plasma levels of 20-30 ng/mL

at around

1½ hours after an 8 mg oral dose of ondansetron. An 8 mg infusion of ondansetron resulted in

peak plasma levels of 80-100 ng/mL. Repeat dosing of an 8 mg tablet every 8 hours for 6 days

increased the peak plasma value to 40 ng/mL. A continuous intravenous infusion of 1 mg/hour

after the initial 8 mg loading dose of ondansetron maintained plasma levels over 30 ng/mL

during the following 24-hour period.

The absolute bioavailability of ondansetron in humans was approximately 60% and the

plasma

protein binding was approximately 73%.

Following oral or IV administration, ondansetron is extensively metabolised and excreted

in the

urine and faeces. In humans, less than 10% of the dose is excreted unchanged in

the urine. The

major urinary metabolites are glucuronide conjugates (45%), sulphate

conjugates (20%) and

hydroxylation products (10%).

The half-life of ondansetron after either an 8 mg oral dose or intravenous dose was

approximately 3-4 hours and may be extended to 6-8 hours in the elderly.

Mean plasma concentration-time curves for ondansetron following 8 mg and 32 mg dose are shown

Page 17 of 29

below:

Mean Plasma Concentration-Time Curve for Ondansetron 8mg and 32 mg IV doses

In a pharmacokinetic study of 16 epileptic patients maintained chronically on carbamazepine

or phenytoin, reduction in AUC, C

and T

of ondansetron was observed. This resulted in a

significant increase in clearance. However, on the basis of the inter-subject variability in the

available data, no dosage adjustment can be

recommended (see DRUG INTERACTIONS –

Drug-Drug Interactions).

Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in

clearance,

and an increase in half-life of ondansetron. However, wide inter-subject

variability resulted in

considerable overlap in pharmacokinetic parameters between

young (< 65 years of age) and

elderly subjects (≥ 65 years of age) and there were no overall differences in safety or efficacy

observed between young and elderly cancer

patients enrolled in CINV clinical trials. (See

DOSAGE AND ADMINISTRATION, Use in Elderly)

Based on more recent ondansetron plasma concentrations and exposure-response

modelling, a

Page 18 of 29

greater effect on QTcF is predicted in patients ≥75 years of age compared to

young adults. Specific

dosing information is provided for patients over 65 years of age

and over 75 years of age for

intravenous dosing. (See DOSAGE AND ADMINISTRATION, Use in Elderly)

STORAGE AND STABILITY

Sterile Solution for Intravenous Injection:

Store at Controlled Room Temperature 15 to 30°C. Do not freeze. Protect from light.

Stability and Storage of Diluted Solutions:

Compatibility studies have been undertaken in polyvinyl chloride infusion bags, polyvinyl chloride

administration sets and polypropylene syringes. Dilutions of ondansetron in sodium chloride 0.9%

w/v or in dextrose 5% w/v have been demonstrated to be stable in polypropylene syringes. It is

considered that ondansetron injection diluted with other compatible infusion fluids (10% w/v

Mannitol Injection; Ringers Injections: 0.3% w/v Potassium Chloride and 0.9% w/v Sodium

Chloride Injection; 0.3% w/v Potassium Chloride and 5% w/v Dextrose Injection) would be stable

in polypropylene syringes. Intravenous solutions should be prepared at the time of infusion.

Auro-Ondansetron Injection, in vials when diluted with the recommended intravenous solutions,

should be used within 24 hours if stored at room temperature 15 to 30°C or used within 72 hours if

stored in a refrigerator 2 to 8°C, due to possible microbial contamination during preparation.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage form

Solution

Strength

4 mg / 2 mL (2 mg / mL),

8 mg / 4 mL (2 mg / mL)

40 mg / 20 mL (2 mg / mL)

Label Claim

Each ml contains 2 mg Ondansetron as Ondansetron hydrochloride dihydrate

Description

Clear, colourless solution filled in clear glass vials.

Composition

Non-medicinal Ingredients:

Citric acid monohydrate, sodium

chloride, sodium citrate (dihydrate),

nitrogen and water for injection.

Non-medicinal Ingredients:

Citric acid monohydrate, sodium chloride, sodium

citrate (dihydrate), nitrogen and water for injection.

Preservatives: Methyl paraben and Propyl

Paraben.

Packaging

2 mg / mL (as hydrochloride dihydrate) for intravenous use is supplied in 2 mL and 4 mL

preservative free single dose glass vials and 20 mL preservative containing multi dose glass

vials.

4 mg / 2 ml: vial of 2 mL in carton of

10 vials each.

8 mg/4 ml: vial of 5 mL in carton of 5

vials each

40 mg / 20 ml: vial of 20 mL in carton of 1 vial

each.

Page 19 of 29

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Ondansetron Hydrochloride

Chemical name:

(3RS)-9-Methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl]-

1,2,3,9-tetrahydro-4H-carbazol- 4-one hydrochloride dihydrate

Molecular formula: C

O, 2H

Molecular mass:

365.9 g/mol

Structural formula:

Physicochemical properties:

Description and Solubility:

Ondansetron hydrochloride dihydrate is a white or almost powder. It is sparingly soluble in

water and in ethanol (96%), soluble in methanol, slightly soluble in methylene chloride.

The melting point of ondansetron hydrochloride dihydrate is about 178.5 to 179.5°C.

Dissociation constant (pKa) is 7.4.

Page 20 of 29

CLINICAL TRIALS

Study results

Clinical trial results showing the number and percentage of patients exhibiting a complete

response to ondansetron (0 emetic episodes) are shown in the tables below for both post-

operative and chemotherapy induced emesis.

Prevention of Chemotherapy Induced Emesis - Response Over 24 Hours

Dose

Ondansetron

hydrochloride*

3 doses of

0.15 mg/kg

Placebo*

3 doses of

placebo

Ondansetron

hydrochloride

8 mg IV +

1 mg/hr,

24 hours

Ondansetron

hydrochloride

8 mg IV

Ondansetron

hydrochloride

32 mg IV

# of patients

Treatment Response

0 emetic episodes

1-2 emetic episodes

2 (14%)

8 (57%)

0 (0%)

0 (0%)

92 (55%)

82 (54%)

97 (56%)

*Results are from an initial study using a different dosing regimen.

Prevention of Post-Operative Emesis – Response Over 24 Hours*

Oral Prevention

Intravenous Prevention

Dose

Ondansetron

hydrochloride

16 mg od

Placebo

p value

Ondansetron

hydrochloride

4 mg IV

Placebo

p value

# of patients

Treatment

Response

0 emetic episodes

126 (50%)

79 (32%)

< 0.001

103 (76%)

62 (46%)

< 0.001

The majority of patients included in the prevention and treatment of post-operative nausea and vomiting studies using

ondansetron hydrochloride have been adult women receiving balanced anaesthesia for gynaecological surgery.

Treatment of Post-Operative Emesis – Response Over 24 Hours

*

Intravenous Treatment

Dose

Ondansetron

hydrochloride

4 mg IV

Placebo

p value

# of patients

Treatment Response

0 emetic episodes

49 (47%)

19 (16%)

< 0.001

The majority of patients included in the prevention and treatment of post-operative nausea and vomiting studies

using ondansetron hydrochloride have been adult women receiving balanced anaesthesia for gynaecological surgery.

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamics:

The ferret provides an excellent model for demonstrating the antiemetic action of drugs. Emesis

can be induced by antineoplastic drugs or whole body irradiation. Behavioural

changes

associated with these treatments are noted in these animals and may also provide

a parallel for the

human experience of nausea.

Page 21 of 29

The antiemetic action of ondansetron has been evaluated in both male and female ferrets

given

cisplatin (9-10 mg/kg), cyclophosphamide (200 mg/kg) or irradiation (2 and 8 Gy, 250 kV).

Intravenous doses of ondansetron (0.1-1 mg/kg) abolished cisplatin-induced

emesis for up to 2

hours. In cyclophosphamide-induced emesis, subcutaneous doses of

0.5 mg/kg ondansetron completely eliminated vomiting, significantly reduced retching

delayed the onset of these responses.

The radiation-induced emesis, 0.5 mg/kg ondansetron alone completely and rapidly

eliminated

retching and vomiting.

The antiemetic effects of ondansetron (0.1 mg/kg) in combination with dexamethasone

(2-5

mg/kg) were potentiated in ferrets with cyclophosphamide-induced emesis, compared

with ondansetron alone. Ondansetron with dexamethasone produced a

significant reduction in

retching (65%) and vomiting (72%).

Serotonin receptors of the 5-HT

type are present both peripherally and on vagal nerve

terminals.

Ondansetron probably acts by preventing activation of these receptors or receptors located in

other regions of the central nervous system. Both the peripheral and

central nervous systems

appear to be involved since both abdominal vagotomy and

microinjection of ondansetron and

other 5-HT

antagonists directly into the area postrema

eliminate cisplatin-induced emesis, while

5-HT

-like (methiothepin maleate) and 5-HT

(ketanserin) antagonists have no effect.

Ondansetron is highly selective for 5-HT

receptors and shows negligible binding to other

receptors

such as 5-HT

-like, 5-HT

, α1 and α2 adrenoceptors, β1 and β2 adrenoceptors,

and D

muscarinic, nicotinic, GABA

and H

receptors.

The pharmacological specificity of ondansetron may explain the observed lack of extrapyramidal

side effects often seen following similar therapy with metoclopramide,

which preferentially

binds to dopamine receptors of the D

subtype.

Among its secondary effects, ondansetron has also been shown to cause a dose-dependent

increase

in the rate of gastric emptying in the guinea pig, which is significant at doses of 0.01-0.1 mg/kg.

As gastric stasis is frequently associated with nausea, stimulation of gastric motility may be a

beneficial action of ondansetron. In the cat, dog and monkey, ondansetron has little effect on

heart rate, blood pressure or ECG at intravenous doses up to 3 mg/kg.

A study in cloned human cardiac ion channels has shown ondansetron has the potential to

affect

cardiac repolarisation via blockade of hERG potassium channels at clinically

relevant

concentrations. Dose-dependent QT prolongation has been observed in a

thorough QT study in

human volunteers (see ACTION AND CLINICAL PHARMACOLOGY - Pharmacodynamics –

Electrocardiography).

Pharmacokinetics:

In mice, rats, rabbits and dogs dosed at 1 mg/kg orally and/or intravenously, the plasma

half-life

of ondansetron was less than 1 hour, but the half-lives of its metabolites were

significantly

longer. Peak plasma concentrations of ondansetron in rats and dogs ranged

from 351 to 419

ng/mL for the IV dose and 8 to 15 ng/mL for the oral dose. Plasma

levels were linear over a

30-fold dose range. In repeat-dose studies there was no apparent

accumulation of ondansetron.

Page 22 of 29

Ondansetron is almost completely absorbed in animals, and is rapidly metabolized by N-

demethylation and hydroxylation of the indole ring, followed by conjugation with

glucuronic acid

and sulphate. There is significant first-pass metabolism after oral doses.

Ondansetron and its metabolites are rapidly and widely distributed in tissues, reaching

higher

levels than the corresponding plasma levels. In the rat and dog, ondansetron binds

reversibly to

tissues containing melanin and elastin. In rats and man, plasma protein

binding is about 73%,

while it is slightly lower in the dog (60%). Ondansetron and its

metabolites cross the blood-brain

barrier to only a slight extent.

Human Pharmacology

Pharmacodynamics:

In vivo pharmacodynamic studies have investigated the effects of ondansetron on gastric

emptying,

small bowel transit time and oesophageal motility.

Both oral (16 mg tid) and intravenous (5-10 mg) doses of ondansetron failed to produce a

significant effect on gastric emptying in both healthy volunteers and in patients suffering from

delayed gastric emptying. However, in one study intravenous doses of 8 mg did

increase gastric

emptying in over half the volunteers tested.

Intravenous infusion of either 1 mg or 5 mg ondansetron tended to increase small bowel

transit

times and single intravenous doses of 10 mg ondansetron have been reported to

decrease

sphincter pressure in the lower oesophagus in some subjects.

In psychomotor testing ondansetron does not impair performance nor cause sedation.

MICROBIOLOGY

Not applicable.

TOXICOLOGY

Acute Toxicity

Single doses of ondansetron up to the LD

in mice and in rats were generally well

tolerated.

Reactions, including tremor and convulsive behaviour, occurred only at near

lethal levels.

Species

LD

50

(mg/kg)

Mice Rats

Oral

IV

10-30

100-150

1.0-2.5

15-20

All deaths resulted from the acute effects of treatment, the observed clinical signs being

consistent

with the central nervous system effects associated with behavioural depression.

These effects were

not associated with any apparent histopathological changes in the

brain. No target organ toxicity

was identified.

Page 23 of 29

Long term Toxicity

Subacute Toxicity Studies

Species

Route

Dose

(mg/kg/day)

Duration

of

Study

Results

Rats

Dogs

Oral

Oral

7.5-25

7 weeks

5 weeks

5 weeks

5 weeks

Well tolerated

Well tolerated

Transient post-dosing clinical reactions associated

with behavioural depression (at highest dose levels)

Maximum daily dose levels in rats were found to be higher when doses were gradually

increased. Identical doses were rapidly lethal to rats not previously exposed to

ondansetron.

Post-dosing reactions, in both rats and dogs, included ataxia, exophthalmia,

mydriasis, tremor and

respiratory changes. Increases in liver enzymes (SGPT and SGOT) were noted at high dose

levels. Dogs dosed at 6.75 mg/kg/day intravenously exhibited

vein irritancy in the form of

constriction and thickening, creating resistance to needle

penetration. The changes were noted

after seven days treatment but were reversed by decreasing the dose concentration.

Chronic Toxicity

Species

Duration

Max. no-effect Dose

(mg/kg/day)

Effects

18 months

12 months

Usually transient and restricted to highest dose

Carcinogenicity Studies

Species

Route

Dose

(mg/kg/day)

Duration

of Study

Results

Mice

Rats

Oral

Oral

1-40 (max.

oral dose 30)

1-25

(max. oral

dose 10)

2 years

2 years

No treatment related increases in tumour incidence.

Proportion of benign/malignant tumours also

remained Consistent with the pathological

background of the Animals studied.

There was no evidence of a tumourigenic effect of ondansetron in any tissue.

Mutagenicity Studies

No evidence of mutagenicity was observed in microbial mutagen tests using mutant

strains of

Salmonella typhimurium, Escherichia coli or Saccharomyces cerevisiae, with

or without a rat-

liver post-mitochondrial metabolizing system.

There was also no evidence of damage to genetic material noted in in vitro V-79 mammalian cell

mutation studies, in vitro chromosome aberration tests using human peripheral lymphocytes, or

in vivo chromosome aberration assays in mouse bone marrow.

Page 24 of 29

Reproduction and Teratology

Ondansetron was not teratogenic in rats and rabbits at dosages up to the maximum non-

convulsive level, (rat: 15 mg/kg/day, rabbit: 30 mg/kg/day; the maternal dose was approximately

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

on body surface area). No adverse effects on pregnancy or foetal and post-natal development

were detected in rats and no foetal abnormalities were

observed in rabbits after oral administration

of ondansetron.

A slight maternal toxicity was observed at the highest dose level in intravenous

organogenesis

(4.0 mg/kg/day) studies in the rabbit. Effects included maternal body weight loss and increased

incidence of early foetal death. In a rat fertility study, there was a dose-related decrease in the

proportion of surviving pups of the F2 generation;

however, the significance of this is unclear.

Administration of ondansetron to pregnant rats and rabbits indicated there was foetal

exposure

to low levels of ondansetron and its metabolites. Ondansetron is retained in the

foetal eye

presumably bound to melanin. In rats, the transfer of ondansetron and its

metabolites into

breast milk was extensive. The concentration of unchanged ondansetron

in breast milk was higher

than in corresponding plasma samples.

Daily administration of ondansetron at dosages up to 15 mg/kg/day to pregnant rats (a

maternal

dose of approximately 6 times the maximum recommended human oral dose of 24 mg/day, based

on body surface area) from day 17 of pregnancy to litter day 22 had no effects on pregnancy of the

parental generation or on post-natal development and mating

of the F1 generation. Foetal

development of the F2 generation was comparable to

controls; however, the number of

implantations and viable foetuses was reduced in the

highest dosage group when compared with

controls.

Page 25 of 29

REFERENCES

Blackwell CP, Harding SM. The clinical pharmacology of ondansetron. Eur J

Cancer Clin Oncol 1989; 25(Suppl. 1):S21-S24.

Bowman A, Allan SG, Warrington PS, Whelan JM, Smyth JM. Clinical trials and

pharmacokinetics of ZOFRAN

, a new antiemetic effective against platinum-

induced vomiting. Proceedings of the European Conference of Clinical

Oncologists 1987; 1063.

Butler A, Hill JM, Ireland SJ, Jordan CC, Tyers MB. Pharmacological properties

ZOFRAN

, a novel antagonist of 5-HT

receptors. Br J Pharmacol 1988;

94:397-

412.

Costall B, Naylor RJ, Tyers MB. Recent advances in the neuropharmacology of 5-

agonists and antagonists. Reviews in Neurosciences 1988; 2:41-65.

Craig JB, Powell BL: Review. The management of nausea and vomiting in

clinical

oncology. Am J Med Sci 1987; 293:34-44.

Cunningham D, Hawthorn J, Pople A, Gazet J-C, Ford HT, Challoner T,

Coombes RC. Prevention of emesis in patients receiving cytotoxic drugs by

ZOFRAN

, a selective 5-HT

receptor antagonist. Lancet 1987; i:1461-1463.

Cunningham D, Turner A, Hawthorn J, Rosin RD. Ondansetron with and without

dexamethasone to treat chemotherapy-induced emesis. Lancet 1989; i:1323.

Green JA, Watkin SW, Hammond P, Griggs J, Challoner T. The efficacy and

safety

of ZOFRAN

in the prophylaxis of ifosfamide-induced nausea and

vomiting.

Cancer Chemother Pharmacol 1989; 24:137-139.

Hawthorn J, Cunningham D. Dexamethasone can potentiate the anti-emetic

action of a

receptor antagonist on cyclophosphamide induced vomiting in

the ferret. Br J

Cancer 1990; 61(1):56-60.

Higgins GA, Kilpatrick GT, Bunce KT, Jones BJ, Tyers MB. 5-HT

antagonists

injected into the area postrema inhibit cisplatin-induced emesis in the ferret. Br J

Pharmacol 1989; 97:247-255.

Kris MG, Gralla RJ, Clark RA, Tyson LB. Dose-ranging evaluation of serotonin

antagonist GR-507/75 (ZOFRAN

) when used as an anti-emetic in patients

receiving

anti-cancer chemotherapy. J Clin Oncol 1988; 6:659-662.

Kris MG, Gralla RJ, Clark RA, Tyson LB. Phase II trials of the serotonin

antagonist GR38032F for the control of vomiting caused by cisplatin. J Natl

Cancer Inst 1989; 81(1):42-46.

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Marty M, Droz JP, Pouillart P, Paule B, Brion N, Bons J. ZOFRAN

, a 5-HT

receptor antagonist, in the prophylaxis of acute cisplatin-induced nausea and

vomiting. Cancer Chemother Pharmacol 1989; 23:389-391.

Priestman T, Challoner T, Butcher M, Priestman S. Control of radiation-induced

emesis with ZOFRAN

. Proc Am Soc Clin Oncol 1988; 7:1089.

Priestman TJ. Clinical studies with ondansetron in the control of radiation-

induced emesis. Eur J Cancer Clin Oncol 1989; 25(Suppl):S29-S33.

Schmoll HJ. The role of ondansetron in the treatment of emesis induced by non-

cisplatin-containing chemotherapy regimens. Eur J Cancer Clin Oncol 1989;

25(Suppl. 1):S35-S39.

Smith DB, Newlands ES, Spruyt OW, Begent RHJ, Rustin GJS, Mellor B,

Bagshawe KD. Ondansetron plus dexamethasone: Effective anti-emetic

prophylaxis

for patients receiving cytotoxic chemotherapy. Br J Cancer 1990;

61(2):323-324.

Stables R, Andrews PLR, Bailey HE, Costall B, Gunning SJ, Hawthorn J, Naylor

Tyers MB. Antiemetic properties of the 5HT

-receptor antagonist

ZOFRAN

. Cancer

Treatment Rev. 1987; 14:333-336.

Tyers MB, Bunce KT, Humphrey PPA. Pharmacological and anti-emetic

properties

of ondansetron. Eur J Cancer Clin Oncol 1989; 25(Suppl. 1):S15-S19.

Van Liessum P, de Mulder P, Kaasa S, Lane-Allman E, Seynaeve C, Verwij J:

ZOFRAN

in the prophylaxis of nausea and vomiting induced by cisplatin. Proc

European Soc Clin Oncol 1988; 13:267.

Zofran

(ondansetron hydrochloride dihydrate)

Injection 2 mg/mL Control Number:

221541. Product Monograph. Novartis Pharmaceuticals Canada Inc.; Date of Revision:

January 8, 2019.

IMPORTANT: PLEASE READ

Page 27 of 29

PART III: CONSUMER INFORMATION

Pr

Auro-Ondansetron Injection

Ondansetron Injection BP

Ondansetron (as ondansetron hydrochloride

dihydrate)

Sterile Solution for Intravenous Injection

2 mg / mL

This leaflet is part III of a three-part "Product

Monograph" published when Auro-Ondansetron

Injection (ondansetron hydrochloride dihydrate) was

approved for sale in Canada and is designed

specifically for Consumers. This leaflet is a

summary and will not tell you everything about

Auro-Ondansetron Injection. Contact your doctor or

pharmacist if you have any questions about the drug

ABOUT THIS MEDICATION

What the medication is used for:

The name of your medicine is Auro-Ondansetron

Injection (ondansetron hydrochloride dihydrate). This

medicine is one of a group called antiemetics.

Auro-Ondansetron Injection is used for:

the prevention of nausea (feeling of sickness)

and vomiting during treatment for cancer

(chemotherapy and radiotherapy).

the prevention and treatment of nausea and

vomiting after surgery.

What it does:

Treatments such as general anaesthesia, cancer

chemotherapy and radiotherapy are thought to cause

the release of a natural substance (serotonin), which

can cause you to feel sick and to vomit. Auro-

Ondansetron Injection helps to stop this from

happening, thus preventing you from vomiting or

feeling sick.

When it should not be used:

Do not take Auro-Ondansetron Injection if:

you have a history of hypersensitivity (an

allergic reaction) to any ingredient in Auro-

Ondansetron Injection.

you are taking apomorphine (used to treat

Parkinson’s disease).

What the medicinal ingredient is:

Auro-Ondansetron Injection contains ondansetron (as

ondansetron hydrochloride dihydrate) as the medicinal

ingredient.

What the nonmedicinal ingredients are:

Auro-Ondansetron Injection may contain the

following nonmedicinal ingredients:

For 4 mg / 2mL and 8 mg / 4mL: citric acid

monohydrate, sodium chloride, sodium citrate

(dihydrate), nitrogen and water for injection.

For 40 mg / 20 mL: citric acid monohydrate, sodium

chloride, sodium citrate (dihydrate), methyl paraben (as

preservative), propyl paraben (as preservative),

nitrogen and water for injection.

What dosage forms it comes in:

Auro-Ondansetron Injection is available as ondansetron

2 mg / mL (as ondansetron hydrochloride dihydrate) for

intravenous use.

WARNINGS AND PRECAUTIONS

Auro-Ondansetron Injection is not recommended for

use during pregnancy.

Breastfeeding is not recommended during treatment with

Auro-Ondansetron Injection. The ingredients can pass

into your breast milk and may affect your baby.

Auro-Ondansetron Injection may harm your unborn

baby. If you are a woman of childbearing age, your

doctor or healthcare provider will check if you are

pregnant and perform a pregnancy test if necessary

before starting treatment with Auro-Ondansetron

Injection. You should use effective birth control

during treatment with Auro-Ondansetron Injection.

Ask your doctor about options of effective birth

control.

BEFORE you use Auro-Ondansetron Injection talk

to your doctor or pharmacist if:

you have a history of hypersensitivity (an

allergic reaction) to any ingredient in Auro-

Ondansetron Injection.

you have had an allergic reaction to medicines

similar to Auro-Ondansetron Injection, such as

medicines containing granisetron or palonosetron.

you are pregnant or likely to become pregnant.

you are breast feeding .

you have liver problems.

you have signs of intestinal obstruction.

you have a history of heart problems.

you have QT/QTc prolongation or a family

history of QT/QTc prolongation

you have low blood levels of potassium,

magnesium, or calcium

If you experience wheezing and tightness of the

chest, heart throbbing, swelling of eyelids, face or

lips, or develop a skin rash, skin lumps or hives, tell

your doctor immediately.

IMPORTANT: PLEASE READ

Page 28 of 29

When given intravenously, Auro-Ondansetron

Injection has an effect on the electrical activity of

the heart known as QT/QTc prolongation. This

effect can be measured as a change in the

electrocardiogram (ECG). In very rare cases, drugs

with this effect on the ECG can lead to disturbances

in heart rhythm (arrhythmias/dysrhythmias) that

could result in dizziness, palpitations (sensation of

rapid, pounding, or irregular heart beat), fainting or

death. These heart rhythm disturbances are more

likely in patients with risk factors, such as heart

disease, or in the presence of certain interacting

drugs. In general, females and people more than 65

years in age are at higher risk. It is important to

follow the instructions of your doctor with regard to

dosing or any special tests. If you experience any

symptoms of a possible heart rhythm disturbance,

such as dizziness, palpitations (sensation of rapid,

pounding, or irregular heartbeat), or fainting, you

should seek immediate medical attention.

Serotonin Syndrome is a rare but potentially life-

threatening reaction that may occur if you take

Auro-Ondansetron Injection with certain other

medications. It may cause serious changes in how

your brain, muscles and digestive system work. Be

sure to tell your healthcare professional all the

medicines you are taking

INTERACTIONS WITH THIS MEDICATION

As with most medicines, interactions with other

drugs are possible. To avoid potentially life-

threatening reactions tell your healthcare

professional about ALL the medications you take,

including those prescribed by other doctors,

vitamins, minerals, natural supplements or

alternative medicines. It is important that your

doctor know about all your medication so that you

get the best possible treatment. Tell your doctor if

you are taking carbamazepine, phenytoin, or

rifampicin. If you are taking any medicines

containing tramadol, Auro-Ondansetron Injection

may decrease its effectiveness.

Also, make sure you tell your doctor or pharmacist

if you are taking:

Drugs used to treat heart rhythm disorders

Other drugs that may disturb heart rhythm

Antipsychotics

Antidepressants

Antibiotics or antifungals

Opioid analgesics (painkillers)

Other drugs to treat nausea and vomiting

Asthma drugs

Cancer drugs

Diuretics

Other drugs that affect serotonin including

SSRI*s, SNRI**s, triptans, MAOIs***

(including the antibiotic linezolid and

methylene blue), drugs that contain

tryptophan, or St. John’s Wort.

*SSRI (Selective Serotonin-Reuptake Inhibitors) –

used to treat depression or anxiety, e.g. escitalopram,

citalopram, fluoxetine, paroxetine, sertraline.

**SNRI (Serotonin Noradrenalin Reuptake

Inhibitors) – used to treat depression or anxiety, e.g.

duloxetine, venlafaxine, desvenlafaxine.

***MAOIs (Monoamine Oxidase Inhibitors) – used

to treat depression, Parkinson’s disease, e.g.,

phenelzine, rasagiline, selegiline.

PROPER USE OF THIS MEDICATION

Auro-Ondansetron Injection is not self-administered

by individual. It should be administered under the

supervision of a health professional.

The solution must be inspected before use. Be sure the

liquid is clear. Do NOT use if the solution is hazy, has

particles or solids, is discoloured or leaking.

Usual dose:

Chemotherapy Induced Nausea and Vomiting

You will receive Auro-Ondansetron Injection by

intravenous infusion. Based on how likely you are to

experience nausea and /or vomiting, caused by your

cancer treatment, your doctor will determine the

appropriate dose regimen for you.

Adult: The single IV dose of Auro-Ondansetron

Injection is between 8 and 16 mg before your

chemotherapy.

Children (4 to 12 years): The dose is 3 to 5 mg/m

just before chemotherapy.

Post-Operative Nausea and Vomiting

Adult: For prevention of post-operative nausea and

vomiting, the dose is 4 mg at the time of surgery. For

treating postoperative nausea and vomiting, the dose

is 4 mg after surgery. If you have a liver problem,

your dose may be altered.

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

You may experience headaches, a feeling of

warmness, flushing or constipation, while taking

Auro-Ondansetron Injection. You may also

experience pain, redness and burning sensation at the

injection site.

IMPORTANT: PLEASE READ

Page 29 of 29

Although uncommon, low blood pressure and hiccups

have also been reported.

If your nausea (feeling of sickness) or vomiting do

not improve while taking Auro-Ondansetron

Injection, consult your doctor for further advice.

If you feel unwell or have any symptoms that you do

not understand, tell your doctor immediately.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN

AND WHAT TO DO ABOUT THEM

Frequency

Side Effect/

Symptom

Talk with your

Doctor

Immediately

Uncommon

Heart problems such as fast/slow

heartbeat, chest pain

Seizures

Upward rolling of the eyes,

abnormal muscular stiffness /

body movements / shaking

Rare

Eye problems such as blurred

vision

Immediate allergic reaction and

symptoms such as swelling of

the mouth, throat, difficulty in

breathing, rash, hives, increased

heart rate

Disturbance in heart rhythm

(dizziness, palpitations, fainting)

Serotonin Syndrome:

Symptoms of Serotonin

Syndrome have been observed

while taking Ondansetron

Injection with certain other

medications.

Symptoms include:

agitation, confusion,

restlessness, hallucinations,

mood changes, unconsciousness,

coma

fast heartbeat, changes in blood

pressure

Muscle shakes, jerks, twitches

or stiffness, overactive reflexes,

loss of coordination

nausea, vomiting, diarrhoea,

fever, sweating, shivering

Very Rare

Eye problems such as temporary

Blindness

Signs of serious skin reactions

(skin rash, redness of the skin,

blistering of the lips, eyes or

mouth, and skin peeling)

This is not a complete list of side effects. For any

unexpected effects while taking Auro-Ondansetron

Injection, contact your doctor.

HOW TO STORE IT

Sterile solution for Intravenous Injection:

Store at Controlled Room Temperature 15 to 30°C. Do

not freeze. Protect from light.

Diluted Solutions:

Up to 24 hours at room temperature or 72 hours refrigerated

at 2 to 8 °C.

Reporting Side Effects

You can report any suspected side effects associated with the

use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/health-canada/services/drugs-

health-products/medeffect-canada/adverse-reaction-

reporting.html) for information on how to report online,

by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical advice

MORE INFORMATION

If you want more information about Auro-Ondansetron

Injection:

Talk to your healthcare professional

Find the full product monograph that is prepared for

healthcare professionals and includes this Consumer

Information by visiting the Health Canada website

(https://health-products.canada.ca/dpd-bdpp/index-

eng.jsp); the manufacturer’s website

http://www.auropharma.ca, or by calling 1-855-648-

6681.

This leaflet was prepared by

Auro Pharma Inc.

3700 Steeles Avenue West, Suite # 402

Woodbridge, Ontario, L4L 8K8,

Canada.

Date of Preparation: August 13, 2019

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