Adults:

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

chemotherapy and radiotherapy.

Imatox is indicated for the prevention and treatment of post-operative nausea and vomiting

(PONV).

Paediatric Population:

Imatox 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.

Chemotherapy and Radiotherapy:

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

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

Emetogenic chemotherapy and radiotherapy: Imatox can be given either by rectal, oral (tablets

or syrup), intravenous or intramuscular administration.

For most patients receiving emetogenic chemotherapy or radiotherapy, Imatox 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.

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

with Imatox 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, Imatox can be given either by oral, rectal, intravenous or intramuscular

administration. Imatox 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 Imatox 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 QTprolongation

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 Imatox 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 rectal treatment

with Imatox 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).

Imatox 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 Imatox in the prevention of

delayed or prolonged CINV. There are no data from controlled clinical trials on the use of

Imatox for radiotherapy-induced nausea and vomiting in children.

Dosing by BSA:

Imatox should be administered immediately before chemotherapy as a single intravenous dose

of 5 mg/m2. The single intravenous dose must not exceed 8 mg.

Oral dosing can commence twelve 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

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours 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).
Imatox 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

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours 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 Imatox 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 Imatox 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.

Post-Operative Nausea and Vomiting (PONV):

Adults:

For the prevention of PONV Imatox can be administered orally or by intravenous or

intramuscular injection.

Imatox 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 Imatox 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 Imatox 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 on the use of Imatox in the treatment of PONV in children below 2 years of

age.

Elderly:

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

the elderly, however Imatox 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 Imatox 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 8 mg 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.

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.

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 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.

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-hourly

intervals, the total daily dose will be higher than if one single dose of 5mg/m2 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).

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, temazepan, furosemide, alfentanil, tramadol,

morphine, lignocaine, 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 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).

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.

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.

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

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

Pregnancy Category B.

Reproduction studies have been performed in pregnant rats and rabbits at intravenous doses up

to 4 mg/kg per day (approximately 1.4 and 2.9 times the recommended human intravenous

dose of 0.15 mg/kg given three times a day, respectively, based on body surface area) and have

revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are,

however, no adequate and well-controlled studies in pregnant women. Because animal

reproduction studies are not always predictive of human response, this drug should be used

during pregnancy only if clearly needed.

Ondansetron has no or negligible influence on the ability to drive and use machines.

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

according to indication and formulation.

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 were reported as cortical in origin.

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

Paediatric population

The adverse event profile in children and adolescents was comparable to that seen in adults.

To report any side effect(s):

• Saudi Arabia:

The National Pharmacovigilance Center (NPC):

Fax: +966-11-205-7662

Call NPC at +966-11-2038222

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

• Other GCC States:

Please contact the relevant competent authority.

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.

Pharmacotherapeutic group: Anti-emetics and Anti-nauseants, (Serotonin (5HT3) antagonist).

ATC code: A04AA01

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 postoperative

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.

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/m2 intravenous + ondansetron 4 mg orally after 8-12 hrs or ondansetron 0.45 mg/kg

intravenous + placebo orally after 8-12 hrs. 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 + ondansetron 4 mg orally) and 41% (0.45

mg/kg intravenous + 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 2-4 mg dexamethasone orally

• 71% of patients when ondansetron was administered as syrup at a dose of 8 mg + 2-4 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 openlabel,

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 four and eight 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 yrs and 8 mg for children aged ≥ 12 yrs (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 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

CR = no emetic episodes, rescue or withdrawal

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. 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. 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).

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 140L. 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 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

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 weightbased

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.

Renal Impairment

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

and volume of distribution are reduced following intravenous administration of ondansetron,

resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4h). 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.

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 (see section 4.2).

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 h) 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.

No additional data of relevance.

Sodium Chloride

Citric Acid Anhydrous

Tri-Sodium Citrate Dihydrate

Hydrochloric Acid

Sodium hydroxide

Water for injection

Imatox 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.

Store below 30°C.

Store in the original package in order to protect from light.

Imatox 4 mg Injection- 2 ml:

2 ml EP type I clear glass ampoule, each five ampoules packaged in tray and carton with

folded leaflet.

Imatox 8 mg Injection- 4 ml:

5 ml EP type I clear glass ampoule, each five ampoules packaged in tray and carton with

folded leaflet.

Imatox Injection should not be autoclaved.

Compatibility with intravenous fluids:

Imatox 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

In keeping with good pharmaceutical practice dilutions of Imatox injection in intravenous

fluids should be prepared at the time of infusion or stored at 2-8oC 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 Ondansetron

Injection 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 Ondansetron Injection diluted with other

compatible infusion fluids would be stable in polypropylene syringes.

Compatibility with other drugs: Imatox 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 Ondansetron Injection 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 400mg in 500ml)

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 10-100mg 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 50-100ml 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.