1.0 TRADE NAME OF THE MEDICINAL PRODUCT 

Ondemet 2mg/ml Injection

2.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution for injection and infusion contains 2mg ondansetron as ondansetron hydrochloride dihydrate.

Each 2 ml ampoule contains 4 mg of ondansetron
Each 4 ml ampoule contains 8 mg of ondansetron

For excipients, see section 6.1.

3.0 PHARMACEUTICAL FORM

Solution for injection and infusion, ampoule.
Clear solution.

4.0 CLINICAL PARTICULARS 

4.1 Therapeutic indications 

Ondemet 2mg/ml Injection is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention of post-operative nausea and vomiting (PONV).

4.2 Posology and method of administration 

For intravenous injection or after dilution for intravenous infusion.

Chemotherapy and radiotherapy induced nausea and vomiting
Adults
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of ondansetron should be flexible and selected as shown below.

Emetogenic chemotherapy and radiotherapy
For patients receiving emetogenic chemotherapy or radiotherapy ondansetron can be given either by oral or intravenous administration.

For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron should initially be administered intravenously immediately before treatment, followed by 8 mg orally twelve hourly.

For oral administration: 8 mg 1-2 hours before treatment, followed by 8 mg 12 hours later.

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg twice daily.

Highly emetogenic chemotherapy
Adults: Either 8 mg as a slow intravenous bolus injection or as a short-term infusion lasting 15 minutes immediately before chemotherapy. If this initial dose has insufficient effect it can be supplemented by either 8 mg (intravenous bolus or 15 minutes' infusion) every 4th hour, at most twice, or continuous infusion of 1 mg/hour for 24 hours. In some cases the initial dose can be increased to 32 mg diluted with a compatible infusion fluid as an infusion lasting at least 15 minutes immediately before chemotherapy.

After 24 hours treatment is changed to the oral route.

The effect of ondansetron may be enhanced by the simultaneous administration of 20 mg dexamethasone intravenously or an equally potent dose of another glucocorticoid for intravenous use.

Children (aged 2 years and over) and adolescents (< 18 years)
Experience in paediatric patients is limited. In children older than two years, ondansetron may be administered as a single intravenous dose of 5 mg/m2 over 15 minutes immediately before chemotherapy, followed by 4 mg orally twelve hours later. Oral treatment with a dose according to the body area should be continued for up to 5 days after a course of treatment. Children with a total body area between 0.6 and 1.2 m2 should receive a dosage schedule of 4 mg 3 times a day, while children with a body area above 1.2 m2 should receive 8 mg 3 times a day.

There is no experience in children younger than 2 years old.

Ondemet 2mg/ml Injection cannot be used in children with a total body surface below 0.6 m2.

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

Please refer also to ”Special populations”.

Post-operative nausea and vomiting (PONV)
Prevention of PONV
For the prevention of PONV ondansetron can be administered orally or by intravenous injection.
Adults: 8 mg as a slow intravenous bolus injection at induction of anaesthesia.

Children aged 2 years and over: 0.1 mg/kg up to a maximum of 4 mg as a slow intravenous bolus injection either before, at or after induction of anaesthesia.

Treatment of established PONV
For the treatment of established PONV intravenous administration is recommended.
Up to 8 mg as a slow bolus injection intravenously or intramuscularly.

Children (aged 2 years and over) and adolescents (< 18 years)
For the prevention and treatment of PONV slow intravenous injection is recommended.
0.1 mg/kg up to a maximum of 4 mg as a slow intravenous bolus injection

Elderly
There is limited experience in the use of ondansetron in the prevention and treatment of post-operative nausea and vomiting (PONV) in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.

Please refer also to “Special populations”.

Special populations
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 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.

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 medicinal product 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 ondansetron or to other selective 5-HT3-receptor antagonists (e.g. granisetron, dolasetron) or to any of the excipients.

4.4 Special warnings and special precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.

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

In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron.

Since there is little experience to date of the use of ondansetron in cardiac patients, caution should be exercised if ondansetron is coadministered with anaesthetics to patients with arrhythmias or cardiac conduction disorders or to patients who are being treated with antiarrhythmic agents or beta-blockers.

The solution for injection contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially ‘sodium- free’.

Ondemet 2mg/ml Injection should not be used in children with a total body surface below 0.6 m2.
The medicinal product should not be used for children younger than two years, as for these patients the experience is limited.

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 coadministered with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, 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.

Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was increased and ondansetron blood concentrations were decreased.

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

4.6 Pregnancy and lactation

Pregnancy
Data on a limited number of exposed pregnancies indicate no adverse effects of ondansetron on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Use in human pregnancy has not been established and is not recommended. If it is absolutely necessary that ondansetron be given caution should be exercised when prescribing to pregnant women especially in the first trimester. A careful risk/benefit assessment should be performed.

Lactation
Tests have shown that ondansetron passes into the milk of lactating animals (see section 5.3). It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies.

4.7  Effects on ability to drive and use machines

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

4.8  Undesirable effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (1/10), common (1/100 and <1/10), uncommon (1/1000 and <1/100), rare (1/10,000 and <1/1000) and very rare (<1/10,000) including isolated reports. 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.

Immune system disorders
Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.

Nervous system disorders
Very common: Headache.

Uncommon: Extrapyramidal reactions (such as oculogyric crisis/dystonic reactions) have been observed without definitive evidence of persistent clinical sequelae; seizures.

Rare: Dizziness during rapid intravenous administration.

Eye disorders
Rare: Transient visual disturbances (eg. blurred vision) predominantly during rapid intravenous administration.

Very rare: transient blindness predominantly during intravenous administration.
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.

Cardiac disorders
Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia.

Vascular disorders
Common: Sensation of warmth or flushing.

Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders
Uncommon: Hiccups.

Gastrointestinal disorders
Common: Constipation. Local burning sensation following insertion of suppositories.

Hepatobiliary disorders
Uncommon: Asymptomatic increases in liver function tests.
These events were observed commonly in patients receiving chemotherapy with cisplatin.

General disorders and administration site conditions
Common: Local intravenous injection site reactions

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.

5.0   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT3) antagonists

ATC Code: A04AA01

Ondansetron is a potent, highly selective 5-HT3 receptor-antagonist.

Its precise antiemetic and antinauseal mechanism of action is not known. Chemotherapeutic agents and radiotherapy may cause release of 5-HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5-HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5-HT 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 5-HT3 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.

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.

5.2  Pharmacokinetic properties

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (bioavailability is about 60%). 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.

The protein binding of ondansetron is 70-76%. A direct effect of plasma concentration and anti-emetic effect has not been established. 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 has no effect on ondansetron’s pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

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.

5.3   Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Ondansetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was 5.2.

A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. The clinical relevance of this finding is uncertain.

6.0 PHARMACEUTICAL  PARTICULARS

6.1 List of excipients 

Sodium chloride.
Citric acid monohydrate.
Sodium citrate.
Water for injections.

6.2 Incompatibilities 

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life  

Unopened 3 years.
After opening: 24 hours stored in a refrigerator (2-8°C).

6.4 Special precautions for storage 

This medicinal product does not require any special storage precautions.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C.

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user

6.5 Nature and contents of container 

Amber glass ampoules, type 1, containing 2 ml or 4 ml solution

Packs of 5 and 5 x 5 ampoules.

Not all pack sizes may be marketed.

6.6. Instructions for use/handling 

For single use only. Any unused solution should be discarded.

The solution is to be visually inspected prior to use (also after dilution). Only clear solutions practically free from particles should be used.

May be diluted with solution for infusion containing: sodium chloride 9 mg/ml (0.9%), glucose 50 mg/ml (5 %), mannitol 100 mg/ml (10 %) potassium chloride 3 mg/ml (0.3%)+ sodium chloride 9 mg/ml (0.9 %) and potassium chloride 3 mg/ml (0.3%) + glucose 50 mg/ml (5 %) as well as Ringer solution for infusion.

Should not be mixed with other pharmaceutical products.

7.0 MARKETING AUTHORISATION HOLDER 

Beacon Pharmaceuticals Ltd
The Regent
The Broadway
Crowborough
East Sussex
TN6 1DA
UK

8.0 MARKETING AUTHORISATION NUMBER 

PL 18157/0018

9.0 DATE OF FIRST AUTHORISATION

March 2006

10.0 DATE OF (PARTIAL) REVISION OF TEXT 

September 2006