SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

Ondansetron 4 mg/2 ml Solution for Injection

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ampoule containing 2 ml solution contains 4 mg ondansetron (as ondansetron hydrochloride dihydrate). The strength of the solution is 2 mg/ml ondansetron.

For excipients, see 6.1.

3.    PHARMACEUTICAL FORM

Solution for injection

The aqueous solution is clear and colourless.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Ondansetron hydrochloride is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of post-operative nausea and vomiting (PONV).

4.2.    Posology and method of administration

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

Emetogenic chemotherapy and radiotherapy:

Ondansetron hydrochloride can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration.

For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron hydrochloride 8 mg should be administered as a slow intravenous or intramuscular injection immediately before treatment, followed by 8 mg orally twelve hourly.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron hydrochloride 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, ondansetron hydrochloride can be given either by rectal, intravenous or intramuscular administration.

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

-    A single dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy

-    A dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy, followed by two further intravenous or intramuscular doses of 8 mg two or four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours

-    A single dose of 32 mg diluted in 50-100 ml of saline or other compatible infusion fluid (see Pharmaceutical Precautions) and infused over not less than 15 minutes immediately before chemotherapy

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

The efficacy of ondansetron hydrochloride in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate, 20 mg administered prior to chemotherapy.

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

Children:

Ondansetron hydrochloride may be administered as a single intravenous dose of 5 mg/m immediately before chemotherapy, followed by 4 mg orally twelve hours later. 4 mg orally twice daily should be continued for up to 5 days after a course of treatment.

Elderly:

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

Patients with renal impairment:

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

Patients with hepatic impairment:

Clearance of ondansetron hydrochloride 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.

Post-operative nausea and vomiting (PONV):

Adults:

For the prevention of PONV ondansetron hydrochloride can be administered orally or by intravenous or intramuscular injection.

Ondansetron hydrochloride may be administered as a single dose of 4 mg given by intramuscular or slow intravenous injection at induction of anaesthesia.

For treatment of established PONV a single dose of 4 mg given by intramuscular or slow intravenous injection is recommended.

Children (aged 2 years and over):

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia.

For treatment of established PONV in paediatric patients, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg.

There is limited data on the use of ondansetron hydrochloride in the prevention and treatment of PONV in children under 2 years of age.

Elderly:

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

Patients with renal impairment:

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

Patients with hepatic impairment:

Clearance of ondansetron hydrochloride 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.

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

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.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.

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

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 drugs commonly co-administered with it. Specific studies have shown that there are no pharmacokinetic interactions when ondansetron is administered with alcohol, temazepan, furosemide, tramadol 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.

Phenytoin, Carbamazepine andRifampicin: 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

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 ondansetron hydrochloride 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.

4.8. Undesirable effects

Ondansetron is known to increase large bowel transit time and may cause constipation in some patients. The following side effects can occur: headache, a sensation of flushing or warmth, hiccups and occasional asymptomatic increases in liver function tests. There have been rare reports of immediate hypersensitivity reactions sometimes severe including anaphylaxis. Rare cases of transient visual disturbances (e.g. blurred vision) and dizziness have been reported during rapid intravenous administration of ondansetron. There have been rare reports suggestive of involuntary movement disorders such as extrapyramidal reactions e.g. oculogyric crisis/dystonic reactions without definitive evidence of persistent clinical sequelae and seizures have been rarely observed although no known pharmacological mechanism can account for ondansetron causing these effects. Chest pain with or without ST segment depression, cardiac arrhythmias, hypotension and bradycardia have been rarely reported.

Occasionally, hypersensitivity reactions around the injection site (e.g. rash, urticaria, itching) may occur, sometimes extending along the drug administration vein.

4.9. Overdose

Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely. There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

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 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.

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 litres. 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 litres at 12 years to 17 litres 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 insignificantly, 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 halflife 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 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

Sodium chloride Citric acid monohydrate Sodium citrate Water for injections

Ondansetron 4 mg/2 ml Solution for Injection should not be administered in the same syringe or infusion as any other medication.

6.3. Shelf life

12 months (unopened). 24 hours (dilutions stored at 2-8°C).

6.4. Special precautions for storage

Do not store above 30°C. Keep ampoules in the outer carton.

Dilutions of Ondansetron 4 mg/2 ml Solution for Injection in compatible intravenous infusion fluids are stable under normal room lighting conditions or daylight for at least 24 hours, thus no protection from light is necessary while infusion takes place.

6.5.    Nature and contents of container

Ondansetron 4 mg/2 ml Solution for Injection, is contained in 2 ml Type I colourless ampoules with a green marking for the One-Point-Cut.

There are packs of 1, 2, 5, 6, 10, 25, 50 and 5x 50 ampoules.

6.6.    Instruction for use and handling

Compatibility with intravenous fluids:

Ondansetron 4 mg/2 ml Solution for Injection should only be admixed with those infusion solutions, which are recommended:

-    Sodium chloride intravenous infusion 0.9 %

-    Glucose intravenous infusion 5 %

-    Mannitol intravenous infusion 10 %

-    Ringer's intravenous infusion

-    Potassium chloride 0.3 % and sodium chloride 0.9 % intravenous infusion

-    Potassium chloride 0.3 % and glucose 5 % intravenous infusion

In keeping with good pharmaceutical practice, dilutions of Ondansetron 4 mg/2 ml Solution for Injection in intravenous fluids should be prepared at the time of infusion or stored at 2-8°C for no more than 24 hours before the start of administration.

Compatibility studies have been undertaken in polyvinyl chloride infusion bags and polyvinyl chloride administration sets. It is considered that adequate stability would also be conferred by the use of polyethylene infusion bags or type I glass bottles.

Dilutions of Ondansetron 4 mg/2 ml Solution for Injection in sodium chloride 0.9 % or in glucose 5 % have been demonstrated to be stable in polypropylene syringes. It is considered that Ondansetron 4 mg/2 ml Solution for Injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.

Compatibility with other drugs:

Ondansetron 4 mg/2 ml Solution for Injection may be administered by intravenous infusion at 1 mg/hour, e.g. from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the Ondansetron 4 mg/2 ml Solution for 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. 2.4 g in 3 litres or 400 mg in 500 ml) administered at a rate of at least 20 ml per hour (500 ml per 24 hours). Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-flourouracil infusions 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 as recommended by the manufacturer (e.g. 2.5 ml for 250 mg and 10 ml for 2 g ceftazidime), and given as an intravenous bolus injection over approximately five minutes.

Cyclophosphamide:

Doses in the range 100 mg to 1 g, reconstituted with water for injections, 5 ml per 100 mg cyclophosphamide, as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes.

Doxorubicin:

Doses in the range 10-100 mg reconstituted with water for injections, 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 20 mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 32 mg of ondansetron diluted in 50-100 ml of a compatible infusion fluid over approximately 15 minutes. Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the same giving set resulting in concentrations in line of 32 microgram - 2.5 mg/ml for dexamethasone sodium phosphate and 8 microgram - 1 mg/ml for ondansetron.

7. MARKETING AUTHORISATION HOLDER

Hospira Enterprises B.V Taurusavenue 19-21 2132 LS Hoopddorp The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 23061/0013

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/05/2006

10    DATE OF REVISION OF THE TEXT

04/05/2006