ZOFRAN INJECTION 2MGML

Israel - English - Ministry of Health

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Active ingredient:
ONDANSETRON AS HYDROCHLORIDE DIHYDRATE
Available from:
NOVARTIS ISRAEL LTD
ATC code:
A04AA01
Pharmaceutical form:
SOLUTION FOR INJECTION
Composition:
ONDANSETRON AS HYDROCHLORIDE DIHYDRATE 2 MG/ML
Administration route:
I.M, I.V
Prescription type:
Required
Manufactured by:
GLAXO SMITHKLINE MANUFACTURING S.P.A., ITALY
Therapeutic group:
ONDANSETRON
Therapeutic area:
ONDANSETRON
Therapeutic indications:
Adults:Zofran is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy. Zofran is indicated for the prevention and treatment of post-operative nausea and vomiting (PONV). Paediatric Population:Zofran is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged ≥6 months, and for the prevention and treatment of PONV in children aged ≥ 1 month.
Authorization number:
049 94 26548 05
Authorization date:
2013-06-30

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

06.2015

םושירה רפסמו תילגנאב רישכת םש

Zofran Injection 2mg/ml )049-94-26548(

םושירה לעב םש

GlaxoSmithKline )ISRAEL( Ltd

:

! דבלב תורמחהה טורפל דעוימ הז ספוט אפורל ןולעב אפורל ןולעב תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Special

Warnings

and

Precautions

for Use

There have been post-marketing reports describing

patients with serotonin syndrome (including altered

mental

status,

autonomic

instability

neuromuscular

abnormalities)

following

concomitant

ondansetron

other

serotonergic drugs (including selective serotonin

reuptake

inhibitors

(SSRI)

serotonin

noradrenaline

reuptake

inhibitors

(SNRIs)).

concomitant treatment with ondansetron and other

serotonergic

drugs

clinically

warranted,

appropriate observation of the patient is advised.

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 ZOFRAN 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.

Interactions

with other

Medicaments

and other

forms of

Interaction

.Caution should be exercised when ondansetron is

coadministered with drugs that prolong the QT

interval and/or cause electrolyte abnormalities. (see

section 4.4)

Use of ondansetron with QT prolonging drugs may

result in additional QT prolongation. Concomitant

use of ondansetron with cardiotoxic drugs (e.g.

anthracyclines such as doxorubicin, daunorubicin or

trastuzimab), antibiotics (such as erythromycin or

ketoconazole), antiarrhythmics (such as amiodarone)

and beta blockers (such as atenolol or timolol) may

increase the risk of arrhythmias. (See Special

warnings and precautions for use)

Caution should be exercised when ondansetron is

coadministered with drugs that prolong the QT interval

and/or cause electrolyte abnormalities. (see section 4.4)

Use of ondansetron with QT prolonging drugs may

result in additional QT prolongation. Concomitant use

of ondansetron with cardiotoxic drugs (e.g.

anthracyclines (such as doxorubicin, daunorubicin) or

trastuzumab), antibiotics (such as erythromycin),

antifungals (such as ketoconazole), antiarrhythmics

(such as amiodarone) and beta blockers (such as

atenolol or timolol) may increase the risk of

arrhythmias. (See Special warnings and precautions for

section 4.4).

Undesirable

Effects

-

Additional data from post marketing experience

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.

General

Flushing. Rare cases of hypersensitivity reactions,

sometimes severe (e.g., anaphylactic reactions,

angioedema, bronchospasm, cardiopulmonary arrest,

hypotension, laryngeal edema, laryngospasm, shock,

shortness of breath, stridor) have also been reported. A

positive lymphocyte transformation test to ondansetron

has been reported, which suggests immunologic

sensitivity to ondansetron.

Hepatobiliary

Liver enzyme abnormalities have been reported. Liver

failure and death have been reported in patients with

cancer receiving concurrent medications including

potentially hepatotoxic cytotoxic chemotherapy and

antibiotics.

Neurological

Oculogyric crisis, appearing alone, as well as with

other dystonic reactions.

Skin

Urticaria , Stevens-Johnson syndrome Toxic skin

eruption, including toxic epidermal necrolysis

Overdose

-

Pediatric cases consistent with serotonin syndrome

have been reported after inadvertent oral overdoses of

ondansetron (exceeding estimated ingestion of 5

mg/kg) in young children. Reported symptoms

included somnolence, agitation, tachycardia,

tachypnea, hypertension, flushing, mydriasis,

diaphoresis, myoclonic movements, horizontal

nystagmus, hyperreflexia, and seizure. Patients

required supportive care, including intubation in some

cases, with complete recovery without sequelae within

1 to 2 days.

תושקובמה תורמחהה תונמוסמ ובש ,ןולעה ב"צמ .בוהצ עקר לע עבצב )ןולעב( ונמוס תורמחה רדגב םניאש םייוניש קורי

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Zofran

®

Injection 2mg/ml

1.

NAME OF THE MEDICINAL PRODUCT

Zofran

Injection 2mg/mL.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Zofran Injection 2mg/mL: 2mL glass ampoules each containing 4mg ondansetron (as hydrochloride

dihydrate) in aqueous solution for intramuscular or intravenous administration. 4mL glass ampoules

each containing 8mg ondansetron (as hydrochloride dihydrate) in aqueous solution for intravenous or

intramuscular administration.

Excipients with a known effect: This product contains 7 mg of sodium per 4 mg dose (see section

4.4). For a full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection (aqueous solution).

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

Adults:

Zofran is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy

and radiotherapy. Zofran is indicated for the prevention and treatment of post-operative nausea and

vomiting (PONV).

Paediatric Population:

Zofran is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in

children aged ≥6 months, and for the prevention and treatment of PONV in children aged ≥ 1 month.

4.2.

Posology and method of administration

Chemotherapy and Radiotherapy

induced nausea and vomiting

Adults:

The emetogenic potential of cancer treatment varies according to the doses and combinations of

chemotherapy and radiotherapy regimens used. The route of administration and dose of Zofran should

be flexible in the range of 8-32mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy:

Zofran can be given either by oral (tablets), intravenous

or intramuscular administration.

For most patients receiving emetogenic chemotherapy or radiotherapy, Zofran 8mg should be

administered as a slow intravenous injection (in not less than 30 seconds) or intramuscular injection,

immediately before treatment, followed by 8mg orally twelve hourly.

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To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Zofran

should be continued for up to 5 days after a course of treatment.

Highly emetogenic chemotherapy

: For patients receiving highly emetogenic chemotherapy, e.g. high-

dose cisplatin, Zofran can be given either by oral, intravenous or intramuscular administration. Zofran

has been shown to be equally effective in the following dose schedules over the first 24 hours of

chemotherapy:

A single dose of 8mg by slow intravenous injection (in not less than 30 seconds) or

intramuscular injection immediately before chemotherapy.

A dose of 8mg by slow intravenous injection (in not less than 30 seconds) or

intramuscular injection immediately before chemotherapy, followed by two further

intravenous injection( in not less than 30 seconds) or intramuscular doses of 8mg four

hours apart, or by a constant infusion of 1mg/hour for up to 24 hours.

A maximum initial intravenous dose of 16mg diluted in 50-100mL of saline or other

compatible infusion fluid

(see section 6.6

) and infused over not less than 15 minutes

immediately before chemotherapy. The initial dose of Zofran may be followed by two

additional 8mg intravenous doses (in not less than 30 seconds) or intramuscular doses

four hours apart.

A single dose greater than 16 mg must not be given due to dose dependent increase of QT-

prolongation risk (see sections 4.4, 4.8 and 5.1)

The selection of dose regimen should be determined by the severity of the emetogenic challenge.

The efficacy of Zofran in highly emetogenic chemotherapy may be enhanced by the addition of a

single intravenous dose of dexamethasone sodium phosphate, 20mg administered prior to

chemotherapy.

To protect against delayed or prolonged emesis after the first 24 hours, oral or treatment with Zofran

should be continued for up to 5 days after a course of treatment.

Paediatric Population:

CINV in children aged ≥ 6 months and adolescents

The dose for CINV can be calculated based on body surface area (BSA) or weight – see below.

Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections

4.4.and 5.1).

Zofran injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible

infusion fluid (see section 6.6) and infused intravenously over not less than 15 minutes.

There are no data from controlled clinical trials on the use of Zofran in the prevention of delayed or

prolonged CINV. There are no data from controlled clinical trials on the use of Zofran for

radiotherapy-induced nausea and vomiting in children.

Dosing by BSA:

Zofran should be administered immediately before chemotherapy as a single intravenous dose of

5 mg/m

. The single intravenous dose must not exceed 8 mg.

Oral dosing can commence 12 hours later and may be continued for up to 5 days (Table 1).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Table 1: BSA-based dosing for Chemotherapy - Children aged ≥6 months and adolescents

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Day 1

(a,b)

Days 2-6

<

0.6 m

5 mg/m

i.v. plus

2 mg p.o. after

12 hrs

2 mg p.o. every

12 hrs

0.6 m

5 mg/m

i.v. plus

4 mg p.o. after

12 hrs

4 mg p.o. every

12 hrs

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg

Dosing by bodyweight:

Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4.

and 5.1).

Zofran should be administered immediately before chemotherapy as a single intravenous dose of

0.15 mg/kg. The single intravenous dose must not exceed 8 mg.

Two further intravenous doses may be given in 4-hourly intervals.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 2).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Table 2: Weight-based dosing for Chemotherapy - Children aged ≥6 months and adolescents

Weight

Day 1

(a,b)

Days 2-6

≤ 10 kg

Up to 3 doses of

0.15 mg/kg

every 4 hrs

2 mg p.o. every

12 hrs

>

10 kg

Up to 3 doses of

0.15 mg/kg

every 4 hrs

4 mg p.o. every

12 hrs

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Elderly:

In patients 65 to 74 years of age, the dose schedule for adults can be followed. All intravenous doses

should be diluted in 50-100 mL of saline or other compatible infusion fluid (see section 6.6) and

infused over 15 minutes.

In patients 75 years of age or older, the initial intravenous dose of Zofran should not exceed 8 mg. All

intravenous doses should be diluted in 50-100 mL of saline or other compatible infusion fluid (see

section 6.6) and infused over 15 minutes. The initial dose of 8 mg may be followed by two further

intravenous doses of 8 mg, infused over 15 minutes and given no less than four hours apart. (see

section 5.2)

Patients with Renal Impairment:

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

Patients with Hepatic Impairment:

Clearance of Zofran is significantly reduced and serum half-life significantly prolonged in subjects

with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg

should not be exceeded and therefore parenteral or oral administration is recommended.

Patients with Poor Sparteine/Debrisoquine Metabolism:

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The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of

sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels

no different from those of the general population. No alteration of daily dosage or frequency of dosing

is required.

Post-Operative Nausea and Vomiting (PONV):

Adults:

For the prevention of PONV: Zofran can be administered orally or by intravenous or intramuscular

injection.

Zofran may be administered as a single dose of 4mg given by intramuscular or slow intravenous

injection at induction of anaesthesia.

For treatment of established PONV:

A single dose of 4mg given by intramuscular or slow intravenous

injection is recommended.

Paediatric population

PONV in children aged ≥1 month and adolescents

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a

single dose of Zofran may be administered by slow intravenous injection (not less than 30 seconds) at

a dose of 0.1mg/kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia.

For the treatment of PONV after surgery in paediatric patients having surgery performed under general

anaesthesia, a single dose of Zofran may be administered by slow intravenous injection (not less than

30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg.

There are no data from clinical trials on the use of Zofran in the treatment of PONV in children below

2 years of age.

Elderly:

There is limited experience in the use of Zofran in the prevention and treatment of PONV in the

elderly; however Zofran is well tolerated in patients over 65 years receiving chemotherapy.

Patients with Renal Impairment:

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

Patients with Hepatic Impairment:

Clearance of Zofran is significantly reduced and serum half-life significantly prolonged in subjects

with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg

should not be exceeded and therefore parenteral or oral administration is recommended.

Patients with poor Sparteine/Debrisoquine Metabolism

The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of

sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure

levels no different from those of the general population. No alteration of daily dosage or frequency of

dosing are required.

4.3.

Contraindications

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Concomitant use with apomorphine (see section 4.5).

Hypersensitivity to any component of the preparation.

4.4.

Special warnings and precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other

selective 5HT

receptor antagonists.

Respiratory events should be treated symptomatically and clinicians should pay particular attention to

them as precursors of hypersensitivity reactions.

Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). In addition, post-

marketing cases of Torsade de Pointes have been reported in patients using ondansetron. 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 patients with electrolyte

abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products

that lead to QT prolongation or electrolyte abnormalities.

Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron administration.

The development of serotonin syndrome has been reported with 5-HT

receptor antagonists. 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 Zofran 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 Zofran and

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

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

especially if Zofran is used concomitantly with other serotonergic drugs (see Sections 4.5 and 4.9).

As ondansetron is known to increase large bowel transit time, patients with signs of sub-acute

intestinal obstruction should be monitored following administration.

In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask

occult bleeding. Therefore, such patients should be followed carefully after ondansetron.

Zofran Injection contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Paediatric Population:

Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be

monitored closely for impaired hepatic function.

CINV:

When calculating the dose on an mg/kg basis and administering three doses at 4

hour intervals, the

total daily dose will be higher than if one single dose of 5mg/m

followed by an oral dose is given. The

comparative efficacy of these two different dosing regimens has not been investigated in clinical trials.

Cross-trial comparison indicates similar efficacy for both regimens (section 5.1).

4.5.

Interactions with other medicinal products and other forms of interaction

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There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs

commonly co-administered with it. Specific studies have shown that there are no interactions when

ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine,

lidocaine, thiopental, or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and

CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme

inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally

compensated by other enzymes and should result in little or no significant change in overall

ondansetron clearance or dose requirement.

Caution should be exercised when ondansetron is coadministered with drugs that prolong the QT

interval and/or cause electrolyte abnormalities. (See section 4.4)

Use of ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant

use of ondansetron with cardiotoxic drugs (e.g. anthracyclines (such as doxorubicin, daunorubicin) or

trastuzumab), antibiotics (such as erythromycin), antifungals (such as ketoconazole), antiarrhythmics

(such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of

arrhythmias. (See section 4.4).

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) [see section 4.4].

Apomorphine:

Based on reports of profound hypotension and loss of consciousness when ondansetron

was administered with apomorphine hydrochloride, concomitant use with apomorphine is

contraindicated.

Phenytoin, Carbamazepine and Rifampicin:

In patients treated with potent inducers of CYP3A4 (i.e.

phenytoin, carbamazepine, and rifampicin), the oral clearance of ondansetron was increased and

ondansetron blood concentrations were decreased.

Tramadol:

Data from small studies indicate that ondansetron may reduce the analgesic effect of

tramadol.

4.6.

Fertillity, pregnancy and lactation

Pregnancy

Based on human experience of epidemiological studies, ondansetron is suspected to cause orofacial

malformations when administered during first trimester of pregnancy.

In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated

with an increased risk of oral clefts (3 additional cases per 10,000 women treated; adjusted relative

risk, 1.24 (95% CI 1.03 to 1.48).

The available epidemiological studies on cardiac malformations show conflicting results. Animal

studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

The use of ondansetron in pregnancy is not recommended.

Breast-feeding

Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore

recommended that mothers receiving Zofran should not breast-feed their babies.

Fertility

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There is no information on the effects of ondansetron on human fertility.

4.7.

Effects on ability to drive and use machines

In psychomotor testing ondansetron does not impair performance nor cause sedation. No detrimental

effects on such activities are predicted from the pharmacology of ondansetron.

4.8.

Undesirable effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as:

very common (

1/10), common (

1/100 to

<

1/10), uncommon (

1/1000 to

<

1/100), rare (

1/10,000 to

<

1/1000) and very rare (

<

1/10,000). Very common, common and uncommon events were generally

determined from clinical trial data. The incidence in placebo was taken into account. Rare and very

rare events were generally determined from post-marketing spontaneous data.

The following frequencies are estimated at the standard recommended doses of ondansetron. The

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

Immune system disorders

Rare:

Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.

Nervous system disorders

Very common:

Headache.

Uncommon:

Seizures, movement disorders (including extrapyramidal reactions such as

dystonic reactions, oculogyric crisis and dyskinesia)

Rare:

Dizziness predominantly during rapid IV administration.

Eye disorders

Rare:

Transient visual disturbances (e.g. blurred vision) predominantly during IV

administration.

Very rare:

Transient blindness predominantly during intravenous administration

Cardiac disorders

Uncommon:

Arrhythmias, chest pain with or without ST segment depression, bradycardia.

Rare:

QTc prolongation (including Torsade de Pointes)

Vascular disorders

Common:

Sensation of warmth or flushing.

Uncommon:

Hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon:

Hiccups.

Gastrointestinal disorders

Common:

Constipation.

Hepatobiliary disorders

Uncommon:

Asymptomatic increases in liver function tests

General disorders and administration site conditions

Common:

Local IV injection site reactions.

1. Observed without definitive evidence of persistent clinical sequelae.

2. The majority of the blindness cases reported resolved within 20 minutes . Most patients had

received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness

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were reported as cortical in origin.

3. These events were observed commonly in patients receiving chemotherapy with cisplatin.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

https://sideeffects.health.gov.il

4.9.

Overdose

Symptoms and Signs

There is limited experience of ondansetron overdose. In the majority of cases, symptoms

were similar to those already reported in patients receiving recommended doses (

see section 4.8

Manifestations that have been reported include visual disturbances, severe constipation, hypotension

and a vasovagal episode with transient second-degree AV block.

Ondansetron prolongs the QT interval in a dose-dependent fashion. ECG monitoring is recommended

in cases of overdose.

Paediatric population

Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral

overdoses of ondansetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12

months to 2 years.

Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing,

mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure.

Patients required supportive care, including intubation in some cases, with complete recovery without

sequelae within 1 to 2 days.

Treatment

There is no specific antidote for ondansetron, therefore in all cases of suspected overdose,

symptomatic and supportive therapy should be given as appropriate.

Further management should be as clinically indicated or as recommended by the poisons centre, where

available

The use of ipecacuanha to treat overdose with ondansetron is not recommended, as patients are

unlikely to respond due to the anti-emetic action of ondansetron itself.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties

Mechanism of Action

Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the

control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause

release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3

receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also

cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may

also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management

of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to

antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system.

The mechanisms of action in post-operative nausea and vomiting are not known but there may be

common pathways with cytotoxic induced nausea and vomiting.

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Ondansetron does not alter plasma prolactin concentrations.

The role of ondansetron in opiate-induced emesis is not yet established.

QT Prolongation

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

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

Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes. At the highest

tested dose of 32 mg, the maximum mean (upper limit of 90% CI) difference in QTcF from placebo

after baseline-correction was 19.6 (21.5) msec. At the lower tested dose of 8 mg, the maximum mean

(upper limit of 90% CI) difference in QTcF from placebo after baseline-correction was 5.8 (7.8) msec.

In this study, there were no QTcF measurements greater than 480 msec and no QTcF prolongation was

greater than 60 msec. No significant changes were seen in the measured electrocardiographic PR or

QRS intervals.

Paediatric population

CINV

The efficacy of ondansetron in the control of emesis and nausea induced by cancer chemotherapy was

assessed in a double-blind randomised trial in 415 patients aged 1 to 18 years (S3AB3006). On the

days of chemotherapy, patients received either ondansetron 5 mg/m

intravenous and ondansetron 4

mg orally after 8 to 12 hours or ondansetron 0.45 mg/kg intravenous and placebo orally after 8 to

12 hours. Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days.

Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m

intravenous and

ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous and placebo orally). Post-chemotherapy

both groups received 4 mg ondansetron syrup twice daily for 3 days. There was no difference in the

overall incidence or nature of adverse events between the two treatment groups.

A double-blind randomised placebo-controlled trial (S3AB4003) in 438 patients aged 1 to 17 years

demonstrated complete control of emesis on worst day of chemotherapy in:

73% of patients when ondansetron was administered intravenously at a dose of 5 mg/m

intravenous together with 2 to 4 mg dexamethasone orally

71% of patients when ondansetron was administered as syrup at a dose of 8 mg together

with 2 to 4 mg dexamethasone orally on the days of chemotherapy.

Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. There was

no difference in the overall incidence or nature of adverse events between the two treatment groups.

The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label,

non-comparative, single-arm study (S3A40320). All children received three 0.15 mg/kg doses of

intravenous ondansetron, administered 30 minutes before the start of chemotherapy and then at 4 and 8

hours after the first dose. Complete control of emesis was achieved in 56% of patients.

Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of one

intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron doses of 4 mg for

children aged < 12 years and 8 mg for children aged ≥ 12 years (total no. of children n= 28). Complete

control of emesis was achieved in 42% of patients.

PONV

The efficacy of a single dose of ondansetron in the prevention of post-operative nausea and vomiting

was investigated in a randomised, double-blind, placebo-controlled study in 670 children aged 1 to 24

months (post-conceptual age ≥44 weeks, weight ≥ 3 kg). Included subjects were scheduled to undergo

elective surgery under general anaesthesia and had an ASA status ≤ III. A single dose of ondansetron

0.1 mg/kg was administered within five minutes following induction of anaesthesia. The proportion of

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subjects who experienced at least one emetic episode during the 24-hour assessment period (ITT) was

greater for patients on placebo than those receiving ondansetron (28% vs. 11%, p <0.0001).

Four double-blind, placebo-controlled studies have been performed in 1469 male and female patients

(2 to 12 years of age) undergoing general anaesthesia. Patients were randomised to either single

intravenous doses of ondansetron (0.1 mg/kg for paediatric patients weighing 40 kg or less, 4 mg for

paediatric patients weighing more than 40 kg; number of patients = 735) or placebo (number of

patients = 734). Study drug was administered over at least 30 seconds, immediately prior to or

following anaesthesia induction. Ondansetron was significantly more effective than placebo in

preventing nausea and vomiting. The results of these studies are summarised in Table 3.

Table 3: Prevention and treatment of PONV in Paediatric

Patients – Treatment response over 24 hours

Study

Endpoint

Ondansetron

Placebo

p value

S3A380

≤0.001

S3GT09

≤0.001

S3A381

≤0.001

S3GT11

no nausea

0.004

S3GT11

no emesis

0.004

CR = no emetic episodes, rescue or withdrawal

5.2.

Pharmacokinetic properties

Following oral administration, ondansetron is passively and completely absorbed from the

gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 30ng/

ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in

ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction

in first pass metabolism at higher oral doses. Mean bioavailability in healthy male subjects, following

the oral administration of a single 8 mg tablet, is approximately 55 to 60%. Bioavailability, following

oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in

healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both

oral bioavailability (65%) and half-life (5 hours) of ondansetron.

The disposition of ondansetron following oral, intramuscular and intravenous dosing in adults is

similar with a terminal half-life of about 3 hours and steady state volume of distribution of about 140

L. Equivalent systemic exposure is achieved after intramuscular and intravenous administration of

ondansetron.

A 4mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma

concentrations of about 65 ng/ml. Following intramuscular administration of ondansetron, peak

plasma concentrations of about 25ng/ml are attained within 10 minutes of injection.

Ondansetron is not highly protein bound (70-76%). Ondansetron is cleared from the systemic

circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5%

of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the

debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics. The pharmacokinetic

properties of ondansetron are unchanged on repeat dosing.

Special Patient Populations

Gender

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Gender differences were shown in the disposition of ondansetron, with females having a greater rate

and extent of absorption following an oral dose and reduced systemic clearance and volume of

distribution (adjusted for weight).

Children and Adolescents (aged 1 month to 17 years)

In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight normalised clearance was

approximately 30% slower than in patients aged 5 to 24 months (n=22) but comparable to the patients

aged 3 to 12 years. The half-life in the patient population aged 1 to 4 month was reported to average

6.7 hours compared to 2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The

differences in pharmacokinetic parameters in the 1 to 4 month patient population can be explained in

part by the higher percentage of total body water in neonates and infants and a higher volume of

distribution for water soluble drugs like ondansetron.

In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the

absolute values for both the clearance and volume of distribution of ondansetron were reduced in

comparison to values with adult patients. Both parameters increased in a linear fashion with weight

and by 12 years of age, the values were approaching those of young adults. When clearance and

volume of distribution values were normalised by body weight, the values for these parameters were

similar between the different age group populations. Use of weight-based dosing compensates for age-

related changes and is effective in normalising systemic exposure in paediatric patients.

Population pharmacokinetic analysis was performed on 428 subjects (cancer patients, surgery patients

and healthy volunteers) aged 1 month to 44 years following intravenous administration of

ondansetron. Based on this analysis, systemic exposure (AUC) of ondansetron following oral or IV

dosing in children and adolescents was comparable to adults, with the exception of infants aged 1 to 4

months. Volume was related to age and was lower in adults than in infants and children. Clearance

was related to weight but not to age with the exception of infants aged 1 to 4 months. It is difficult to

conclude whether there was an additional reduction in clearance related to age in infants 1 to 4 months

or simply inherent variability due to the low number of subjects studied in this age group. Since

patients less than 6 months of age will only receive a single dose in PONV a decreased clearance is

not likely to be clinically relevant.

Elderly

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 to support a different

dosing recommendation for the elderly.

Based on more recent ondansetron plasma concentrations and exposure-response modelling, a 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 IV dosing (see

section 4.2).

Renal Impairment

In patients with renal impairment (creatinine clearance 15-60 mL/min), both systemic clearance and

volume of distribution are reduced following IV administration of ondansetron, resulting in a slight,

but clinically insignificant, increase in elimination half-life (5.4 hours). A study in patients with severe

renal impairment who required regular haemodialysis (studied between dialyses) showed

ondansetron's pharmacokinetics to be essentially unchanged following intravenous administration.

Hepatic Impairment

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Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment,

ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15- 32

hours) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.

5.3.

Preclinical safety data

No additional data of relevance.

6. PHARMACEUTICAL PARTICULARS

6.1.

List of excipients

Sodium chloride, citric acid monohydrate, sodium citrate, water for injection.

6.2.

Incompatibilities

Zofran injection should not be administered in the same syringe or infusion as any other medication.

Ondansetron injection should only be mixed with those infusion solutions that are recommended.

6.3.

Shelf life

The expiry date of the product is indicated on the packaging materials

6.4.

Special precautions for storage

Protect from light. Store below 30ºC.

Dilutions of Zofran injection in compatible intravenous infusion fluids are stable under normal room

lighting conditions or daylight for at least 24 hours, thus no protection from light is necessary while

infusion takes place.

6.5.

Nature and contents of container

Type I clear glass one-point-cut ampoules.

5 ampoules are packed in a carton.

6.6.

Special precautions for disposal and other handling

Zofran Injection should not be autoclaved.

Compatibility with intravenous fluids

Zofran injection should only be mixed with those infusion solutions which are recommended:

Sodium Chloride Intravenous Infusion BP 0.9%w/v

Glucose Intravenous Infusion BP 5%w/v

Mannitol Intravenous Infusion BP 10%w/v

Ringers Intravenous Infusion

Potassium Chloride 0.3%w/v and Sodium Chloride 0.9%w/v Intravenous Infusion BP

Potassium Chloride 0.3%w/v and Glucose 5%w/v Intravenous Infusion BP

ZOF INJ API 02APR20

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In keeping with good pharmaceutical practice dilutions of Zofran injection in intravenous fluids

should be prepared at the time of infusion or stored at 2-8°C for no more than 24 hours before the start

of administration.

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

administration sets. It is considered that adequate stability would also be conferred by the use of

polyethylene infusion bags or Type 1 glass bottles. Dilutions of Zofran in sodium chloride 0.9%w/v

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

that Zofran injection diluted with other compatible infusion fluids would be stable in polypropylene

syringes.

Compatibility with other drugs:

Zofran may be administered by intravenous infusion at 1mg/hour,

e.g. from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of

the Zofran giving set for ondansetron concentrations of 16 to 160 micrograms/mL (e.g. 8 mg/500 mL

and 8 mg/50 mL respectively);

Cisplatin:

Concentrations up to 0.48 mg/mL (e.g. 240 mg in 500 mL) administered over one to eight

hours.

5-Fluorouracil:

Concentrations up to 0.8 mg/mL (e.g. 2.4g in 3 litres or 400 mg in 500 mL)

administered at a rate of at least 20 mL per hour (500 mL per 24 hours). Higher concentrations of 5-

fluorouracil may cause precipitation of ondansetron. The 5-fluorouracil infusion may contain up to

0.045%w/v magnesium chloride in addition to other excipients shown to be compatible.

Carboplatin:

Concentrations in the range 0.18 mg/mL to 9.9 mg/mL (e.g. 90 mg in 500 mL to 990 mg

in 100 mL), administered over ten minutes to one hour.

Etoposide:

Concentrations in the range 0.14 mg/mL to 0.25 mg/mL (e.g. 72 mg in 500 mL to 250 mg

in 1 litre), administered over thirty minutes to one hour.

Ceftazidime:

Doses in the range 250 mg to 2000 mg reconstituted with Water for Injections BP as

recommended by the manufacturer (e.g. 2.5 mL for 250 mg and 10 mL for 2g ceftazidime) and given

as an intravenous bolus injection over approximately five minutes.

Cyclophosphamide:

Doses in the range 100 mg to 1g, reconstituted with Water for Injections BP, 5

mL per 100 mg cyclophosphamide, as recommended by the manufacturer and given as an intravenous

bolus injection over approximately five minutes.

Doxorubicin:

Doses in the range 10-100 mg reconstituted with Water for Injections BP, 5 mL per 10

mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection

over approximately 5 minutes.

Dexamethasone:

Dexamethasone sodium phosphate 20mg may be administered as a slow intravenous

injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 16mg of ondansetron

diluted in 50-100 mL of a compatible infusion fluid over approximately 15 minutes. Compatibility

between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting

administration of these drugs through the same giving set resulting in concentrations in line of 32

microgram - 2.5mg/ mL for dexamethasone sodium phosphate and 8 microgram - 1mg/mL for

ondansetron.

7.

Manufacturer

GlaxoSmithKline Manufacturing S.p.A., Parma, Italy.

ZOF INJ API 02APR20

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Page 14 of 14

8.

Registration holder

Novartis Israel Ltd., P.O.B 7126, Tel-Aviv

9.

Registration number

049 -94 -26548

This leaflet format has been determined by the Ministry of Health and its content has been checked

and approved

in November 2016 and was updated according to the guidelines of the Ministry of

Health in April 2020.

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

23.7.2013

םש

רישכת

תילגנאב

רפסמו

םושירה

Zofran Injection 2mg/ml

(49-94-

26548)

םש

לעב

םושירה

GlaxoSmithKline (ISRAEL) Ltd

:

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

אפורל ןולעב אפורל ןולעב תורמחהה

תושקובמה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Posology and Method

of Administration

Elderly:

Zofran is well tolerated

by patients over 65

years and no alteration

of dosage, dosing

frequency or route of

administration are

required.

Elderly:

In patients 65 to 74 years of age, the dose

schedule for adults can be followed. All

intravenous doses should be diluted in 50-100

ml of saline or other compatible infusion

fluid (see section 6.6) and infused over 15

minutes.

In patients 75 years of age or older, the

initial intravenous dose of Zofran should not

exceed 8 mg. All intravenous doses should be

diluted in 50-100 ml of saline or other

compatible infusion fluid (see section 6.6)

and infused over 15 minutes. The initial dose

of 8 mg may be followed by two further

intravenous doses of 8 mg, infused over

15 minutes and given no less than four hours

apart. (see section 5.2)

Special Warnings and

Special Precautions for

Use

Rarely, transient ECG

changes including QT

interval prolongation

have been reported in

patients receiving

ondansetron. In

addition, post-marketing

cases of Torsade de

Pointes have been

reported in patients

using ondansetron.

Ondansetron should be

administered with

caution to patients who

have or may develop

prolongation of QTc.

These conditions

include patients with

electrolyte

abnormalities, with

Ondansetron prolongs the QT interval in a

dose-dependent manner (see section 5.1). In

addition, post-marketing cases of Torsade de

Pointes have been reported in patients using

ondansetron. 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 patients with

electrolyte abnormalities, congestive heart

failure, bradyarrhythmias or patients taking

other medicinal products that lead to QT

prolongation or electrolyte abnormalities.

There have been post-marketing reports

describing patients with serotonin syndrome

(including altered mental status, autonomic

instability and neuromuscular abnormalities)

following the concomitant use of ondansetron

and other serotonergic drugs (including

congenital long QT

syndrome, or patients

taking other medicinal

products that lead to QT

prolongation. Therefore,

caution should be

exercised in patients

with cardiac rhythm or

conduction disturbances,

in patients treated with

anti-arrhythmic agents

or beta-adrenergic

blocking agents and in

patients with significant

electrolyte disturbances.

selective serotonin reuptake inhibitors (SSRI)

and serotonin noradrenaline reuptake

inhibitors (SNRIs)). If concomitant treatment

with ondansetron and other serotonergic

drugs is clinically warranted, appropriate

observation of the patient is advised.

Interaction with Other

Medicaments and

Other Forms of

Interaction

Use of Zofran with QT

prolonging drugs may

result in additional QT

prolongation.

Concomitant use of

Zofran with cardiotoxic

drugs (e.g.

anthracyclines) may

increase the risk of

arrhythmias (section

4.4).

Caution should be exercised when

ondansetron is coadministered with drugs

that prolong the QT interval and/or cause

electrolyte abnormalities. (see section 4.4)

Use of ondansetron with QT prolonging

drugs may result in additional QT

prolongation. Concomitant use of

ondansetron with cardiotoxic drugs (e.g.

anthracyclines such as doxorubicin,

daunorubicin or trastuzimab), antibiotics

(such as erythromycin or ketoconazole),

antiarrhythmics (such as amiodarone) and

beta blockers (such as atenolol or timolol)

may increase the risk of arrhythmias. (See

Special warnings and precautions for use).

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

שקובמה תו

לע

עקר

בוהצ

.

םייוניש

םניאש

רדגב

תורמחה

ונמוס

)ןולעב( עבצב

קורי

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