4.1. Therapeutic indications

Adults

Management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.

Prevention of post-operative nausea and vomiting.

Paediatric Population

Management of nausea and vomiting induced by cytotoxic chemotherapy in children and adolescents aged from 6 months to 17 years..

No studies have been conducted in children on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting; IV injection may be recommended for this purpose.

4.2. Posology and method of administration

CHEMOTHERAPY AND RADIOTHERAPY INDUCED NAUSEA AND VOMITING (CINV and RINV):

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.

CINV and RINV in Adults:

The recommended oral dose is 8 mg (10 ml, i.e., two 5 ml spoonfuls) 1-2 hours before treatment, followed by 8 mg (10 ml, i.e., two 5 ml spoonfuls) orally 12 hours later.

Highly emetogenic chemotherapy:

For patients receiving highly emetogenic chemotherapy a single oral dose of up to 24 mg (30 ml, i.e., six 5 ml spoonfuls) ondansetron taken together with 12 mg oral dexamethasone sodium phosphate, 1 to 2 hours before chemotherapy, may be used. After the first 24 hours, oral treatment with ondansetron should be continued for up to 5 days and rectal treatment for up to 3 days after a course of treatment. The recommended oral dose is 8 mg (10 ml, i.e., two 5 ml spoonfuls) to be taken twice daily.

Paediatric Population

CINV in Children and Adolescents (aged 6 months to 17 years):

The dose of CINV can be calculated based on body surface area (BSA) or weight. Weight-based dosing results in higher total daily doses compared to BSA-based dosing (section 4.4 and 5.1).

There are no data from controlled clinical trials on the use of ondansetron in the prevention of chemotherapy-induced delayed or prolonged nausea and vomiting. There are no data from controlled clinical trials on the use of ondansetron for radiotherapy-induced nausea and vomiting in children.

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.

Dosing by Body Surface Area (BSA)

Ondansetron should be administered immediately before chemotherapy as a single IV dose of 5 mg/m2. The single IV 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 CINV (aged 6 months to 17 years)

BSA

Day 1 (a, b)

Days 2-6 (b)

< 0.6 m2

5 mg/m2 IV plus 2 mg syrup (equivalent to 2.5 mls of syrup or the smaller end of spoon supplied in original pack) after 12 hours

2 mg syrup (equivalent to 2.5 mls of syrup or the smaller end of spoon supplied in original pack) every 12 hours

> 0.6 m2 to ≤ 1.2 m2

5 mg/m2 IV plus 4 mg syrup (equivalent to 5 mls of syrup or the larger end of spoon supplied in original pack) or one 4 mg tablet after 12 hours

4 mg syrup (equivalent to 5 mls of syrup or the larger end of spoon supplied in original pack) or one 4 mg tablet every 12 hours

a The intravenous dose must not exceed 8 mg

b the total dose over 24 hours 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 (section 4.4 and 5.1).

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

On Day 1, two further IV 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 32 mg.

Table 2. Weight-based dosing for CINV (aged 6 months to 17 years)

Body Weight

Day 1 (a, b)

Days 2-6 (b)

≤ 10 kg

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

2 mg syrup (equivalent to 2.5 mls of syrup or the smaller end of spoon supplied in original pack) every 12 hours

> 10 kg

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

4 mg syrup (equivalent to 5 mls of syrup or the larger end of spoon supplied in original pack) every 12 hours

a The intravenous dose must not exceed 8 mg

b the total dose over 24 hours must not exceed adult dose of 32 mg

CINV and RINV in Elderly:

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

POST-OPERATIVE NAUSEA AND VOMITING:

PONV in Adults:

For prevention of post-operative nausea and vomiting the recommended oral dose is16 mg (20 ml, i.e., four 5 ml spoonfuls) given one hour prior to anaesthesia.

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

Paediatric Population

PONV in Children and Adolescents (aged 1 month to 17 years):

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.

There are no data on the use of ondansetron in the treatment of post-operative nausea and vomiting in children under 2 years of age.

Elderly:

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

PATIENTS WITH RENAL/HEPATIC IMPAIRMENT:

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 IV or oral 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 is required.

Method of administration:

► Use the 2.5-5 ml double-ended spoon supplied in the pack (see below) to measure the required dose.

► The solution should be swallowed.

► The spoon should be washed with clean water after taking every dose.

► Once measured, the solution should be consumed within 3 hours

Double-ended Spoon

4.3. Contraindications

Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated (see section 4.5).

Hypersensitivity to ondansetron or to any of the excipients listed in section 6.1.

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.

Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). 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, conduction disturbances and in patients taking anti-arrhythmic agents or beta-adrenergic blocking agents or 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 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.

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.

Paediatric Population

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

Chemotherapy-induced nausea and vomiting:

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 indicate similar efficacy for both regimens (section 5.1).

Excipient warnings:

Sorbitol (E420): This medicinal product contains 2100 mg sorbitol in each 5 ml dose which is equivalent to 420 mg/ml. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. Sorbitol may cause gastrointestinal discomfort and mild laxative effect.

Sodium benzoate (E211): This medicinal product contains 6 mg sodium benzoate in each 5 ml dose which is equivalent to 1.2 mg/ml.

Propylene glycol (E1520): This medicinal product contains 14.1 mg/5 ml propylene glycol in each 5 ml dose which is equivalent to 2.82 mg/ml.

Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per 5 ml dose, that is to say 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 interactions when ondansetron is administered with alcohol, temazepam, frusemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P450 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 coadministered with drugs that prolong the QT interval (including some Cytotoxics) 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 or 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 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. 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 do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

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

Pregnancy testing

Pregnancy status should be verified in women of child-bearing potential prior to starting the treatment with ondansetron.

Breast-feeding

There is insufficient information on the excretion of ondansetron/metabolites in human milk or the effects of ondansetron on milk production. Available pharmacodynamic/toxicological data in animals have shown excretion of ondansetron/metabolites in milk (for details see 5.3). A risk to the newborns/infants cannot be excluded. Ondansetron should not be used during breast-feeding.

Fertility

There are no data 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 according to indication and formulation. The adverse event profiles in children and adolescents were comparable to that seen in adults.

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 oculogyric crisis, dystonic reactions, and dyskinesia) 1

Rare:

Dizziness predominantly during rapid IV administration.

Eye disorders

Rare:

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

Very rare:

Transient blindness predominantly during intravenous administration 2.

Cardiac disorders

Uncommon:

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

Rare:

QTc prolongation (including Torsades de Pointes)

Frequency 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.

Local burning sensation following insertion of suppositories.

Hepatobiliary disorders

Uncommon:

Asymptomatic increases in liver function tests 3.

Skin and subcutaneous tissue disorders

Very rare:

Toxic skin eruption, including toxic epidermal necrolysis.

General disorders and administration site conditions

Common:

Local IV injection site reactions.

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.

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 Website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 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.

Treatment

There is no specific antidote for ondansetron therefore in 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.