4.1. Therapeutic indications

Adults

Ondansetron 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.

Paediatric population

In children over 6 months old and adolescents ondansetron is indicated for the management of chemotherapy‑induced nausea and vomiting.

In children over 1 month old and adolescents ondansetron is indicated for the prevention and treatment of post‑operative nausea and vomiting.

4.2. Posology and method of administration

Posology

The emetogenic potential of cytostatic or radiotherapy varies depending on the dose level and therapeutic regimen. The selection of dose regimen should be determined by the severity of the emetogenic challenge.

Ondansetron is also available for rectal and/or oral administration and allows the dosage to be individually adjusted. For rectal or oral administration refer to the relevant product information.

Adults

Chemotherapy and radiotherapy induced nausea and vomiting

The recommended dose is 8 mg ondansetron intravenously (IV) or intramuscularly (IM) immediately before chemotherapy or radiotherapy.

In highly emetogenic chemotherapy, a maximum initial dose of 16 mg can be administered as an intravenous infusion over not less than 15 minutes.

A single dose greater than 16 mg must not be given due to dose dependent increase of the risk of QT prolongation (see section 4.4).

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

Intravenous doses greater than 8 mg and up to a maximum dose of 16 mg must be diluted in 50‑100 ml of 9 mg/ml (0.9%) sodium chloride or 50 mg/ml (5%) glucose solution for infusion or other compatible solution for infusion (see section 6.6) and infused over at least 15 minutes.

Doses of ondansetron 8 mg or less do not need to be diluted and can be administered as a slow intramuscular injection or intravenous infusion over a period of at least 30 seconds.

The initial dose of ondansetron may be followed by two additional 8 mg intravenous or intramuscular doses 2 to 4 hours apart or a continuous infusion of 1 mg/hour for up to 24 hours.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron is recommended.

The total maximum daily dose for adults is 32 mg.

Post-operative nausea and vomiting

To prevent postoperative nausea and vomiting, the recommended dose is 4 mg ondansetron as a single dose given by intramuscular or slow intravenous injection at induction of anaesthesia.

For treatment of existing postoperative nausea and vomiting, a single dose of 4 mg given by intramuscular or slow intravenous injection is recommended.

Paediatric population

Chemotherapy‑induced nausea and vomiting in children and adolescents form 6 months to 17 years

The dose can be calculated based on body surface area or body weight. In paediatric clinical studies, ondansetron was given by intravenous infusion diluted in 25 to 50 ml of sodium chloride or other compatible infusion fluid (see section 6.6). The infusion must not last less than 15 minutes.

Posology based on body surface area

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 12 hours later and may be continued for up to 5 days (see Table 1). The adult dose must not be exceeded.

Table 1 Posology based on body surface area for children and adolescents form 6 months to 17 years

Body surface area

Day 1

Days 2‑6

< 0.6 m2

5 mg/m2 IV and 2 mg orally* after 12 hours

2 mg orally* every 12 hours

≥ 0.6 m2 to ≤ 1.2 m2

5 mg/m2 IV and 4 mg orally* after 12 hours

4 mg orally* every 12 hours

> 1.2 m2

5 mg/m2 IV or 8 mg IV and 8 mg orally* after 12 hours

8 mg orally* every 12 hours

* Appropriate oral dosage form available (e.g. syrup, oral solution, tablets) should be used

Posology based on body weight

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. On Day 1, two further intravenous doses may be given in 4‑hourly intervals. Oral dosing can commence 12 hours later and may be continued for up to 5 days (see Table 2). The adult dose must not be exceeded.

Table 2 Posology based on body weight for children and adolescents form 6 months to 17 years

Body weight

Day 1

Days 2‑6

≤ 10 kg

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

2 mg orally* every 12 hours

> 10 kg

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

4 mg orally* every 12 hours

* Appropriate oral dosage form available (e.g. syrup, oral solution, tablets) should be used

Post‑operative nausea and vomiting in children and adolescents from 1 month to 17 years

For prevention of postoperative nausea and vomiting 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 0.1 mg/kg (up to a maximum dose of 4 mg) either prior to, at or after induction of anaesthesia or after surgery.

For the treatment of existing postoperative nausea and vomiting in paediatric patients, the dose 0.1 mg/kg (up to a maximum dose of 4 mg) ondansetron is recommended, administered by slow intravenous injection.

Elderly ≥ 65 years

Chemotherapy and radiotherapy induced nausea and vomiting

In patients 65 years of age or older, all intravenous doses should be diluted and infused over 15 minutes. If repeated dosing is necessary, these should be given at least 4 hours apart.

In patients 65 to 74 years of age, the initial dose of 8 mg or 16 mg may be administered as an infusion over 15 minutes. This may be followed by two further doses of 8 mg, infused over 15 minutes and given no less than 4 hours apart.

In patients 75 years of age or older, the initial dose of ondansetron, administered as an infusion over 15 minutes, must not exceed 8 mg. This may be followed by two further intravenous doses of 8 mg, infused over 15 minutes and given no less than 4 hours apart (see section 5.2).

Post-operative nausea and vomiting

There is limited experience in the use of ondansetron in the prevention and treatment of postoperative nausea and vomiting in the elderly. However, ondansetron is well tolerated by patients over 65 years.

Patients with hepatic impairment

Clearance of ondansetron is significantly reduced and serum half‑life significantly prolonged in patients with moderate or severe hepatic impairment. In these patients a total daily dose of 8 mg must not be exceeded.

Patients with renal impairment

No dose adjustment, frequency of administration, or method of administration are required.

Patients with poor sparteine/debrisoquine metabolism

The elimination half‑life of ondansetron is not altered in patients classified as poor metabolisers of sparteine and debrisoquine. Consequently, in these patients repeat dosing will give drug exposure levels no different from those of the general population. No adjustment of daily dose or frequency of dosing are required.

Compatibility with other drugs

Ondansetron may be administered by intravenous infusion (1 mg/hour). Although ondansetron must not at the same time be mixed with other medicinal products for infusion, the following medicinal products may be administered via the Y‑site of the ondansetron giving set for ondansetron concentrations of 16 to 160 mcg/ml (e.g. 8 mg/500 ml and 8 mg/50 ml, respectively).

‒ Cisplatin: Concentrations up to a maximum of 0.48 mg/ml (e.g. 240 mg in 500 ml) can be administered over 1 to 8 hours.

‒ 5‑Fluorouracil: Concentrations up to a maximum of 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/hour (500 ml/24 hours). Higher concentrations of 5‑fluorouracil may cause precipitation of ondansetron. The 5‑fluorouracil infusion may contain up to 0.045% 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 10 minutes to one hour.

‒ Etoposide: Concentrations in the range 0.144 mg/ml to 0.25 mg/ml (e.g. 72 mg in 500 ml to 250 mg in 1000 ml), administered over 30 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 5 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 5 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 sodium phosphate: 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 mg or 16 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 mcg/ml to 2.5 mg/ml for dexamethasone sodium phosphate and 8 mcg/ml to 1 mg/ml for ondansetron.

Method of administration

For intravenous or intramuscular use.

Ondansetron can be administered as a slow intravenous injection or slow intravenous infusion, or intramuscular injection.

For instructions on dilution of the medicinal product before administration and compatible solutions, see section 6.6.

4.3. Contraindications

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

Severe hypotension and loss of consciousness have been reported to occur when ondansetron was co‑administered with apomorphine hydrochloride.

Concomitant use with apomorphine is contraindicated (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.

If respiratory difficulties occur, these should be treated symptomatically and carefully monitored by the medical staff, as respiratory difficulties may be a sign 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 receiving ondansetron therapy. Ondansetron should be avoided in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop prolongation of QT, including patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities.

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.

Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron administration.

Care should therefore be taken when administering ondansetron to patients with arrhythmias or cardiac conduction disorders as well as to patients treated with antiarrhythmic agents or beta‑blockers and patients with significant electrolyte imbalance.

Serotonin syndrome has been described after co‑administration of ondansetron and other serotonergic agents (see section 4.5). If concomitant treatment with ondansetron and other serotonergic agents is clinically justified, appropriate observation of the patient is advised.

As ondansetron may increase large bowel transit time, caution is advised in patients with impaired bowel motility (or intestinal obstruction). These patients should be carefully monitored for their bowel function.

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

Paediatric population

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

Excipients

This medicinal product contains 3.52 mg sodium per ml, equivalent to 0.18% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental, or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P450 enzymes (CYP3A4, CYP2D6 and CYP1A2). As a large number of hepatic enzymes are involved in the degradation of ondansetron, the risk of competitive metabolic interactions is low and enzyme inhibition or reduced activity of enzyme systems (e.g. genetic CYP2D6 deficiency) is compensated for by other implicated enzyme systems; as a result, even in these cases, overall clearance of ondansetron is almost unchanged.

Caution should be exercised when ondansetron is co‑administered with medicinal products that prolong the QT interval and/or lead to electrolyte imbalances. Use of ondansetron with QT prolonging medicinal products may further prolong the QT interval. 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).

Apomorphine

Severe hypotension and loss of consciousness have been reported to occur when ondansetron was administered with apomorphine hydrochloride. Concomitant use with apomorphine is contraindicated (see section 4.3).

Phenytoin, carbamazepine and rifampicin

In patients treated with highly potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine or rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.

Serotonergic agents (e.g. SSRIs and SNRIs)

Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) has been reported after concomitant use of ondansetron and other serotonergic medicinal products including selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) (see section 4.4).

Tramadol

Two small interaction studies indicate that ondansetron may reduce the analgesic effect of tramadol.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

In a cohort study including 1.8 million pregnant women, the use of ondansetron in first trimester was associated with an increased risk of cleft lip, jaw and palate (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.

Breast-feeding

It is not known whether ondansetron is excreted in breast milk. No data are available on the influence of ondansetron on the breast‑fed child or on the production of breast milk. However, it has been shown that ondansetron is excreted in the breast milk of lactating animals (rats). It is therefore recommended that breast‑feeding be discontinued prior to treatment with ondansetron.

Fertility

Ondansetron has no effect on fertility.

Women of childbearing potential

Women of childbearing potential should consider the use of contraception.

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 reactions are listed below by system organ class (according to the MedDRA database) and frequency (all reported events). Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Very common, common and uncommon adverse reactions were generally determined from clinical trial data; the incidence of adverse reactions with placebo was taken into account. Rare and very rare adverse reactions were generally determined on the basis of spontaneous reporting data.

The following frequencies are estimated at the standard recommended doses of ondansetron.

Immune system disorders

Rare:

immediate‑type hypersensitivity reactions, which can sometimes be serious, including anaphylaxis.

Nervous system disorders

Very common:

Uncommon:

Rare:

headache.

seizures, movement disorders (including extrapyramidal symptoms such as dystonic reactions, oculogyric crisis and dyskinesia) observed without definitive evidence of persistent clinical sequelae.

dizziness, mainly with too rapid IV administration.

Eye disorders

Rare:

Very rare:

transient visual disturbances (e.g. blurred vision) mainly with too rapid IV administration.

transient blindness, mainly with IV administration.

In the majority of the blindness cases, a full recovery was made within 20 minutes. Most patients had received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness were of cortical origin.

Cardiac disorders

Uncommon:

Rare:

Not known:

chest pain with or without ST segment depression on ECG, bradycardia and arrhythmias.

prolongation of the QT interval (including torsade de pointes).

myocardial ischemia (see section 4.4).

Vascular disorders

Common:

Uncommon:

sensation of warmth or hot flushes.

hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon:

hiccups.

Gastrointestinal disorders

Common:

Not known:

constipation.

dry mouth.

Hepatobiliary disorders

Uncommon:

asymptomatic increases in liver function tests. These events were observed commonly in patients receiving chemotherapy with cisplatin.

Skin and subcutaneous tissue disorders

Common:

Very rare:

flushing.

toxic skin rash including toxic epidermal necrolysis.

General disorders and administration site conditions

Common:

local irritation after IV administration.

Paediatric population

The adverse effect 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, Website: 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. However, in the event of accidental overdosing the following symptoms of intoxication can be expected: visual disturbances, severe constipation, hypotension and a vasovagal episode with a transient second-degree AV block. In all cases, the events resolved completely.

Ondansetron prolongs the QT interval in a dose-dependent manner. 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. 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 antiemetic action of ondansetron itself.