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After the initial ondansetron injection, you may be given ondansetron tablets for up to 5 days to prevent any further nausea & vomiting.

Children aged over 6 months and adolescents

The doctor will decide the dose. Look at the label for more

information.

On the day of chemotherapy or radiotherapy

•    the first dose is given by an injection into a vein, just before your child's treatment. After chemotherapy, your child's medicine will usually be given by mouth; the usual dose is a 4mg ondansetron tablet or 4mg ondansetron syrup twelve hours later.

On the following days

•    one 4mg tablet or 4mg syrup twice a day.

•    this can be given for up to five days.

To prevent nausea and vomiting after an operation: the usual adult dose is 4 mg given by intravenous or intramuscular injection before the operation.

For children aged over 1 month and adolescents, the doctor will decide the dose. The maximum dose is 4mg given as an injection into the vein. This will be given just before the operation.

To treat nausea and vomiting after an operation: the usual adult dose is 4 mg given as intravenous or intramuscular injection. For children aged over 1 month and adolescents, the doctor will decide the dose. The maximum dose is 4mg given as an injection into the vein.

Patients with moderate or severe liver disease: the total daily dose should not be more than 8 mg.

If you think you may have missed a dose or had too much, let your doctor or nurse know immediately.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Ondansetron can have side effects, although not everybody gets them.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

A few people can be allergic to some medicines; if any of the following rare side effects come on soon after having your injection, tell your doctor immediately:

•    Sudden chest tightness or wheezing

•    Swelling of eyelids, face or lips

•    Skin rash - red spots or hives (skin lumps)

•    Collapse

The following side effects are very rare but if you have them you should let your doctor know immediately:

•    Upward rolling of the eyes

•    Abnormal muscular stiffness, body movements or shaking

•    Fits

•    Blurring of vision

•    Temporary blindness

•    Yellowing of the skin or whites of the eyes caused by liver problems

•    Low blood pressure (symptoms may include dizziness, fainting and nausea)

Other possible side effects are:

•    Headache

•    Feeling of warmth in the head or stomach

•    Dizziness or lightheaded feeling

•    Slow or irregular heartbeat

•    Chest pain

•    Flushes of the face

•    Hiccups

•    Upset bowels - constipation

•    Irritation and redness at the site of injection

If you have any blood tests to check how your liver is working, this medicine may affect the results. If you feel unwell or have any other unusual discomfort you do not understand, tell your doctor as soon as possible.

5. HOW TO STORE ONDANSETRON SOLUTION FOR INJECTION OR INFUSION

Keep out of the reach and sight of children.

Do not store above 25°C.

Keep the ampoule in the outer carton.

Do not use Ondansetron Solution for Injection or Infusion after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.

Chemical and physical in use stability has been demonstrated for 24 hours at 25°C and 5°C. From a microbiological point of view, the product should be used immediately If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2-8°C, unless opening and dilution has taken place in controlled and validated aseptic conditions. For single use. Discard any unused product immediately after use.

6. FURTHER INFORMATION

What Ondansetron solution for injection or infusion contains

•    The active substance is Ondansetron (as Ondansetron hydrochloride dihydrate).

•    Each ampoule contains either 4mg or 8mg Ondansetron (as Ondansetronhydro-chloridedihydrate)

•    The other ingredients are sodium chloride, sodium citrate, citric-acid monohydrate and water for injections

•    Do not use Ondansetron injection

if the ampoule is damaged or if the solution contains particles or is cloudy

•    This medicinal product contains less than 1 mmol sodium (23mg) per ampoule, i.e. essentially 'sodium-free'.

What Ondansetron solution for injection or infusion looks like and contents of the pack

Ondansetron 2mg/ml Solution for Injection or Infusion is a clear colourless solution.

Ondansetron Injection is available in 1,5, or 10, ampoules at 2 ml or 1,5, or 10, at 4 ml.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Wockhardt UK Limited, Ash Road North, Wrexham

LL13 9UF, United Kingdom.

Manufacturer

CP Pharmaceuticals Limited, Ash Road North, Wrexham L13 9UF, United Kingdom.

Other formats:

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK Only)

Please be ready to give the following information:

Product name	Reference number
Ondansetron 2mg/ml Solution for Injection or Infusion	29831/0153 29831/0154

This is a service provided by the Royal National Institute of Blind People.

This leaflet was revised in November 2012.

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.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

ATC code:- A04 Antiemetics and antinauseants ATC group:- A04AAO 1 Serotonin (5HT3) antagonist

Ondansetron is a potent, highly selective 5HTs 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 vomoting reflex by activating vagal afferents via 5HTs 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.

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% Cl) 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% Cl)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.

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.

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

Study	Endpoint	Ondansetron %	Placebo	% p value
S3A380	CR	68	39	0.001
S3GT09	CR	61	35	0.001
S3A381	CR	53	17	0.001
S3GT11	no nausea	64	51	0.004
S3GT11	no emesis	60	47	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 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. 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 (five 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 (IM) and intravenous (IV) dosing is similar with a terminal half life of about three 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 five 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 20-30ng/ml are attained, typically six 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 six 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

104878/3

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.

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 (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.

Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. However, it is anticipated that the half-life of ondansetron after rectal administration in these populations will be similar to that seen in healthy volunteers, since the rate of elimination of ondansetron following rectal administration is not determined by systemic clearance.

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.

5.3. Preclinical safety data

No additional data of relevance.

6.    PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

Citric acid monhydrate Sodium citrate Sodium chloride Water for injections.

6.2.    Incompatibilities

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

6.3.    Shelf life

36 months (unopened).

After dilution, see section 6.4 Special precautions for storage.

6.4.    Special precautions for storage Do not store above 25°C.

Keep the ampoule in the outer carton Keep out of the reach and sight of children After dilution:-

Chemical and physical in use stability has been demonstrated for 24 hours at 25°C and 5°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2-8°C, unless opening and dilution has taken place in controlled and validated aseptic conditions.

6.5.    Nature and contents of container

Type I Ph Eur amber glass 3ml capacity ampoules. Each pack contains one, five or ten ampoules.

6.6.    Special precautions for disposal

For single use. Discard any unused product immediately after use.

Ondansetron injection should not be autoclaved.

Compatibility with intravenous fluids:

Ondansetron injection should only be admixed 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 Ondansetron Injection in intravenous fluids should be prepared at the time of infusionalthough chemical and physical in use stability after dilution has been demonstrated for 24 hours at 25°C and 5°C.

Compatibility with other drugs: Ondansetron 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 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 20ml 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 0.18mg/ml to 9.9mg/ml (e.g. 90mg in 500ml to 990mg in 100ml), administered over ten minutes to one hour.

Etoposide: Concentrations in the range 0.14 mg/ml to 0.25 mg/ml (e.g. 72mg in 500ml 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. 2.5ml for 250mg and 10ml for 2g ceftazidime) and given as an intravenous bolus injection over approximately five minutes.

Cyclophosphamide: Doses in the range 100mg to 1g, reconstituted with Water for Injections BP, 5ml per 100mg 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, 5ml per 10mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes.

Dexamethasone: Dexamethasone sodium phosphate 20mg may be administered as a slow intravenous injection over two to five 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 micrograms to 2.5mg/ml for dexamethasone sodium phosphate and 8 micrograms to 1mg/ml for ondansetron.

7.    MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF U.K

8.    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0154

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/06/2007

10. DATE OF REVISION OF THE TEXT

06/11/2012

'/WOCKHARDT