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May 2015

Zofran® Tablets 4mg

Zofran® Tablets 8mg
1. Trade Name of the Medicinal Product

Zofran Tablets 4mg

Zofran Tablets 8mg

2 Qualitative and Quantitative Composition

Each Zofran Tablet 4mg is a yellow, oval, film coated tablet engraved
"GXET3" on one face and plain on the other. Each tablet contains ondansetron
4mg (as hydrochloride dihydrate).
Each Zofran Tablet 8mg is a yellow, oval, film coated tablet engraved
"GXET5" on one face and plain on the other. Each tablet contains ondansetron
8mg (as hydrochloride dihydrate).

3. Pharmaceutical Form

Film coated tablet.

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 nausea and vomiting induced by
cytotoxic chemotherapy.

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 selection
of dose regimen should be determined by the severity of the emetogenic
challenge.
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 Emetogenic Chemotherapy and Radiotherapy: Zofran can be given either by
oral (tablets), intravenous or intramuscular administration.

For oral administration: 8mg taken 1 to 2 hours before chemotherapy or

radiation treatment, followed by 8mg every 12 hours for a maximum of 5 days
to protect against delayed or prolonged emesis.

For highly emetogenic chemotherapy: To protect against delayed or prolonged

emesis after the first 24 hours, oral treatment with Zofran may be continued
for up to 5 days after a course of treatment.

The recommended dose for oral administration is 8mg to be taken twice daily.

Paediatric Population:

Ondansetron may be administered as a single intravenous dose of 5mg/m2

immediately before chemotherapy, followed by 4mg orally twelve hours later.
4mg orally twice daily can be continued for up to 5 days after a course of
treatment.

Elderly:

Zofran is well tolerated by patients over 65 years. No alteration of oral dose or

frequency of administration is required.

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.

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 is
required.

Post operative nausea and vomiting:

Adults:

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 For the prevention of PONV: Zofran can be administered orally or by
intravenous or intramuscular injection.
For oral administration: 16mg taken one hour prior to anaesthesia.

For the treatment of established PONV: Intravenous or intramuscular

administration is recommended.

Children and Adolescents aged 2 years and over

No studies have been conducted on the use of orally administered ondansetron

in the prevention or treatment of post operative nausea and vomiting; slow i.v.
injection is recommended for this purpose.

Elderly:

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

treatment of post-operative nausea and vomiting 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.

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 is
required.

4.3 Contra-indications

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 5HT3 receptor antagonists. Respiratory
events should be treated symptomatically and clinicians should pay particular
attention to them as precursors of hypersensitivity reactions.

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 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.

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 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.

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

signs of subacute 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.

Paediatric Population:

Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic

agents should be monitored closely for impaired hepatic function.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other Medicaments and other forms of Interaction

There is no evidence that ondansetron either induces or inhibits the

metabolism of other drugs commonly coadministered 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

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 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 (e.g. SSRIs and SNRIs): 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 SSRIs
and 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 Pregnancy and Lactation

Pregnancy
The safety of ondansetron for use in human pregnancy has not been
established. Evaluation of experimental animal studies does not indicate direct
or indirect harmful effects with respect to the development of the embryo, or
foetus, the course of gestation and peri- and post-natal development. However
as animal studies are not always predictive of human response 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.

4.7 Effects on Ability to Drive and Use Machines

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 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 and
1/10), uncommon (1/1000 and 1/100), rare (1/10,000 and 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)(1)
Rare: Dizziness during rapid IV administration.

Eye disorders
Rare: Transient visual disturbances (eg. blurred vision)
predominantly during IV administration.
Very rare: Transient blindness predominantly during IV administration. (2)
Cases of transient blindness, have been reported. These cases of
transient blindness were reported to resolve within a few
minutes up to 48 hours. Transient blurred vision, in some cases
associated with abnormalities of accommodation, have also
been reported.

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.

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 Respiratory, thoracic and mediastinal disorders
Uncommon: Hiccups.

Gastrointestinal disorders
Common: Constipation.

Hepatobiliary disorders
Uncommon: Asymptomatic increases in liver function tests.(3)

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

1. Observed without definitive evidence of persistent clinical sequelae.

2. The majority of the blindness cases reported resolved within 48 hours.
Most patients had received chemotherapeutic agents, which included
cisplatin. Some cases of transient blindness were reported as cortical in
origin.
3. These events were observed commonly in patients receiving chemotherapy
with cisplatin.

Reporting of 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
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 (http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.
.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.

Treatment
There is no specific antidote for ondansetron, therefore in all cases of
suspected overdose, symptomatic and supportive therapy should be given as
appropriate.
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.

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.

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,
randomized, 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
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 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.

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/m2 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/m2 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/m2 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.

5.2 Pharmacokinetic Properties

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 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 8mg dose. For doses above 8mg 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.

The disposition of ondansetron following oral, intramuscular(IM) and

intravenous(IV) dosing is similar with a terminal half life of about 3 hours and
steady state volume of distribution of about 140L. Equivalent systemic
exposure is achieved after IM and IV administration of ondansetron.

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

peak plasma concentrations of about 65ng/mL. Following intramuscular
administration of ondansetron, peak plasma concentrations of about 25ng/mL
are attained within 10 minutes of injection.

Following administration of ondansetron suppository, plasma ondansetron

concentrations become detectable between 15 and 60 minutes after dosing.
Concentrations rise in an essentially linear fashion, until peak concentrations
of 20-30 ng/mL are attained, typically 6 hours after dosing. Plasma
concentrations then fall, but at a slower rate than observed following oral
dosing due to continued absorption of ondansetron. The absolute
bioavailability of ondansetron from the suppository is approximately 60% and
is not affected by gender. The half life of the elimination phase following
suppository administration is determined by the rate of ondansetron
absorption, not systemic clearance and is approximately 6 hours. Females
show a small, clinically insignificant, increase in half-life in comparison with
males.

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

Gender differences were shown in the disposition of ondansetron, with

females having a greater rate and extent of absorption following an oral dose

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 and reduced systemic clearance and volume of distribution (adjusted for
weight).

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 intravenous dosing.

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 IV administration.

Hepatic impairment

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. The
pharmacokinetics of ondansetron following administration as a suppository
have not been evaluated in patients with hepatic impairment.

5.3 Preclinical Safety Data

No additional data of relevance.

Pharmaceutical Particulars
6.1 List of Excipients

Lactose (anhydrous), microcrystalline cellulose, pregelatinised maize starch,

methylhydroxypropylcellulose, titanium dioxide (E171), iron oxide (E172)
magnesium stearate.

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6.2 Incompatibilities

None reported.

6.3 Shelf Life

The expiry date of the product is indicated on the label and packaging.

6.4 Special Precautions for Storage

Store below 30oC.

6.5 Nature and Contents of Container

Blister packs of 10 tablets comprising blister film and foil lidding.

6.6 Instructions for Use/Handling

None stated.

Administrative Data
7. Manufacturer

Aspen Bad Oldesloe GmbH, Bad Oldesloe, Germany

8. Registration Holder

Novartis Israel Ltd., 36 Shacham St., Petach-Tikva

9. License Number

Zofran Tablets 4 mg 049 96 26549

Zofran Tablets 8 mg 049 95 26560

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