4.1. Therapeutic indications

Adults:

The management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention of post-operative nausea and vomiting in adults.

Paediatric Population:

Ondansetron is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged ≥ 6 months.

No studies have been conducted on the use of orally administered ondansetron in the prevention and treatment of PONV in children aged ≥ 1 month administration by IV injection is recommended for this purpose.

4.2. Posology and method of administration

Posology

Chemotherapy and radiotherapy induced nausea and vomiting (CINV)

Adults:

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The selection of dose regimen should be determined by the severity of the emetogenic challenge.

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

For oral administration: 8mg taken 1 to 2 hours before chemotherapy or radiation treatment, followed by 8mg every 12 hours for a maximum of 5 days to protect against delayed or prolonged emesis.

For highly emetogenic chemotherapy): a single dose of up to 24mg ondansetron taken with 12mg oral dexamethasone sodium phosphate, 1 to 2 hours before chemotherapy, may be used.

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.

Paediatric Population:

CINV in children aged ≥ 6 months and adolescents

The dose for 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 and infused over not less than 15 minutes.

Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4).

Ondansetron injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid (see section 6.6) and infused intravenously over not less than 15 minutes.

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/m2. The intravenous dose must not exceed 8 mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 1).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

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

BSA

Day 1(a, b)

Days 2 – 6(b)

< 0.6m2

5mg/m2 i.v. plus

2mg syrup after 12 hrs

2mg syrup every 12 hours

≥ 0.6 m2 to ≤ 1.2 m2

5mg/m2 i.v. plus

4mg syrup or tablet after 12 hrs

4mg syrup or tablet every 12 hrs

>1.2m2

5mg/m2 or 8mg IV plus

8mg syrup or tablet after 12 hours

8mg syrup or tablet every 12 hours

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours (given as divided doses) 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 (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.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 2). The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32mg.

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

Weight

Day 1 (a, b)

Days 2 – 6 (b)

≤ 10kg

Up to 3 doses of 0.15 mg/kg every 4 hours

2mg syrup every 12 hours

>10kg

Up to 3 doses of 0.15 mg/kg every 4 hours

4mg syrup or tablet every 12 hours

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Elderly:

Ondansetron is well tolerated by patients over 65 years. No alteration of oral dose or frequency of administration is required.

Post operative nausea and vomiting (PONV).

Adults:

For the prevention of PONV: Ondansetron can be administered orally or by intravenous or intramuscular injection.

For oral administration: 16mg one hour prior to anaesthesia.

For the treatment of established PONV: Intravenous or intramuscular administration is recommended.

Paediatric population

PONV in children aged ≥ 1 month and adolescents

Oral formulation:

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

Injection:

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia.

For the treatment of PONV after surgery in paediatric patients having surgery performed under general anaesthesia, a single dose of Ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg.

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

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 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 8mg should not be exceeded.

Patients with poor Sparteine/Debrisoguine 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.

Method of administration

Oral

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Concomitant use with apomorphine (see section 4.5).

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.

Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.

Cases of myocardial ischemia have been reported in patients treated with ondansetron. In some patients, especially in the case of intravenous administration, symptoms appeared immediately after administration of ondansetron. Patients should be alerted to the signs and symptoms of myocardial ischaemia.

Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). In addition, post-marketing cases of Torsades de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital 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 hypomagnesaemia 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 patients is advised.

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.

Ondansetron Syrup contains sodium benzoate (E211), which may increase jaundice (yellowing of the skin and eyes) in new born babies (up to 4 weeks old).

This medicine contains Xylitol (E 967) which may have a laxative effect and has a calorific value of 2.4 kcal/g xylitol.

Paediatric Population:

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

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 5mg/m2 followed by an oral dose is given. The comparative efficacy of these two different dosing regimes has not been investigated in clinical trials. Cross-trial comparison indicates similar efficacy for both regimes (section 5.1).

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, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental and 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.

Caution should be exercised when ondansetron is co-administered with drugs that prolong the QT interval and/or cause electrolyte abnormalities (see section 4.4).

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 trastuzumab), antibiotics (such as erythromycin), antifungals (such as ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of arrhythmias (see section 4.4).

Serotonergic Drugs (e.g. SSRIs and SNRIs): 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 apomorphone 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. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should consider the use of contraception.

Pregnancy

Based on human experience from epidemiological studies, ondansetron is suspected to cause orofacial malformations when administered during the first trimester of pregnancy.

In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10 000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)).

The available epidemiological studies on cardiac malformations show conflicting results.

Animal studies does not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Ondansetron should not be used during the first trimester of pregnancy.

Breast-feeding

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.

Fertility

There is no information on the effects of ondansetron on human fertility.

4.7. Effects on ability to drive and use machines

Ondansetron has no or negligible influence on the 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 and <1/10), uncommon (≥ 1/1000 and <1/100), rare (≥ 1/10,000 and <1/1000) and 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.

System organ class

Frequency

Undesirable effects

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 dyskinesia1

Rare

Dizziness during rapid IV administration

Eye disorders

Rare

Transient visual disturbances (e.g. blurred vision) predominantly during IV administration

Very rare

Transient blindness predominantly during intravenous administration2.

Cardiac disorders

Uncommon

Arrhythmias, chest pain with or without ST segment depression, bradycardia

Rare

QTc prolongation (including Torsades de Pointes)

Unknown

Myocardial ischemia (see section 4.4)

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 tests3.

1 Observed without definitive evidence of persistent clinical sequelae.

2 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 profiles in children and adolescents were comparable to that seen in adults.

Reporting of suspected adverse reactions

Reporting of 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

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

Paediatric population

Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12 months to 2 years.

Management

There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

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.