SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ondansetron 4mg/5ml Oral Solution

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each 5ml contains 4mg of ondansetron as the hydrochloride dihydrate.

For a full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Oral solution.

A clear, colourless sucrose-free solution with an odour of strawberry.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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 Chemotherapy and radiotherapy induced nausea and vomiting Adults (including the elderly):

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

For oral administration: 8mg 1-2 hours before treatment, followed by 8mg 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 dose for oral administration is 8mg twice daily.

Highly emetogenic chemotherapy (e.g. high dose cisplatin): Ondansetron can be given either by rectal, intravenous or intramuscular administration.

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 dose for oral administration is 8mg twice daily.

Children:

Ondansetron may be administered as a single intravenous dose of 5mg/m² immediately before chemotherapy, followed by 4mg orally twelve hours later.

4mg orally twice daily should be continued for up to 5 days after a course of treatment.

Post operative nausea and vomiting (PONV)

Adults:

For oral administration: 16mg one hour prior to anaesthesia. Alternatively, 8mg one hour prior to anaesthesia followed by two further doses of 8mg at eight hourly intervals.

Children (aged 2 years and above):

For the prevention and treatment of PONV: slow intravenous injection is recommended.

Elderly:

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

For both indications:

Patients with renal impairment:

No special requirements.

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 8mg 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.

Contraindications

Hypersensitivity to any ingredient of the formulation.

Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

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.

Very rarely and predominantly with intravenous Ondansetron, transient ECG changes including QT interval prolongation have been reported. Therefore caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic agents or beta-adrenergic blocking agents and in patients with significant electrolyte disturbances.

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

Ondansetron 4mg/5ml Oral Solution contains sorbitol and therefore patients with rare hereditary problems with fructose intolerance should not take this medicine.

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.

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, tamazepam, 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, Carbamezapine 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.

Use with ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines) may increase the risk of arrhythmias (section 4.4).

4.6 Fertility, 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 Oral Solution should not breastfeed their babies.

4.7 Effects on ability to drive and use machines

None reported.

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.

Immune system disorders

Rare: immediate hypersensitivity reactions sometimes severe, including anaphylaxis. Nervous system disorders

Very common: headache.

Uncommon: Seizures, movement disorders including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia have been observed without definitive evidence of persistent clinical sequelae.

Eye disorders

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.

Rare: QTc prolongation (including Torsade de Pointes).

Vascular disorders

Common: Sensation of warmth or flushing.

Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: Hiccups.

Gastrointestinal disorders

Common: Constipation.

Hepatobiliary disorders

Uncommon: Asymptomatic increases in liver function tests^*.

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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

Ondansetron is a potent, highly selective 5HT₃ receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT₃ receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT₃ receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in postoperative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.

Ondansetron does not alter plasma prolactin concentrations.

The role of Ondansetron in opiate-induced emesis is not yet established.

5.2    Pharmacokinetic properties

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

ATC Code: A04AA01.

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 (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 140L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.

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.

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.

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

No additional data of relevance.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium citrate Citric acid anhydrous Saccharin sodium Sorbitol solution 70% w/w Sodium benzoate Strawberry flavour Purified water

6.2 Incompatibilities

None reported.

6.3 Shelf life

Unopened:    24 months

After opening use within 28 days.

6.4    Special precautions for storage

Store upright, below 30°C. Do not refrigerate.

6.5    Nature and contents of container

Amber glass bottle with child resistant tamper evident cap. The product is supplied with a 5ml / 2.5ml double ended measuring spoon.

Pack sizes available: 50ml

6.6    Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Transdermal Limited 35 Grimwade Avenue Croydon CR0 5DJ UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 14308/0015

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/12/2014

10    DATE OF REVISION OF THE TEXT

18/12/2014