Consumer medicine information

Ondansetron Accord

Ondansetron

BRAND INFORMATION

Brand name

Ondansetron Accord

Active ingredient

Ondansetron

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ondansetron Accord.

What is in this leaflet

This leaflet answers some common questions about Ondansetron Accord Injection. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Ondansetron Accord Injection against the benefits this medicine is expected to have for you.

This medicine is likely to be used while you are at the clinic or in hospital. If possible, please read this leaflet carefully before this medicine is given to you. In some cases this leaflet may be given to you after the medicine has been used.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Ondansetron Accord is used for

Ondansetron Accord Injection contains a medicine called ondansetron. This belongs to a group of medicines called antiemetics/antinauseants.

Ondansetron Accord Injection is used to prevent the nausea (feeling sick) and vomiting that may occur after surgery or after therapy with anticancer medicines (chemotherapy) or radiation.

Ondansetron Accord Injection may be used for the management of other conditions that are not mentioned above. Your doctor will be able to tell you about the specific condition for which you have been prescribed Ondansetron Accord Injection.

This medicine is available only with a doctor’s prescription.

Before you are given Ondansetron Accord

When you must not be given it

Do not use Ondansetron Accord Injection if:

  • you have an allergy to ondansetron or any of the ingredients listed at the end of this leaflet
  • you are pregnant or trying to become pregnant
  • you are breastfeeding
  • you are taking apomorphine (used to treat Parkinson’s disease)

If you are not sure whether any of these apply to you, check with your doctor.

Before you are given it

Tell your doctor if:

  • you have any allergies to:
    - any other medicine
    - any other substances, such as foods, preservatives or dyes
  • you are pregnant or intend to become pregnant
  • you are breastfeeding or plan to breastfeed
  • you have liver problems
  • you have an abnormal heart rhythm (QT prolongation)
  • you have any blood problems, including abnormal salt levels in your blood.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and ondansetron may interfere with each other. These include:

  • pain killers such as tramadol
  • antibacterials such as rifampicin
  • medicines that are known to lead to an abnormal heart rhythm (QT prolongation)

Your doctor will advise you about any dosage adjustments needed and continuing to take other medicines while you are receiving Ondansetron Accord Injection.

How Ondansetron Accord is given

Ondansetron Accord Injection is given by injection into the muscle or by slow injection into a vein. It must only be given by a doctor or nurse.

Your doctor will decide what dose and how long you will receive Ondansetron Accord Injection.

The clinical safety of Ondansetron in children under 2 years has not been established.

If you are given too much (overdose)

This rarely happens as Ondansetron Accord Injection is administered under the care of a highly trained doctor.

However, if you are given too much ondansetron, you may experience some of the effects listed under “Side effects” below.

Your doctor has information on how to recognise and treat an overdose.

Ask your doctor if you have any concerns.

Side Effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given Ondansetron Accord Injection or if your nausea and vomiting does not go away.

Like other medicines, Ondansetron Accord Injection can cause some side effects. If they occur, most are likely to be minor or temporary. However, some may be serious and need medical attention.

Ask your doctor or pharmacist to answer any questions that you may have.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor or nurse if you notice any of the following:

  • headache
  • a sensation of warmth or flushing
  • mild stomach cramps
  • constipation or diarrhoea
  • dry mouth
  • pain, redness or burning at place of injection
  • hiccups

These are all common side effects.

Tell your doctor or nurse immediately if you notice any of the following:

  • ‘wheezy’ symptoms
  • chest pain or tightness of the chest
  • changes in the way your heart beats, e.g. if you notice it beating faster or slower than normal, or if it beats irregularly or if it ‘throbs’
  • disturbance in heart rhythm (sometimes causing a sudden loss of consciousness)
  • patients may experience “serotonin syndrome” (confusion, sweating, unsteadiness, shaking, diarrhoea) when Ondansetron Accord Injection is taken in combination with other serotonergic drugs can include certain types of antidepressants, opioid pain medicines such as tramadol and fentanyl, and lithium. Please note, this is not an exhaustive list. Please discuss with your pharmacist or doctor if you have any concerns.
  • Severe skin reaction where the top layer of the skin detaches from the lower layers.
  • low blood pressure
  • fits or convulsions
  • swelling of the eyelids, face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • skin rash, skin lumps or hives
  • blurred vision
  • dizziness

These are serious side effects, some of which include symptoms of an allergic reaction. You may need urgent medical attention. Serious side effects are rare.

Other side effects not listed above may also occur in some patients.

Storage

Stored below 25°C. Protect from Light.

Disposal

Any Ondansetron Accord from a single dose preparation which is not used, will be disposed of in a safe manner by your doctor or pharmacist.

Product Description

What it looks like

Ondansetron Accord Injection is a clear, colourless to almost colourless solution in a clear or amber glass ampoules in packs of 5 or 10. Or in a syringe in a 1 pack.

Not all presentations and pack sizes may be marketed.

Ingredients

Active ingredient:
Ondansetron (as ondansetron hydrochloride dihydrate)

Inactive ingredients:
sodium chloride
sodium citrate dihydrate
citric acid monohydrate
sodium hydroxide
hydrochloric acid
water for injections

Name and Address of the Sponsor

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

Australian Registration Numbers

Ampoule
4 mg/2 mL: AUST R 205594
8 mg/4 mL: AUST R 205599

Syringe
4 mg/2 mL: AUST R 338224
8 mg/4 mL: AUST R 338227

Date of Preparation

This leaflet was prepared on 09 November 2020.

Published by MIMS December 2020

BRAND INFORMATION

Brand name

Ondansetron Accord

Active ingredient

Ondansetron

Schedule

S4

 

1 Name of Medicine

Ondansetron hydrochloride dihydrate.

2 Qualitative and Quantitative Composition

Ondansetron Accord Injection contains 2 mg/mL ondansetron (as ondansetron hydrochloride dihydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ondansetron Accord Injection is a clear, colourless to almost colourless, sterile, isotonic, preservative-free solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Ondansetron Accord injection is indicated:
for the prevention and treatment of nausea and vomiting induced by cytotoxic therapy and radiotherapy;
for the prevention and treatment of post-operative nausea and vomiting.

4.2 Dose and Method of Administration

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 in the range of 8 to 32 mg a day and selected as shown below. The lowest effective dose should be used.
The product is for single use in one patient only. Discard any residue.

Use in adults.

Emetogenic chemotherapy and radiotherapy.

For the control of chemotherapy or radiotherapy induced emesis or nausea in adults, a single dose of ondansetron 8 mg should be administered as a slow intravenous injection in not less than 30 seconds, immediately before treatment.

Highly emetogenic chemotherapy.

A single dose of ondansetron 8 mg by slow intravenous injection immediately before chemotherapy has been shown to be effective in many patients.
Higher doses may be required in some patients, particularly those on high dose cisplatin, and the doses should be adjusted according to the severity of the emetogenic challenge. If required, additional intravenous doses may be given up to a maximum of 32 mg in 24 hours.
Intravenous doses of more than 8 mg should be given by slow intravenous infusion over at least 15 minutes, since rapid intravenous administration of ondansetron has been associated with a higher incidence of transient visual disturbances. A single dose greater than 16 mg should not be given (see Section 4.4 Special Warnings and Precautions for Use).
Dexamethasone sodium phosphate as a single intravenous dose of 20 mg may be given prior to the first intravenous dose of ondansetron before chemotherapy, to potentiate the antiemetic effects of ondansetron.

Post-operative nausea and vomiting (injection only).

For prevention of post-operative nausea and vomiting in adults, ondansetron may be administered as a single dose of 4 mg, given by intramuscular or slow intravenous injection at induction of anaesthesia.
For treatment of established post-operative nausea and vomiting, a single dose of 4 mg given by intramuscular or slow intravenous injection is recommended in most patients. If necessary, the dose may be increased to 8 mg.

Use in children.

Emetogenic chemotherapy and radiotherapy.

Experience is currently limited but ondansetron was effective and well tolerated in children over 4 years of age, when given intravenously at a dose of 5 mg/m2 over 15 minutes immediately before chemotherapy, followed by oral therapy, if required. The dose of 5 mg/m2 is based on limited data.

Post-operative nausea and vomiting (injection only).

For prevention of post-operative nausea and vomiting in children aged 2 to 12 years having surgery under general anaesthesia, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at, or after induction of anaesthesia.
For treatment of established post-operative nausea and vomiting, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg.

PONV in children and adolescents aged 1 month to 17 years (injection only).

Slow IV injection (not less than 30 seconds) is recommended for this purpose.
Repeat dosing has not been studied in paediatric patients who experience nausea and/or vomiting despite receiving ondansetron prophylaxis or who continue to experience symptoms after ondansetron treatment.

Use in the elderly.

Emetogenic chemotherapy and radiotherapy.

Efficacy and tolerance in patients aged over 65 years was similar to that seen in younger adults, indicating no need to alter dosage or route of administration in the elderly.

Post-operative nausea and vomiting (injection only).

There is limited experience in the use of ondansetron in the prevention and treatment of post-operative nausea and vomiting in the elderly.

Use in patients with impaired renal function.

No alteration of daily dosage, frequency of dosing or route of administration is required.

Use in patients with impaired hepatic function.

A study which investigated the effect of hepatic impairment on the pharmacokinetics of ondansetron in 24 subjects showed that the plasma clearance of ondansetron is reduced to about 20% of normal and the serum half-life is significantly prolonged in subjects with severe impairment of hepatic function.
The results in patients with only mildly or moderately impaired hepatic function were less clear. The study showed that in this group, the plasma clearance of ondansetron fell to about 50% of that seen in healthy volunteers. Subjects with mild and moderate impairment were not distinguishable from each other for any parameter. This was believed to be partly due to the lack of sensitivity of the Pugh classification system in distinguishing between patients with mild or moderate impairment.
It is recommended that a total daily dose of 8 mg should not be exceeded for patients with moderate or severe hepatic dysfunction. For optimum clinical effect, it is recommended that this total daily dose be administered before chemotherapy or radiotherapy.
The severity of the liver disease was assessed according to Pugh's modification of Child's classification (Pugh et al., Brit. J. Surg. 1973; 60 (8): 646-649). Patients with a Pugh score of 5 or less were considered to have good hepatic function. A patient with a score of 6 was graded as having mild hepatic impairment, 7 to 9 as moderate hepatic impairment and 10 or more as severe hepatic impairment. The clinical features used in the grading and the weighting system applied are shown in Table 1.

Use in patients with poor sparteine/debrisoquine metabolism.

There were no significant differences among poor and extensive debrisoquine categorised metabolisers with regard to ondansetron disposition (area under the curve, total systemic clearance, elimination half-life) following a single 8 mg intravenous dose. The effect of repeated dosing was not investigated, nevertheless dosage adjustments will probably not be required in patients receiving ondansetron by the intravenous route.

Compatibility with other drugs.

Administration recommendations: slow intravenous injection from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the ondansetron giving set for ondansetron concentrations of 16 to 160 microgram/mL (i.e. 8 mg/500 mL and 8 mg/50 mL respectively).

Cisplatin.

Concentrations of up to 0.48 mg/mL (i.e. 240 mg/500 mL) administered over one to eight hours.

Carboplatin.

Concentrations in the range 0.18 to 9.9 mg/mL (i.e. 90 mg/500 mL to 990 mg/100 mL) administered over ten minutes to one hour.

Fluorouracil.

Concentrations up to 0.8 mg/mL (i.e. 2.4 g in 3 litres or 400 mg in 500 mL) administered at a rate of at least 20 mL per hour (500 mL per 24 hours). Higher concentrations of fluorouracil may cause precipitation of ondansetron. The fluorouracil infusion may contain up to 0.045% w/v magnesium chloride in addition to other excipients shown to be compatible.

Etoposide.

Concentrations in the range 0.14 to 0.25 mg/mL (i.e. 72 mg/500 mL to 250 mg/L) administered over 30 minutes to one hour.

Ceftazidime.

Doses in the range 250 mg to 2 g reconstituted with Water for Injections BP as recommended by the manufacturer (i.e. 2.5 mL for 250 mg and 10 mL for ceftazidime 2 g) and given as an intravenous bolus injection over approximately five minutes.

Cyclophosphamide.

Doses in the range 100 mg to 1 g reconstituted with Water for Injections BP, 5 mL per cyclophosphamide 100 mg, as recommended by the manufacturer, and given as an intravenous bolus injection over approximately five minutes.

Doxorubicin.

Doses in the range 10 to 100 mg, 5 mL per doxorubicin 10 mg, as recommended by the manufacturer, and given as an intravenous bolus injection over approximately five minutes.

Dexamethasone.

Dexamethasone sodium phosphate 20 mg may be administered as a slow intravenous injection over 2-5 minutes. The intravenous administration of dexamethasone should be physically separated from ondansetron either by administration via a different line or by flushing the line with 0.9% Sodium Chloride injection in between the two drugs.

Intravenous fluids.

Ondansetron Injection should not be administered in the same syringe or infusion as any other medication.
Ondansetron Injection should only be admixed with those infusion solutions which are recommended.
Ondansetron Injection has been shown to be stable for seven days when stored at room temperature (below 25°C) or in a refrigerator (2-8°C) with the following intravenous fluids: Sodium Chloride Intravenous Infusion BP 0.9% w/v; Glucose Intravenous Infusion BP 5% w/v; Mannitol Intravenous Infusion BP 10% w/v; Ringer's intravenous infusion; Potassium Chloride 0.3% w/v and Sodium Chloride 0.9% w/v Intravenous Infusion BP; Potassium Chloride 0.3% w/v and Glucose 5% w/v Intravenous Infusion BP.
Compatibility studies have been undertaken in polyvinyl chloride infusion bags with polyvinyl chloride administration sets, polyethylene infusion bags, type 1 glass bottles and polypropylene syringes.
Dilutions of Ondansetron Accord Injection in 10% mannitol injection, Ringer's injection, 0.3% potassium chloride and 0.9% sodium chloride injection, 0.3% potassium chloride and 5% glucose injection, 0.9% sodium chloride injection and 5% glucose injection have been demonstrated to be stable in polyvinyl chloride infusion bags and polyvinyl chloride administration sets, polyethylene infusion bags, type 1 glass bottles and polypropylene syringes.
Although the chemical and physical stability of Ondansetron Accord Injection diluted with the listed intravenous infusion fluids has been demonstrated for seven days at room temperature (below 25°C) or in a refrigerator (2-8°C), it is recommended that, in order to reduce microbial contamination hazards, the diluted solutions should be prepared immediately prior to use and infusion commenced as soon as practicable after preparation of the mixture. If storage is necessary, hold at 2°C-8°C. The diluted infusion solution should be used within 24 hours and any residue discarded.
Diluted solutions which are hazy, discoloured or contain visible particulate matter must be discarded.

4.3 Contraindications

Hypersensitivity to ondansetron or to any component of the preparation (see Section 4.4 Special Warnings and Precautions for Use).
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.
Ondansetron prolongs the QT interval in a dose-dependent manner. In addition, post-marketing cases of torsades 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 or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities.
Hypokalemia and hypomagnesemia should be corrected prior to ondansetron administration.
Serotonin syndrome has been described following the concomitant use of ondansetron and other serotonergic drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). 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.
Repeat dosing has not been studied in paediatric patients who experience nausea and/or vomiting despite receiving ondansetron prophylaxis or who continue to experience symptoms after ondansetron treatment.

Myocardial ischaemia.

Cases of myocardial ischaemia 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.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Use in patients with impaired hepatic function.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Use in patients with impaired renal function.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Use in the elderly.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Use in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it; specific studies have been limited to alcohol, temazepam and alfentanil to date.
Ondansetron is metabolised by multiple hepatic cytochrome P450 drug 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. Hence no dosage adjustment is recommended for patients on these drugs.
Caution should be exercised when ondansetron is coadministered with drugs that prolong the QT interval and/or cause electrolyte abnormalities (see Section 4.4 Special Warnings and Precautions for Use).
Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.
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.
Following a single 8 mg tablet dose of ondansetron, a threefold to fourfold decrease in the systemic exposure has been seen in adult epileptic subjects maintained on chronic doses of carbamazepine (n = 8) or phenytoin (n = 8) and not receiving chemotherapy. The effect of these enzyme inducing agents on intravenous ondansetron has not been assessed, but the absence of any first pass effects would be expected to result in a smaller change in exposure than seen following oral dosing. Due to the limited efficacy data in subjects on antiepileptics and the many variables that may influence exposure and response, the clinical significance of this drug interaction in cancer patients receiving chemotherapy is not known.

Serotonergic drugs (e.g. SSRIs and SNRIs).

Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) has been described following the concomitant use of ondansetron and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) (see Section 4.4 Special Warnings and Precautions for Use).
Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
Also see Section 4.2 Dose and Method of Administration, Compatibility with other drugs.

4.6 Fertility, Pregnancy and Lactation

Effects of fertility.

Oral doses of ondansetron up to 15 mg/kg/day in rats had no effect on male or female fertility.
Women of childbearing potential should consider the use of contraception.
(Category B1)
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 or 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.
 Tests have shown that ondansetron is excreted in the breast milk of rats. It is therefore recommended that mothers receiving ondansetron should not breastfeed their babies.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (greater than or equal to 1/10), common (greater than or equal to 1/100 and < 1/10), uncommon (greater than or equal to 1/1,000 and < 1/100), rare (greater than or equal to 1/10,000 and < 1/1,000) 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: seizures, movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions and dyskinesia have been observed without definitive evidence of persistent clinical sequelae).
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 IV 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 torsades de pointes).
Unknown: myocardial ischaemia.

Vascular disorders.

Common: sensation of warmth or flushing.
Uncommon: hypotension.

Respiratory, thoracic and mediastinal disorders.

Uncommon: hiccups.

Gastrointestinal disorders.

Common: constipation, xerostomia, local anal/rectal 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.

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.
To date, there has been limited safety experience in controlled trials following intramuscular administration.
Of 7,400 patients who received intravenous ondansetron during clinical trials, eleven experienced major cardiovascular events, including three fatalities, which were considered to be drug-related by the investigators (one probable, ten possible). It is well known that cardiovascular events, especially of a vascular occlusive nature, are not uncommon among patients with cancer, and these events are further increased with cytotoxic chemotherapy, particularly cisplatin.
Table 2 shows adverse events occurring in greater than or equal to 5% of paediatric patients (either group) in three pivotal clinical trials for prevention of post-operative nausea and vomiting. Ondansetron appears to be as well tolerated as placebo.
The overall incidence of adverse events was similar for ondansetron (53%) and placebo (56%). The most commonly reported adverse events were eye disorder(s) as a result of ophthalmic operations, wound problems at the surgical site, nausea and/or vomiting, drowsiness/sedation, anxiety/agitation and headache. These events are not unexpected in patients undergoing surgery and there was little difference of these between treatment groups. However, the incidence of nausea and/or vomiting reported as an adverse event was significantly higher in patients who had received placebo (11%) compared to those who had received ondansetron (6%).
Table 3 shows adverse events occurring in greater than or equal to 1% of paediatric patients in one pivotal clinical trial for treatment of post-operative nausea and vomiting.
Fewer adverse events were reported with ondansetron (36%) than with placebo (47%). The most common adverse events were similar to those reported in clinical trials for the prevention of post-operative nausea and vomiting.
Occasionally, local reactions at the site of intravenous injection have been reported.
Table 4 shows adverse events occurring in greater than or equal to 1% of adult patients receiving either intravenous ondansetron or placebo for the prevention or treatment of post-operative nausea and vomiting.
The overall incidence rate was 45% in the placebo group and 47% in the intravenous ondansetron group.
The neurological body system was associated with the highest incidence of adverse events (placebo approximately 23%; ondansetron 24%). These events were predominantly headache, dizziness and drowsiness.
Cardiovascular adverse events (bradycardia and hypotension) occurred in approximately 4% in both placebo and ondansetron groups; gastrointestinal adverse events (constipation, nausea/vomiting, flatulence and abdominal pain) occurred in approximately 7% of patients both receiving placebo and intravenous ondansetron.
The incidence rates were generally similar in both treatment groups for all body systems.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Little is known at present about overdosage with ondansetron, however, a limited number of patients have 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.

Treatment.

There is no specific antidote for ondansetron, therefore in cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
Ondansetron prolongs QT interval in a dose-dependent fashion. ECG monitoring is recommended in cases of overdose.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Class of drug.

Antinauseant/antiemetic.

Mechanism of action.

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 due to antagonism of 5HT3-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 psychomotor testing ondansetron does not impair performance or cause sedation. Ondansetron does not alter plasma prolactin concentrations.
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.
The clinical safety of ondansetron in children under 2 years has not been established. Increased incidence of mortality with no specific target organ toxicity has been observed in young rats with immature drug metabolising enzymes.

Clinical trials.

Chemotherapy and radiotherapy induced nausea and vomiting.

Adult studies.

Highly emetogenic chemotherapy.

In a double-blind, randomised study, 152 patients were given ondansetron 8 mg intravenously as a single dose and 173 patients were given 32 mg intravenously as a single dose 30 minutes prior to cisplatin (greater than or equal to 50 mg/m2).
No significant difference in terms of emesis control or grade of nausea was demonstrated between 8 mg or 32 mg. However, in some studies conducted in patients receiving medium (50 to 90 mg/m2) or high doses (greater than or equal to 100 mg/m2) of cisplatin chemotherapy, the 32 mg single dose has demonstrated a statistically significant superiority over the 8 mg single dose with regard to control of emesis.
In a double-blind, randomised, crossover trial, 103 chemotherapy naive patients scheduled to receive cisplatin (50 to 120 mg/m2) chemotherapy were recruited. 91 patients completed both courses of ondansetron 0.15 mg/kg (8 mg) intravenously (three doses) with or without dexamethasone 20 mg intravenously. The combination of ondansetron and dexamethasone was shown to be significantly superior to ondansetron alone.
In a randomised, double-blind parallel group study, 420 patients were randomised to receive either an ondansetron 16 mg suppository prior to cisplatin chemotherapy (greater than or equal to 50 mg/m2) on day 1 followed by an ondansetron 16 mg suppository once daily for a further two days, or ondansetron 8 mg intravenously prior to cisplatin chemotherapy followed by ondansetron 8 mg orally twice daily for a further two days. Results from the primary efficacy analysis (i.e. less than or equal to two emetic episodes on day 1) show that an ondansetron suppository and combined ondansetron intravenous and oral regimens are equivalent. However, results from the secondary efficacy analyses (e.g. number of emetic episodes on day 1, the worst day of days 1 to 3 and overall of days 1 to 3) showed that the ondansetron suppository was less effective. Patients on a combined ondansetron intravenous and oral regimen remained free of emesis for significantly longer than patients receiving ondansetron suppository.
In a randomised, double-blind, parallel group study, 542 patients were randomised to receive either ondansetron tablets (3 x 8 mg) plus dexamethasone capsules (2 x 6 mg), or intravenous ondansetron 8 mg plus intravenous dexamethasone 20 mg, prior to cisplatin infusion. Ondansetron 24 mg administered orally was as effective as ondansetron 8 mg given intravenously in controlling acute emesis and nausea induced by cisplatin chemotherapy.
There are no studies on the use of suppositories in radiation induced nausea and vomiting.

Emetogenic chemotherapy.

In a double-blind, parallel group study, 82 patients were randomised to either ondansetron 8 mg intravenously prior to cyclophosphamide (greater than or equal to 500 mg/m2) based chemotherapy (doxorubicin or epirubicin greater than or equal to 40 mg/m2) followed by 8 mg orally three times a day for three to five days or metoclopramide 60 mg intravenously prior to chemotherapy followed by 20 mg orally three times a day for three to five days. Ondansetron was shown to be significantly superior to metoclopramide.
In a randomised, single-blind study, ondansetron 8 mg orally twice daily in 155 patients was compared with ondansetron 8 mg orally three times daily in 153 patients for three to five days following chemotherapy. Ondansetron 8 mg intravenously was given prior to cyclophosphamide (greater than or equal to 500 mg/m2) based chemotherapy (doxorubicin or epirubicin greater than 40 mg/m2) on day 1. Ondansetron 8 mg given orally twice daily was as effective as ondansetron 8 mg given orally three times daily.
In a randomised, double-blind, parallel group study, 406 patients were randomised to receive either an ondansetron 16 mg suppository once daily for three days or ondansetron 8 mg orally twice daily for three days. The first administration of the suppository and tablet began two hours and one to two hours respectively prior to cyclophosphamide chemotherapy (greater than or equal to 500 mg/m2) on day 1. Results from the primary efficacy analysis (less than or equal to two emetic episodes on the worst day of days 1 to 3) show that the ondansetron suppository treatment is equivalent to the ondansetron oral treatment. The ondansetron suppository was less effective than ondansetron oral treatment for a number of other secondary efficacy criteria (complete control of emesis on the worst day of days 1 to 3, total number of emetic episodes days 1 to 3 and number of emetic episodes on worst day of days 1 to 3).
Paediatric studies. Three open-label, uncontrolled, non-comparative studies have been performed with 182 patients aged 4 to 18 years with cancer who were given a variety of cisplatin or non-cisplatin regimens. In these trials, an initial intravenous dose of ondansetron was followed by oral administration of ondansetron. In these studies, 58% of the 170 evaluable patients had no emetic episodes on day 1.

Post-operative nausea and vomiting (PONV).

Prevention of PONV.

Adult studies*.

Surgical patients received ondansetron immediately before the induction of general balanced anaesthesia. In a double-blind, placebo-controlled study, ondansetron 4 mg intravenously given to 136 patients immediately prior to general anaesthesia was significantly more effective than placebo.
In a double-blind, placebo-controlled study, 207 patients were given a single oral dose of ondansetron 16 mg and 204 patients were given placebo one hour prior to induction of anaesthesia. A significantly greater proportion of surgical patients had no emesis during the 0 to 24 hour post-recovery period compared with placebo.
*The majority of patients included in the prevention of PONV studies using ondansetron have been adult women receiving balanced anaesthesia for gynaecological surgery.

Paediatric studies.

Three large, double-blind, placebo-controlled studies have been performed in 1,049 male and female patients (2 to 12 years of age) undergoing general anaesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or without adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomised to either single intravenous doses of ondansetron (0.1 mg/kg for children weighing 40 kg or less, a single 4 mg dose for children weighing more than 40 kg) or placebo. Study drug was administered over at least 30 seconds, immediately prior to or following anaesthesia induction. Ondansetron showed significant statistical superiority over placebo in preventing post-operative nausea and vomiting. Repeat dosing was not undertaken in these studies. Children at greater risk of post-operative nausea and vomiting are more likely to benefit from prophylaxis; this includes children with a history of motion sickness or previous post-operative nausea and vomiting. No comparisons with other drugs for the prevention of nausea and/or vomiting are available.
Treatment of PONV.

Adults studies*.

221 adult surgical patients receiving general balanced anaesthesia, who received no prophylactic antiemetics and who experienced nausea and/or vomiting within two hours post-operatively, were evaluated in a double-blind study. Patients who experienced an episode of post-operative nausea and/or vomiting were given ondansetron 4 mg intravenously over two to five minutes, and this was significantly more effective than placebo.
*The majority of patients treated for PONV in studies using ondansetron have been adult women receiving balanced anaesthesia for gynaecological surgery.

Paediatric studies.

One large, double-blind, placebo-controlled study was performed in 351 male and female outpatients (2 to 12 years of age) who received general anaesthesia with nitrous oxide and no prophylactic antiemetics. Surgical procedures were restricted. Patients who experienced two or more emetic episodes within two hours following discontinuation of nitrous oxide were randomised to a single intravenous dose (0.1 mg/kg for children weighing 40 kg or less, a single 4 mg dose for children weighing more than 40 kg) or placebo administered over at least 30 seconds. Ondansetron demonstrated statistically significant superiority over placebo in preventing further episodes of nausea and vomiting. Repeat dosing was not a feature of this study. No data involving comparisons with active treatments have been evaluated.

5.2 Pharmacokinetic Properties

Distribution.

The terminal elimination half-life of ondansetron after intravenous dosing is 2.5 to 6.1 hours. The half-life may be prolonged in the elderly. Extent of absorption following intramuscular injection into a lateral compartment of the thigh is identical to intravenous injection and absorption is rapid with Tmax occurring approximately ten minutes after administration. The Cmax after intramuscular administration is 61% lower than that following intravenous administration. In patients with severe hepatic impairment, systemic clearance is markedly reduced with prolonged elimination half-lives (15 to 32 hours).

Metabolism and excretion.

Ondansetron is extensively metabolised in humans, with approximately 5% of a radiolabelled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacological activity, these are not found in plasma concentrations likely to significantly contribute to the biological activity of ondansetron. Ondansetron is a substrate for multiple human hepatic cytochrome P-450 enzymes including CYP1A2, CYP2D6 and CYP3A4. This multiplicity of metabolic enzymes capable of metabolising ondansetron means that inhibition or loss of one enzyme (e.g. CYP2D6 genetic deficiency) results in little change in overall rates of ondansetron elimination.
The plasma protein binding is 70 to 76%. The volume of distribution is 1.8 L/kg.
In a study of 21 children aged 3 to 12 years receiving elective surgery with general anaesthesia, the clearance and volume of distribution of ondansetron following a single intravenous dose of 2 mg (3 to 7 years old) or 4 mg (8 to 12 years old) were reduced. The size of the change was age-related with clearance falling from about 300 mL/minute at 12 years of age to 100 mL/minute at 3 years. Volume of distribution fell from about 75 L at 12 years to 17 L at 3 years.

5.3 Preclinical Safety Data

Genotoxicity.

Ondansetron did not induce mutations in Salmonella typhimurium, Escherichia coli or Chinese hamster ovary cells in the presence or absence of metabolic activation, and showed no potential for causing chromosomal damage in vitro in peripheral human lymphocytes or in vivo in a mouse micronucleus assay. No evidence for DNA damage was observed with ondansetron in a yeast mitotic gene conversion assay.

Carcinogenicity.

No evidence for carcinogenic activity was found in two year studies at ondansetron doses up to 10 mg/kg/day by gavage in rats or up to 30 mg/kg/day via drinking water in mice.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, Sodium citrate dihydrate, Citric acid monohydrate, Hydrochloric acid, Sodium hydroxide, Water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Ondansetron Accord injection 4 mg/2 mL and 8 mg/4 mL is supplied in clear or amber glass ampoules (Type-I) or amber glass syringes (Type-I).

Ondansetron Accord injection, 4 mg/2 mL.

Ampoules or syringes each containing 4 mg ondansetron (as hydrochloride dihydrate) in 2 mL aqueous solution for intramuscular or intravenous administration in packs of five and ten. ampoules or a pack of one syringe.

Ondansetron Accord injection, 8 mg/4 mL.

Ampoules or syringes each containing 8 mg ondansetron (as hydrochloride dihydrate) in 4 mL aqueous solution for intravenous administration in packs of five and ten. ampoules or a pack of one syringe.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Ondansetron hydrochloride dihydrate is a white or almost white powder with a melting point of 173°C. It is sparingly soluble in water and in ethanol, soluble in methanol and slightly soluble in methylene chloride. The pKa of ondansetron hydrochloride dihydrate is 7.4. The partition coefficient, log P in n-octanol: water is 2.14.

Chemical name.

1,2,3,9-tetrahydro- 9-methyl-3- [(2-methyl- 1H-imidazol-1-yl) methyl]- 4H-carbazol-4-one, hydrochloride dihydrate.

Molecular formula.

C18H19N3O.HCl.2H2O.

Molecular weight.

365.9.

Chemical structure.


CAS number.

99614-01-4 (ondansetron hydrochloride dihydrate), 99614-02-5 (ondansetron).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes