Consumer medicine information

APX-Ondansetron

Ondansetron

BRAND INFORMATION

Brand name

APX-Ondansetron

Active ingredient

Ondansetron

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APX-Ondansetron.

What is in this leaflet

Please read this leaflet carefully before you use APX-ONDANSETRON.

This leaflet answers some common questions about APX-ONDANSETRON. It does not contain all of 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 expected benefits of you taking APX-ONDANSETRON against the risks this medicine could have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What APX-ONDANSETRON is used for

APX-ONDANSETRON contains a medicine called ondansetron. This belongs to a group of medicines called serotonin receptor-3 antagonists.

APX-ONDANSETRON is used to help stop the nausea (sick feeling) and vomiting which can occur after medical treatments and operations.

APX-ONDANSETRON should only be used to treat the nausea and vomiting for which they have been prescribed.

Your doctor may have prescribed APX-ONDANSETRON for another reason. If you want more information, ask your doctor.

APX-ONDANSETRON is not addictive.

Before you take APX-ONDANSETRON

Do not take if:

You must not take APX-ONDANSETRON if:

  • you are taking apomorphine (used to treat Parkinson’s disease);
  • you have ever had an allergic reaction to ondansetron or any of the ingredients listed toward the end of this leaflet (see "Ingredients");
  • you are pregnant, trying to become pregnant or breastfeeding, unless your doctor says it is safe;
  • the expiry date printed on the pack has passed; or
  • the packaging is torn or shows signs of tampering.

Tell your doctor if:

You must tell your doctor if:

  • you are allergic to foods, dyes, preservatives or any other medicines;
  • you have had to stop taking another medicine for your nausea or vomiting;
  • you are taking any other medicines, including medicines you buy without a prescription;
  • you have or used to have liver problems; or
  • you are breastfeeding, pregnant or trying to become pregnant.

Some medicines may affect the way others work. Your doctor or pharmacist will be able to tell you what to do when taking APX-ONDANSETRON with other medicines.

How to take it

How much to take

Take APX-ONDANSETRON as directed by your doctor or pharmacist.

Do NOT take MORE TABLETS than your doctor or pharmacist tells you.

Do NOT take the tablets MORE OFTEN than your doctor or pharmacist tells you.

If you vomit within one hour taking your first APX-ONDANSETRON tablet of each course prescribed to you, you should take the same dose again. If you continue to vomit, tell your doctor.

How to take APX-ONDANSETRON

Swallow each tablet with a drink of water. Do not crush the tablet. If you have trouble swallowing your tablet, please tell your doctor.

How long to take APX-ONDANSETRON for

Do not stop taking APX-ONDANSETRON, or change the dose without first checking with your doctor.

If you forget to take APX-ONDANSETRON

If you miss your dose and you do not feel sick, take your next dose when you are meant to

If you miss your dose and you feel sick, take the missed dose as soon as possible, then go back to taking APX-ONDANSETRON as you would normally. If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, if you think you or anyone else may have taken too much APX-ONDANSETRON, even if there are no signs of discomfort or poisoning. If you are not sure what to do, contact your doctor or pharmacist.

While you are taking it

Things you must do

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise, your doctor may think that it was not working as it should and change your treatment unnecessarily.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use APX-ONDANSETRON to treat any other complaints unless your doctor says to.

Side effects

Check with your doctor as soon as possible if you think you are experiencing any side effects or allergic reactions due to taking APX-ONDANSETRON, even if the problem is not listed below.

Like other medicines, APX-ONDANSETRON can cause some side effects. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

The most commonly reported side-effects are:

  • headache;
  • a sensation of warmth or flushing;
  • mild stomach cramps;
  • constipation or diarrhoea;
  • dry mouth; or
  • hiccups.

These are all mild side effects. There is no immediate reason to stop taking your tablets unless you are concerned.

Tell your doctor 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 APX-ONDANSETRON is taken in combination with other serotonergic drugs. 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; or
  • skin rash, skin lumps or hives.

These are all serious side effects. You may need urgent medical attention. Serious side effects are rare.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Do not be alarmed by this list of possible side effects. You may not experience any of them. If your nausea (feeling of sickness) or vomiting does not go away, ask your doctor what to do.

In certain illnesses and treatments where APX-ONDANSETRON has been used, blood vessel blockage has occurred.

However, it is important to note that blood vessel blockage has also occurred in these illnesses and treatments when APX-ONDANSETRON has NOT been used. Discuss this with your doctor if you have any concerns.

If you feel unwell or have any symptoms that you do not understand, you should tell your doctor immediately.

After taking it

Storage

Keep this medicine where children cannot reach it, such as in a locked cupboard.

Keep APX-ONDANSETRON in a cool, dry place where it stays below 25°C.

Do not leave in a car, on window sill or in bathroom.

Keep APX-ONDANSETRON in their blister pack until time to take.

Return any unused or expired medicine to your pharmacist.

Product description

What it looks like

APX-ONDANSETRON 4 & 8 (4 & 8 mg ondansetron as hydrochloride dihydrate) are presented in pack sizes* of 4, 10, 30 & 90 tablets in blister.

APX-ONDANSETRON 4 (AUST R 173184)
White to off-white, oval shaped, film-coated tablets debossed with ‘E’ on one side and ‘01’ on the other side.

APX-ONDANSETRON 8 (AUST R 173182)
Yellow coloured, oval shaped, film-coated tablets debossed with ‘E’ on one side and ‘02’ on the other side.

Do NOT use your tablets if they have changed colour.

Ingredients

Active Ingredient:

Ondansetron hydrochloride dihydrate

Each tablet contains either 4 mg or 8 mg of ondansetron.

Other Ingredients:

  • Lactose anhydrous;
  • Cellulose microcrystalline;
  • Magnesium stearate;
  • Starch-pregelatinised maize;
  • The 4 mg tablet also contains glycerol triacetate, titanium dioxide and Hypromellose;
  • The 8 mg tablet also contains Opadry yellow 03K52033.

This medicine contains sugars as lactose.

*Some of these pack sizes are not marketed.

Please read this leaflet carefully before you start taking APX-ONDANSETRON. You may wish to keep it to read again.

Sponsor/Marketing Authorisation Holder

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne
Victoria 3121
Australia

This leaflet was prepared in September 2021.

Published by MIMS March 2022

BRAND INFORMATION

Brand name

APX-Ondansetron

Active ingredient

Ondansetron

Schedule

S4

 

1 Name of Medicine

Ondansetron hydrochloride dihydrate.

2 Qualitative and Quantitative Composition

APX-Ondansetron is available as tablets containing 4 mg or 8 mg of ondansetron as hydrochloride dihydrate.

Excipient of known effect.

Contains sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APX-Ondansetron (4 mg).

White to off-white, oval shaped, film-coated tablets debossed with 'E' on one side and '01' on the other side.

APX-Ondansetron (8 mg).

Yellow coloured, oval shaped, film-coated tablets debossed with 'E' on one side and '02' on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Ondansetron is indicated for the prevention and treatment of nausea and vomiting induced by cytotoxic therapy and radiotherapy.

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 8-32 mg a day and selected as shown below. The lowest effective dose should be used.

Adults.

Emetogenic chemotherapy and radiotherapy.

For the control of chemotherapy or radiotherapy induced emesis or nausea in adults, two oral doses of 8 mg each at 12 hourly intervals may be given, the first dose being administered 2 hours prior to chemotherapy or radiotherapy.
To protect against delayed emesis after the first 24 hours, ondansetron should be continued orally at a dosage of 8 mg twice daily.

Children.

Emetogenic chemotherapy and radiotherapy. Experience is currently limited but ondansetron was effective and well tolerated in children over 4 years of age following chemotherapy, oral therapy at doses of 4 mg twice daily for up to five days can be given.
PONV in children and adolescents (aged 1 month to 17 years).

Oral formulations.

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting.
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.

Elderly patients.

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.
CINV and RINV in elderly patients. Ondansetron is well tolerated by patients over 65 years of age.

Oral formulations.

No alteration of oral dose or frequency of administration is required.

Patients with renal impairment.

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

Patients with hepatic impairment.

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 systems applied are shown in Table 1:

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 either the oral or intravenous route.

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.
Hypersensitivity to any component of the preparation (see Section 4.4 Special Warnings and Precautions for Use).

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.
Each 4 mg film-coated tablet contains 19.137 mg of lactose and each 8 mg film-coated tablet contains 38.274 mg of lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose free diet should take this amount into consideration.

Myocardial ischaemia.

Cases of myocardial ischaemia have been reported in patients treated with ondansetron. In some patients, especially in 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 the elderly.

No data available.

Paediatric use.

No data available.

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 shown that there are no pharmacokinetic interactions when ondansetron is administered with alcohol, temazepam, alfentanil, furosemide (frusemide), tramadol or propofol.
Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.
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 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.

4.6 Fertility, Pregnancy and Lactation

Effects on 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 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.
Category B1: defined as Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have not shown evidence of an increased occurrence of foetal damage.
 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 (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000) and very rare (< 1/10,000), including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data.
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 have been observed without definitive evidence of persistent clinical sequelae).
Rare: Dizziness during rapid i.v. administration.

Eye disorders.

Rare: Transient visual disturbances (e.g. blurred vision) predominantly during i.v. administration.
Very rare: Transient blindness predominantly during i.v. 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.

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 i.v. injection site reactions.
To date there has been limited safety experience in controlled trials following intramuscular administration.
Of 7,400 patients who have received intravenous ondansetron during clinical trials, 11 experienced major cardiovascular events, including 3 fatalities, which were considered to be drug-related by the investigators (1 probable, 10 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 ≥ 1% 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%). See Table 3.
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 postoperative nausea and vomiting. Occasionally local reactions at the site of intravenous injection have been reported. See Table 4.
The overall incidence rate was 45% in the placebo group and 47% in the IV 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 IV 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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Little is at present known about overdosage with ondansetron, however, a limited number of patients received overdoses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second-degree AV block. In all instances, the events resolved completely.

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.
Cases consistent with serotonin syndrome have been reported in young children following oral overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 neurones 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 nor 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.

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 i.v. single dose and 173 patients were given 32 mg i.v. single dose 30 minutes prior to cisplatin (≥ 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 (50-90 mg/m2) or high doses (≥ 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 (see Section 4.2 Dose and Method of Administration).
In a double-blind, randomised, cross-over trial, 103 chemotherapy naive patients scheduled to receive cisplatin (50-120 mg/m2) chemotherapy were recruited. Ninety-one patients completed both courses of ondansetron 0.15 mg/kg (8 mg) i.v. x 3 with or without dexamethasone 20 mg i.v. 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 ondansetron 16 mg suppository prior to cisplatin chemotherapy (≥ 50 mg/m2) on day 1 followed by ondansetron 16 mg suppository once daily for a further 2 days, or ondansetron 8 mg i.v. prior to cisplatin chemotherapy followed by ondansetron 8 mg orally twice daily for a further 2 days. Results from the primary efficacy analysis (i.e. ≤ 2 emetic episodes on day 1) show that the ondansetron suppository and ondansetron i.v. and oral combined 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 - 3 and over all of Days 1 - 3) showed that the ondansetron suppository was less effective. Patients on ondansetron i.v. and oral combined 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 i.v. ondansetron 8 mg plus i.v. dexamethasone 20 mg, prior to cisplatin infusion. Administered orally, 24 mg of ondansetron was as effective as ondansetron 8 mg given i.v. in controlling acute emesis and nausea induced by cisplatin chemotherapy. One ondansetron 24 mg tablet has been shown to be bioequivalent to three ondansetron 8 mg tablets.
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 i.v. prior to cyclophosphamide (≥ 500 mg/m2) based chemotherapy (doxorubicin or epirubicin ≥ 40 mg/m2) followed by 8 mg orally three times a day for 3-5 days or metoclopramide 60 mg i.v. prior to chemotherapy followed by 20 mg orally three times a day for 3-5 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 3-5 days following chemotherapy. Ondansetron 8 mg i.v. was given prior to cyclophosphamide (≥ 500 mg/m2) based chemotherapy (doxorubicin or epirubicin > 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 ondansetron 16 mg suppository once daily for 3 days or ondansetron 8 mg orally twice daily for 3 days. The first administration of suppository and tablet began 2 hours and 1-2 hours respectively prior to cyclophosphamide chemotherapy (≥ 500 mg/m2) on day 1. Results from the primary efficacy analysis (≤ 2 emetic episodes on the worst day of days 1-3) 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 1-3, total number of emetic episodes Days 1-3 and number of emetic episodes on worst day of Days 1-3).
Paediatric studies. Three open-label, uncontrolled, non-comparative studies have been performed with 182 patients, aged 4-18 years old with cancer who were given a variety of cisplatin or non-cisplatin regimens. In these trials an initial i.v. dose of ondansetron was followed by oral administration of ondansetron. In these studies, 58% of the 170 evaluable patients had 0 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 136 patients given ondansetron 4 mg i.v. 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 0-24 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 i.v. 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 postoperative nausea and vomiting. No comparisons with other drugs for the prevention of nausea and/or vomiting are available.
Treatment of PONV.

Adult studies*.

Two hundred and twenty-one adult surgical patients receiving general balanced anaesthesia, who received no prophylactic anti-emetics and who experienced nausea and/or vomiting within 2 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 i.v. over 2-5 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 anti-emetics. Surgical procedures were restricted. Patients who experienced two or more emetic episodes within 2 hours following discontinuation of nitrous oxide were randomised to a single i.v. dose of (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

Absorption.

Following oral dosing with ondansetron, peak plasma concentrations are achieved in approximately 1.5 hours. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher doses. The absolute bioavailability of the ondansetron tablet is approximately 60% (range 36-112%).

Distribution.

The plasma protein binding is 70-76%. The volume of distribution is 1.8 L/kg.

Metabolism.

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 sulphate 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.

Excretion.

The terminal elimination half-life of ondansetron after oral dosing is 4.1 to 11.6 hours. The half-life may be prolonged in the elderly. In patients with severe hepatic impairment, systemic clearance is markedly reduced with prolonged elimination half-lives (15 to 32 hours) and an oral bioavailability approaching 100% because of reduced pre-systemic metabolism.

Children.

In a study of 21 children aged 3-12 years receiving elective surgery with general anaesthesia, the clearance and volume of distribution of ondansetron following a single intravenous dose of 2 mg (37 years old) or 4 mg (8-12 years old) were reduced. The size of the change was age-related with clearance falling from about 300 mL/min at 12 years of age to 100 mL/min at 3 years. Volume of distribution fell from about 75 L at 12 years to 17 L at 3 years.
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.

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

APX-Ondansetron tablets contain the following inactive ingredients: Lactose, microcrystalline cellulose, pregelatinised maize starch and magnesium stearate. The 4 mg tablet also contains triacetin, titanium dioxide and hypromellose. The 8 mg tablet also contains Opadry Complete Film Coating System 03K52033 Yellow.

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). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

APX-Ondansetron (4 and 8 mg ondansetron as hydrochloride dihydrate) are presented in pack sizes* of 4, 10, 30 or 90 film-coated tablets in a blister (PVC/Al).
* Some of these pack sizes are not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Active ingredient: Ondansetron (as hydrochloride dihydrate).
Chemical name: (3RS)-9-Methyl-3-[(2-methyl-]-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one hydrochloride dihydrate.
Molecular weight: 365.9.
Molecular formula: C18H20ClN3O,2H2O.

CAS number.

103639-04-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes