Consumer medicine information

Onsetron Tablets

Ondansetron

BRAND INFORMATION

Brand name

Onsetron Tablets

Active ingredient

Ondansetron

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Onsetron Tablets.

What is in this leaflet

This leaflet answers some common questions about ONSETRON.

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 benefits and risks. Your doctor has weighed the risks of you taking ONSETRON against the benefits they expect it will have for you.

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

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

What ONSETRON is used for

ONSETRON is used to help stop the nausea and vomiting which can occur after some medical treatments.

ONSETRON belongs to a group of medicines called serotonin receptor -3 antagonists.

Your doctor may have prescribed ONSETRON for another reason. Ask your doctor if you have any questions about why ONSETRON has been prescribed for you.

ONSETRON is available only with a doctor's prescription.

There is no evidence that ONSETRON is addictive.

Before you take ONSETRON

When you must not take it

Do not take ONSETRON if

  • you are taking apomorphine (a medicine used to treat Parkinson’s disease)
  • you are allergic to medicines containing ondansetron, any other serotonin receptor antagonists or any of the ingredients listed at the end of this leaflet.
  • if you are pregnant, trying to become pregnant or breastfeeding, unless your doctor says it is safe.
    ONSETRON may affect your developing baby if you take it during pregnancy. It also passes into breast milk and may affect your baby.
  • the expiry date (Exp.) printed on the pack has passed.
  • the packaging shows signs of tampering or the tablets do not look quite right.

Before you start to take it

Tell your doctor if

  • you are allergic to any other medicines, foods, dyes or preservatives.
  • if you have had to stop taking another medicine for your nausea and vomiting.
  • you plan to become pregnant or to breastfeed
  • you have, or have had, any medical conditions, especially liver problems.

If you have not told your doctor about any of the above, tell them before you start taking ONSETRON.

Taking other medicines

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

Some medicines may be affected by ONSETRON, or may affect how well it works. These include:

  • medicines to treat epilepsy
  • tramadol, a pain reliever.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ONSETRON.

How to take ONSETRON

How much to take

Your doctor will tell you how many tablets you need to take each day and when to take them.

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.

Follow all directions given to you by your doctor and pharmacist carefully.

If you vomit within one hour of taking the first ONSETRON 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 ONSETRON

Swallow the tablets with a glass of water.

If you forget to take ONSETRON

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 ONSETRON 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.

How long to take ONSETRON for

Keep taking ONSETRON for as long as your doctor recommends.

If you take too much ONSETRON (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much ONSETRON. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking ONSETRON

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking ONSETRON.

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 use ONSETRON to treat any other conditions unless your doctor tells you to.

Do not give ONSETRON to anyone else, even if they have the same condition as you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ONSETRON.

Like all other medicines, ONSETRON may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

Tell your doctor if you notice any of the following and they worry you:

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

These are 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
  • changes in the way your heart beats (faster or slower than normal or if it beats irregularly or throbs)
  • disturbance in heart rhythm (sometimes causing sudden loss of consciousness)
  • 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, lumps or hives.

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

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

If your nausea or vomiting does not go away, ask your doctor what to do.

In certain illnesses and treatments where ONSETRON 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 ONSETRON have 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, tell your doctor immediately.

After using ONSETRON

Storage

Keep ONSETRON where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store ONSETRON or any other medicine in the bathroom or near a sink.

Do not leave ONSETRON in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking ONSETRON, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

ONSETRON comes in 2 strengths of tablets:

  • ONSETRON 4 - round white tablet marked “4” on one side
  • ONSETRON 8 - round white tablet marked “8” on one side and a scoreline on the other.

Each pack contains 4 or 10 tablets.

Ingredients

The active ingredient in ONSETRON is ondansetron (as hydrochloride dihydrate)

  • each ONSETRON 4 tablet contains 4mg of ondansetron.
  • each ONSETRON 8 tablet contains 8mg of ondansetron.

The tablets also contain:

  • lactose
  • microcrystalline cellulose
  • maize starch
  • magnesium stearate
  • Opadry Y-1-7000 White.

The tablets are gluten free.

Sponsor

Medis Pharma Pty Ltd
Level 3, 5 Essex St
The Rocks NSW 2000
Australia

Distributor

Actavis Pty Ltd
Level 5, 117 Harrington St
The Rocks NSW 2000
Australia
Phone: 1800 554 414

Australian registration numbers:
ONSETRON 4 - AUST R 121359
ONSETRON 8 - AUST R 121368

Date of preparation:
16 April 2014

Published by MIMS November 2019

BRAND INFORMATION

Brand name

Onsetron Tablets

Active ingredient

Ondansetron

Schedule

S4

 

Name of the medicine

Ondansetron (as hydrochloride dihydrate).

Excipients.

Lactose, microcrystalline cellulose, maize starch, magnesium stearate and Opadry Y-1-7000 White. The tablets are gluten free.

Description

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 formula: C18H19N3O.HCl.2H2O. MW: 365.9. Melting point: 177°C. CAS: 99614-01-4. Ondansetron hydrochloride dihydrate is a white to off white powder. It is sparingly soluble in water and alcohol, soluble in methanol and slightly soluble in methylene chloride. It is soluble in saline (0.9% w/v) to about 8 mg/mL. The pKa of ondansetron hydrochloride dihydrate as determined by a solubility procedure is 7.4. The distribution coefficient between n-octanol and water is pH dependent with log D = 2.2 at a pH of 10.6 and log D = 0.6 at a pH of 5.95.
Onsetron tablets come in two strengths and contain either 4 mg or 8 mg of ondansetron (as hydrochloride dihydrate). The tablets also contain the following excipients: lactose, microcrystalline cellulose, maize starch, magnesium stearate and Opadry Y-1-7000 White. The tablets are gluten free.

Pharmacology

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 postoperative 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 (human ether-a-go-go-related gene) potassium channels. The clinical relevance of this finding is uncertain.

Pharmacokinetics.

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 to 112%). 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. 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) and an oral bioavailability approaching 100% because of reduced presystemic 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 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 P450 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.
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.
Following rectal administration with an ondansetron suppository, peak plasma concentrations of 15 to 40 nanogram/mL are reached in approximately six hours. Plasma concentrations then fall, but at a slower rate than after an oral dose due to continued absorption of ondansetron. The elimination half-life is approximately six hours. Females show a small clinically insignificant increase in half-life when compared to males. The absolute bioavailability of ondansetron from the suppository is approximately 60%. The relative bioavailability of the suppository compared to an 8 mg tablet was 77%.

Clinical Trials

Chemotherapy and radiotherapy induced nausea and vomiting.

Adult studies.

Highly emetogenic chemotherapy.

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. One ondansteron 24 mg tablet has been shown to be bioequivalent to three ondansetron 8 mg tablets.

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 > 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, noncomparative studies have been performed with 182 patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin 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.

Postoperative nausea and vomiting (PONV). Prevention of PONV.

Adults.*

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 postrecovery 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 postoperative nausea and vomiting. Repeat dosing was not undertaken in these studies. Children at greater risk of postoperative 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.

Indications

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

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 Precautions).

Precautions

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 Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc, including patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias 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 Interactions with Other Medicines). 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.

Carcinogenecity/ genotoxicity/ effects on fertility.

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. 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. Oral doses of ondansetron up to 15 mg/kg/day in rats had no effect on male or female fertility.

Use in pregnancy.

(Category B1)
The safety of ondansetron for use in human pregnancy has not been established. Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo or fetus, the course of gestation, and perinatal and postnatal development. However, as animal studies are not always predictive of human response, the use of ondansetron in pregnancy is not recommended.

Use in lactation.

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.

Interactions

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly coadministered with it. Specific studies have shown that there are no pharmacokinetic interactions when ondansetron is administered with alcohol, temazepam, alfentanil, furosemide, tramadol or propofol.
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 or dose requirement.
Caution should be exercised when ondansetron is coadministered with drugs that prolong the QT interval and/or cause electrolyte abnormalities (see Precautions).
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 three 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. 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 Precautions).
Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

Adverse 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 postmarketing 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 intravenous administration.

Eye disorders.

Rare: transient visual disturbances (e.g. blurred vision) predominantly during intravenous administration.
Very rare: transient blindness predominantly during intravenous 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 Torsade de Pointes).

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 intravenous 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.
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%).
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.
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.

Dosage and 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.

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 two 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.

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 following chemotherapy, an oral therapy at doses of 4 mg twice daily for up to five days can be given.
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.

Impaired renal function.

No alteration of daily dosage or frequency of dosing is required.

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 4.

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.

Overdosage

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 atrioventricular (A-V) 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.
Contact the Poisons Information Centre on 131 126 (Australia) for advice on the management of overdosage.

Presentation

Onsetron 4.

4 mg: round, white film-coated tablet with “4” on one side. Blister packs (PVC/PVDC/Al) of 4 or 10 tablets.

Onsetron 8.

8 mg: round, white film-coated tablet with “8” on one side and a scoreline on the other side. Blister packs (PVC/PVDC/Al) of 4 or 10 tablets.

Storage

Store below 25°C.

Poison Schedule

S4.