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1. NAME OF THE MEDICINAL PRODUCT

Ondansetron 8mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains ondansetron 8 mg (as ondansetron hydrochloride dihydrate). Excipient(s) with known effect:

Each tablet contains 148 mg lactose as lactose anhydrous lactose monohydrate. For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Film coated tablet.

Each Ondansetron 8mg Tablet is a yellow, oval, film coated tablet.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults:

Management of nausea and vomiting induced by cytotoxic chemotherapy and Radiotherapy. Prevention and treatment of post-operative nausea and vomiting (PONV).

Paediatric Population:

Management of chemotherapy-induced nausea and vomiting in children aged > 6 months. Prevention and treatment of post-operative nausea and vomiting in children aged >1 month.

4.2 Posology and method of administration

Oral use.

Chemotherapy and radiotherapy induced nausea and vomiting

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

Adults

Emetogenic Chemotherapy and Radiotherapy: Ondansetron can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration.

The recommended oral dose is 8 mg 1 to 2 hours before treatment, followed by 8 mg orally 12 hours later.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron should be continued for up to 5 days after a course of treatment.

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

Highly Emetogenic Chemotherapy: For patients receiving highly emetogenic chemotherapy e.g. high-dose cisplatin, ondansetron can be given by oral, IV, IM or rectal administration.

The recommended oral dose is 24 mg taken together with oral dexamethasone sodium phosphate 12 mg, 1 to 2 hours before treatment.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron should be continued for up to 5 days after a course of treatment.

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

Paediatric Population

Chemotherapy-induced nausea and vomiting (CINV) in children aged > 6 months and adolescents

The dose for chemotherapy induced nausea and vomiting (CINV) can be calculated based on body surface area (BSA) or weight - see below. In paediatric clinical studies, ondansetron was given by IV infusion diluted in 25 to 50 ml of saline or other compatible infusion fluid (see IV product - Instructions for Use and Handling) and infused over not less than 15 minutes.

Weight-based dosing results in higher total daily doses compared to BSA-based dosing - see sections 4.4 and 5.1. There are no data from controlled clinical trials on the use of ondansetron in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of ondansetron for radiotherapy-induced nausea and vomiting in children.

Dosing by BSA:

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m . The intravenous dose must not exceed 8 mg.

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

See Table 1 below.

The total daily dose must not exceed adult dose of 32 mg.

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

BSA	Day 1a,b	Days 2-6°
< 0.6 m2	5 mg/m2 i.v. 2 mg syrup or tablet after 12 hours	2 mg syrup or tablet every 12 hours
> 0.6 m2	5 mg/m i.v. plus 4 mg syrup or tablet after 12 hours	4 mg syrup or tablet every 12 hours
> 1.2 m2	5 mg/m2 IV or 8 mg IV plus 8 mg syrup or tablet after 12 hours	8 mg syrup or tablet every 12 hours

^a The intravenous dose must not exceed 8 mg. ^b The total daily dose 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 - see sections 4.4 and 5.1.

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg.

Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32 mg.

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

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

Weight	Day1a,b	Days 2-6b
<10 kg	Up to 3 doses of 0.15 mg/kg at 4-hourly intervals.	2 mg syrup or tablet every 12 hours
> 10 kg	Up to 3 doses of 0.15 mg/kg at 4-hourly intervals.	4 mg syrup or tablet every 12 hours

^a The intravenous dose must not exceed 8 mg. ^b The total daily dose must not exceed adult dose of 32 mg.

Populations - Elderly

Ondansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required.

Populations - Renal Impairment

No alteration of daily dosage or frequency of dosing, or route of administration are required. Populations - Hepatic Impairment

Clearance of ondansetron 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.

Populations - 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.

Postoperative nausea and vomiting (PONV):

Adults

The recommended oral dose is 16 mg given 1 hour prior to anaesthesia.

For treatment of established post-operative nausea and vomiting ondansetron administration by injection is recommended.

Paediatric population -Post-operative nausea and vomiting in children aged > 1 month and adolescents

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post operative nausea and vomiting (PONV); slow i.v. injection (in not less than 30 seconds) is recommended for this purpose.

There are no data on the use of ondansetron in the prevention and treatment of PONV in children under 2 years of age.

Populations - Elderly

There is limited experience in the use of ondansetron in the prevention and treatment of postoperative nausea and vomiting in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.

Populations - Renal Impairment

No alteration of daily dosage or frequency of dosing, or route of administration are required. Populations - Hepatic Impairment

Clearance of ondansetron 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.

Populations - 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

Concomitant use with apomorphine (see section 4.5). Hypersensitivity to ondansetron or to any of the excipients.

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 (e.g. granisetron, dolasetron). 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 Clinical Pharmacology). 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.

Hypokalemia and hypomagnesemia 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.

Ondansetron is not indicated for prevention and treatment of post-operative nausea and vomiting in children after intra-abdominal surgery.

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.

Ondansetron film-coated tablets should not be used in children with a total body surface below 0.6 m².

Paediatric Population

Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be monitored closely for impaired hepatic function.

Chemotherapy -induced nausea and vomiting: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 5 mg/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 (see section 5.1).

This medicine contains lactose.

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 medicinal products and other forms of interaction

There is no evidence that ondansetron either induces or inhibits the metabolism of other medicinal products 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, lignocaine, propofol and thiopental.

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.

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 section 4.).

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

Fertility, 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.

Lactation

Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies.

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 (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); 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.

	Very common	Common	Uncommon	Rare	Very rare
Immune system disorders				Immediate hypersensitivi ty reactions sometimes severe, including anaphylaxis.
Nervous system disorders	Headache.		Seizures, movement disorders (including extrapyramida l reactions such as dystonic reactions, oculogyric crisis and dyskinesia) 1	Dizziness during rapid IV administration
Eye disorders				Transient visual disturbances (e.g. blurred vision) predominantl y during IV administration	Transient blindness predominantl y during intravenous administration 2

	Very common	Common	Uncommon	Rare	Very rare
Cardiac disorders			Arrhythmias, chest pain with or without ST segment depression, Bradycardia.	QTc prolongation (including Torsade de pointes)
Vascular disorders		Sensation of warmth or flushing.	Hypotension.
Respiratory , thoracic and mediastinal disorders			Hiccups.
Gastrointest inal disorders		Constipation
Hepatobilia ry disorders			Asymptomati c increases in liver function tests3

¹ Observed without definitive evidence of persistent clinical sequelae.

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.

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 QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose.

Treatment

There is no specific antidote for ondansetron, therefore in 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 antiemetic action of ondansetron itself.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT₃) antagonists. ATC code: A04A A01

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.

In a pharmaco-psychological study in volunteers ondansetron has not shown a sedative effect. 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 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.

Clinical Studies

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 to12 hours or ondansetron 0.45 mg/kg intravenous and placebo orally after 8 to 12 hours. Post-chemotherapy both groups received4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst dayof 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 received4 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 i.v.

together with 2-4 mg dexamethasone p.o. and in

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

dexamethasone p.o. 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.

(S3A239) investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron

mg for children aged < 12 years 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 the following table :

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 30 ng/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. 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 (IM) and intravenous (IV) dosing 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 IM and IV administration of ondansetron.

A 4 mg 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 25 ng/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.

In a study of 21 paediatric patients aged between 3 and 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron following a single intravenous dose of 2 mg (3-7 years old) or 4 mg (8-12 years old) were reduced. The magnitude of the change was age-related, with clearance falling from about 300 ml/min at 12 years of age to 100 ml/min at 3 years. Volume of distribution fell from about 75 l at 12 years to 17 l at 3 years. Use of weight-based dosing (0.1 mg/kg up to 4 mg maximum) compensates for these changes and is effective in normalising systemic exposure in paediatric patients.

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 h). 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.

Special 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 1 to 4 month patient population 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.

Table C. Pharmacokinetics in Paediatric Patients 1 Month to 18 Years of Age

¹    Ondansetron single intravenous dose: 0.1 or 0.2 mg/kg

²    Population PK Patients: 64% cancer patients and 36% surgery patients.

3

Population estimates shown; AUC based on dose of 0.15 mg/kg.

⁴    Ondansetron single intravenous dose: 2 mg (3 to 7 years) or 4 mg (8 to 12 years)

5.3. Preclinical safety data

No additional data of relevance.

PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

Core

lactose anhydrous, cellulose microcrystalline, starch pregelatinised, magnesium stearate Coat

hypromellose, lactose monohydrate, titanium dioxide (E171), glycerol triacetate, iron oxide yellow (E172)

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf life

24 months.

6.4.    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

Blister made of bilaminate foil (PVC/PVdC) and aluminium foil VMCH coated.

Pack sizes

Blisters containing: 2, 4, 6, 10, 10x1, 15, 30, 30x1, 50, 50x1 and 100 film-coated tablets Hospital pack containing 20x1 film-coated tablets

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 04416/0505

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15^th November 2004

10 DATE OF REVISION OF THE TEXT

23/07/2014