ONDANSETRON 2 MG / ML SOLUTION FOR INJECTION OR INFUSION - patient leaflet, side effects, dosage

Read all of this leaflet carefully before this medicine is administered to you because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have further questions, ask your doctor or your pharmacist.
• If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

• 1. What Ondansetron Solution for Injection or Infusion is and what it is used for

• 2. What you need to know before Ondansetron Solution for Injection or Infusion is administered

• 3. How to administer Ondansetron Solution for Injection or Infusion

• 4. Possible side effects

• 5. How to store Ondansetron Solution for Injection or Infusion

• 6. Contents of the pack and other information

The name of your medicine is Ondansetron 2mg/ml Solution for Injection or Infusion (also referred to as Ondansetron injection or Ondansetron throughout this leaflet).

1. what ondansetron solution for injection is and what it is used for

Ondansetron injection contains a medicine called ondansetron. This belongs to a group of medicines called anti-emetics.

Ondansetron injection is used for:

• preventing nausea and vomiting caused by chemotherapy (in adults and children) or radiotherapy for cancer (adults only)
• preventing nausea and vomiting after surgery.

Ask your doctor, nurse or pharmacist if you would like any further explanation about these uses.

2. what you need to know before ondansetron solution for injection is administered if you are taking apomorphine (used to treat parkinson’s disease)

• if you are allergic to ondansetron or any of the other ingredients of this medicine (listed in section 6).

If you are not sure, talk to your doctor, nurse or pharmacist before having Ondansetron injection.

Warnings and precautions

Talk to your doctor, nurse or pharmacist before having Ondansetron Solution for Injection:

• if you have ever had heart problems (e.g. congestive heart failure which causes shortness of breath and swollen ankles)
• if you have an uneven heart beat (arrhythmias)
• if you are allergic to medicines similar to ondansetron, such as granisetron or palonosetron
• if you have liver problems
• if you have a blockage in your gut
• if you have problems with the levels of salts in your blood, such as potassium, sodium and magnesium.

If you are not sure if any of the above apply to you, talk to your doctor, nurse or pharmacist before having ondansetron injection.

Other medicines and Ondansetron

Tell your doctor, nurse or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because ondansetron can affect the way some medicines work. Also some other medicines can affect the way ondansetron works.

In particular, tell your doctor, nurse or pharmacist if you are taking any of the following medicines:

• carbamazepine or phenytoin used to treat epilepsy
• rifampicin used to treat infections such as tuberculosis (TB)
• antibiotics such as erythromycin or ketoconazole
• anti-arrhythmic medicines used to treat an uneven heart beat
• beta-blocker medicines used to treat certain heart or eye problems, anxiety or prevent migraines
• tramadol, a pain killer
• medicines that affect the heart (such as haloperidol or methadone)
• cancer medicines (especially anthracyclines and trastuzumab)
• SSRIs (selective serotonin reuptake inhibitors) used to treat depression and/or anxiety including fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram
• SNRIs (serotonin noradrenaline reuptake inhibitors) used to treat depression and/or anxiety including venlafaxine, duloxetine.

If you are not sure if any of the above applies to you, talk to your doctor, nurse or pharmacist before having ondansetron injection.

Ondansetron injection should not be given in the same syringe or infusion (drip) as any other medication.

Pregnancy and Breast-feeding

Only use Ondansetron Injection during the first trimester of pregnancy after discussion with your doctor of the potential benefits and risks to you and your unborn baby of the different treatment options. This is because Ondansetron Injection can slightly increase the risk of a baby being born with cleft lip and/or cleft palate (openings or splits in the upper lip and/or the roof of the mouth). If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before having Ondansetron Injection. If you are a woman of childbearing potential you may be advised to use effective contraception.

Do not breast-feed if you have ondansetron. This is because small amounts pass into the mother’s milk. Ask your doctor or midwife for advice.

Ondansetron Injection contains sodium

This medicinal product contains less than 1mmol (23mg) of sodium in each ampoule. It is essentially ‘sodium-free’.

• 3. How to administer Ondansetron Solution for Injection

Ondansetron injection is normally given by a nurse or doctor. The dose you have been prescribed will depend on the treatment you are having.

To prevent nausea and vomiting from chemotherapy or radiotherapy in adults

On the day of chemotherapy or radiotherapy

• the usual adult dose is 8 mg given by a slow injection into your vein or muscle, just before your treatment, and another 8 mg twelve hours later. After chemotherapy, your medicine will usually be given by mouth as an 8 mg ondansetron tablet or 10 ml (8 mg) ondansetron syrup.

On the following days

• the usual adult dose is one 8 mg tablet or 10 ml (8 mg) syrup taken twice a day
• this may be given for up to 5 days.

If your chemotherapy or radiotherapy is likely to cause severe nausea and vomiting, you may be given more than the usual dose of ondansetron. Your doctor will decide this.

To prevent nausea and vomiting from chemotherapy in children aged over 6 months and adolescents

The doctor will decide the dose depending on the child’s size (body surface area) or weight. Look at the label for more information

On the day of chemotherapy

• the first dose is given by an injection into the vein, just before your child’s treatment. After chemotherapy, your child’s medicine will usually be given by mouth twelve hours later, as ondansetron syrup or a ondansetron tablet.

On the following days

• 2.5 ml (2 mg) syrup twice a day for small children and those weighing 10 kg or less
• one 4 mg tablet or 5 ml (4 mg) syrup twice a day for larger children and those weighing more than 10 kg
• two 4 mg tablets or 10 ml (8 mg) syrup twice a day for teenagers (or those with a large body surface area)
• these doses can be given for up to five days

To prevent and treat nausea and vomiting after an operation

Adult:

• The usual dose for adults is 4 mg given by a slow injection into your vein or an injection into your muscle. For prevention, this will be given just before your operation.

Children:

• For children aged over 1 month and adolescents the doctor will decide the dose. The maximum dose is 4 mg given as a slow injection into the vein. For prevention, this will be given just before the operation.

Patients with moderate or severe liver problems

The total daily dose should not be more than 8 mg.

If you keep feeling or being sick

Ondansetron injection should start to work soon after having the injection. If you continue to be sick or feel sick, tell your doctor or nurse.

If you have more ondansetron injection than you should

Your doctor or nurse will give you or your child ondansetron so it is unlikely that you or your child will receive too much. If you think you or your child have been given too much or have missed a dose, tell your doctor or nurse.

4. possible side effects

Like all medicines, Ondansetron can cause side effects, although not everybody gets them.

Allergic reactions

If you have an allergic reaction, tell your doctor or a member of the medical staff straight away. The signs may include:

• sudden wheezing and chest pain or chest tightness
• swelling of your eyelids, face, lips, mouth or tongue
• skin rash – red spots or lumps under your skin (hives) anywhere on your body
• collapse.

Other side effects include:

headache.

Common (may affect up to 1 in 10 people)

• a feeling of warmth or flushing
• constipation
• changes to liver function test results (if you have ondansetron injection with a medicine called cisplatin, otherwise this side effect is uncommon)
• irritation and redness at the site of injection.

Uncommon (may affect up to 1 in 100 people)

• hiccups
• low blood pressure, which can make you feel faint or dizzy
• uneven heart beat
• chest pain
• fits
• unusual body movements or shaking.

Rare (may affect up to 1 in 1,000 people)

• feeling dizzy or light headed
• blurred vision
• disturbance in heart rhythm (sometimes causing a sudden loss of consciousness).

Very rare (may affect up to 1 in 10,000 people)

• poor vision or temporary loss of eyesight, which usually comes back within 20 minutes.

Not known (frequency cannot be estimated from the available data)

Myocardial ischaemia

Signs include:

• sudden chest pain or
• chest tightness.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via

Yellow Card Scheme at Website: or search for MHRA Yellow Card in the Google Play or Apple App Store

By reporting side effects you can help provide more information on the safety of this medicine.

5. how to store ondansetron infusion

Keep this medicine out of the sight and reach of children.

Do not store above 25°C.

Keep the ampoule in the outer carton.

Do not use Ondansetron Solution for Injection or Infusion after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.

Chemical and physical in use stability has been demonstrated for 24 hours at 25°C and 5°C. From a microbiological point of view, the product should be used immediately. If not used immediately, inuse storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2–8°C, unless opening and dilution has taken place in controlled and validated aseptic conditions.

For single use. Discard any unused product immediately after use.

Do not use if the ampoule is damaged or if the solution is cloudy or contains particles.

6. contents of the pack and other information the active substance is ondansetron (as ondansetron hydrochloride dihydrate).

• Each ampoule contains either 4mg or 8mg Ondansetron (as Ondansetron hydrochloride dihydrate)
• The other ingredients are sodium chloride, sodium citrate, citric acid monohydrate and water for injections
• This medicinal product contains less than 1 mmol sodium (23mg) per ampoule, i.e. essentially ‚sodium-free‘.

What Ondansetron solution for injection or infusion looks like and contents of the pack

Ondansetron 2mg/ml Solution for Injection or Infusion is a clear colourless solution.

Ondansetron Injection is available in 1, 5, or 10, ampoules at 2 ml or 1, 5, or 10, at 4 ml.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Wockhardt UK Ltd, Ash Road North, Wrexham LL13 9UF, UK

Manufacturer

CP Pharmaceuticals Limited, Ash Road North, Wrexham, L13 9UF, United Kingdom.

Other formats:

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge: 0800 198 5000

Please be ready to give the following information:

Product name	Reference number
Ondansetron 2mg/ml Solution for Injection or Infusion	PL 29831/0153 PL 29831/0154

This is a service provided by the Royal National Institute of Blind People.

This leaflet was last revised in 02/2022.

SUMMARY OF PRODUCT CHARACTERISTICS

Ondansetron 2mg/ml Solution for Injection or Infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 2mg of ondansetron (as hydrochloride dihydrate)

Each 2ml ampoule contains 4mg of ondansetron (as hydrochloride dihydrate)

Each 4ml ampoule contains 8mg of ondansetron (as hydrochloride dihydrate)

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Solution for injection or infusion

Clear, colourless solution, free from particles.

• 4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Adults

Ondansetron hydrochloride is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy. Ondansetron hydrochloride is indicated for the prevention and treatment of post-operative nausea and vomiting (PONV).

Paediatric Population

Ondansetron hydrochloride is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged >6 months, and for the prevention and treatment of PONV in children aged >1 month.

4.2. Posology and method of administration

Adults: 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 hydrochloride should be flexible in the range of 8–32mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy: Ondansetron hydrochloride can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration.

For most patients receiving emetogenic chemotherapy or radiotherapy, Ondansetron hydrochloride 8mg should be administered as a slow intravenous or intramuscular injection immediately before treatment, followed by 8 mg orally twelve hourly.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with Ondansetron hydrochloride should be continued for up to five days after a course of treatment. Highly emetogenic chemotherapy: For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, Ondansetron hydrochloride can be given either by oral, rectal, intravenous or intramuscular administration.

Ondansetron hydrochloride has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy:

• – A single dose of 8mg by slow intravenous or intramuscular injection (in not less than 30 seconds) immediately before chemotherapy.

• – A dose of 8mg by slow intravenous or intramuscular injection (in not less than 30 seconds) immediately before chemotherapy, followed by two further intravenous injection (in not less than 30 seconds) or intramuscular doses of 8mg four hours apart, or by a constant infusion of 1mg/hour for up to 24 hours.

• – A maximum initial intravenous dose of 16mg diluted in 50-l00ml of saline or other compatible infusion fluid (see section 6.6) and infused over not less than 15 minutes immediately before chemotherapy. The initial dose of ondansetron hydrochloride may be followed by two additional 8 mg intravenous doses (in not less than 30 seconds) or intramuscular doses four hours apart.

A single dose greater than 16 mg must not be given due to dose dependent increase of QT-prolongation risk (see sections 4.4, 4.8 and 5.1).

The selection of dose regimen should be determined by the severity of the emetogenic challenge.

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

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron hydrochloride should be continued for up to five days after a course of treatment.

Paediatric Population

CINV in children aged >6 months and adolescents

The dose for CINV can be calculated based on body surface area (BSA) or weight – see below.

In paediatric clinical studies, ondansetron was given by IV infusion diluted in 25 to 50 ml of saline or other compatible infusion fluid and infused over not less than 15 minutes.

Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4.and 5.1).

Ondansetron hydrochloride should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid (see section 6.6) and infused intravenously over not less than 15 minutes. There are no data from controlled clinical trials on the use of ondansetron hydrochloride in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of ondansetron hydrochloride for radiotherapy-induced nausea and vomiting in children.

Dosing by BSA

Ondansetron hydrochloride should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m2. The single intravenous dose must not exceed 8 mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 1).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Table 1: BSA-based dosing for Chemotherapy – Children aged >6 months and adolescents

BSA	Day 1 (a,b)	Days 2–6 (b)
<0.6m2	5 mg/m2 i.v. plus 2 mg syrup after 12 hrs	2 mg syrup every 12 hrs
>0.6m2 to <1.2m2	5 mg/m2 i.v. plus 4 mg syrup or tablet after 12 hrs	4 mg syrup or tablet every 12 hrs
>1.2m2	5 mg/m2 or 8 mg i.v. plus 8mg syrup or tablet after 12 hrs	8 mg syrup or tablet every 12 hrs

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg

Dosing by bodyweight

Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4. and 5.1).

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

Two further intravenous doses may be given in 4-hourly intervals.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 2).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32mg.

Table 2: Weight-based dosing for Chemotherapy – Children aged >6 months and adolescents

BSA

Day 1 (a,b)

Days 2–6 (b)

< 10 Kg	Up to 3 doses of 0.15mg/kg i.v. every 4 hrs	2 mg syrup every 12 hrs
>10 Kg	Up to 3 doses of 0.15mg/kg i.v. every 4 hrs	4 mg syrup or tablet every 12 hrs

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Elderly:

In patients 65 to 74 years of age, the dose schedule for adults can be followed. All intravenous doses should be diluted in 50–100 ml of saline or other compatible infusion fluid (see section 6.6) and infused over 15 minutes.

In patients 75 years of age or older, the initial intravenous dose of ondansetron should not exceed 8 mg. All intravenous doses should be diluted in 50–100 ml of saline or other compatible infusion fluid (see section 6.6) and infused over 15 minutes. The initial dose of 8 mg may be followed by two further intravenous doses of 8 mg, infused over 15 minutes and given no less than four hours apart (see section 5.2).

Patients with Renal Impairment: No alteration of daily dosage or frequency of dosing, or route of administration are required.

Patients with hepatic Impairment: Clearance of Ondansetron hydrochloride is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg should not be exceeded and therefore parenteral or oral administration is recommended.

Patients with Poor Sparteine/Debri­soquine Metabolism: The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine.

Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.

Post-operative nausea and vomiting (PONV):

Adults: For the prevention of PONV ondansetron hydrochloride can be administered orally or by intravenous or intramuscular injection.

Ondansetron hydrochloride may be administered as a single dose of 4mg given by intramuscular or slow intravenous injection at induction of anaesthesia.

For treatment of established PONV a single dose of 4mg given by intramuscular or slow intravenous injection is recommended.

Paediatric population

PONV in children aged >1 month and adolescents.

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia.

For the treatment of PONV after surgery in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron hydrochloride may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg. There are no data on the use of ondansetron hydrochloride in the treatment of PONV in children below 2 years of age.

Elderly: There is limited experience in the use of ondansetron hydrochloride in the prevention and treatment of PONV in the elderly, however ondansetron hydrochloride is well tolerated in patients over 65 years receiving chemotherapy.

Patients with renal impairment: No alteration of daily dosage or frequency of dosing, or route of administration are required.

Patients with hepatic impairment: Clearance of ondansetron hydrochloride is significantly reduced and serum half life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg should not be exceeded and therefore parenteral or oral administration is recommended.

Patients with poor sparteine/debri­soquine metabolism: The elimination half-life of ondansetron hydrochloride is not altered in subjects classified as poor metabolisers ofsparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.

4.3. Contraindications

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

Concomitant use with apomorphine (see section 4.5).

4.4. Special warnings and precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT3 receptor antagonists. Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.

Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). In addition, postmarketing 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.

Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron administration.

There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with ondansetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.

In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron. This medicinal product contains less than 1mmol (23mg) of sodium in each ampoule. It is essentially ‘sodium-free’.

Paediatric Population

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

CINV

When calculating the dose on an mg/kg basis and administering three doses at 4-hourly intervals, the total daily dose will be higher than if one single dose of 5mg/m2 followed by an oral dose is given. The comparative efficacy of these two different dosing regimens has not been investigated in clinical trials. Cross-trial comparison indicates similar efficacy for both regimens (section 5.1).

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.

4.5. Interaction with other medicinal products and other forms of interaction

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it. Specific studies have shown that there are no interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome 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 coadministered with drugs that prolong the QT interval and/or cause electrolyte abnormalities. (See section 4.4).

Use of ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines (such as doxorubicin, daunorubicin) or trastuzumab), antibiotics (such as erythromycin), antifungals (such as ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of arrhythmias. (See section 4.4).

Serotonergic Drugs (e.g. SSRIs and SNRIs): There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including SSRIs and SNRIs). (See section 4.4)

Apomorphine: Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

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

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

4.6. Fertility, pregnancy and lactation

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 foetus, the course of gestation and peri- and postnatal development. However as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended.

Breast-feeding

Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies.

Fertility

There is no information on the effects of ondansetron on human fertility.

4.7. Effects on ability to drive and use machines

In psychomotor testing ondansetron does not impair performance nor cause sedation. No detrimental effects on such activities are predicted from the pharmacology of ondansetron.

4.8. Undesirable effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000) and very rare (<1/10,000). Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data.

The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation. The adverse event profiles in children and adolescents were comparable to that seen in adults.

Immune system disorders

Rare: Immediate hypersensitivity reactions, sometimes severe including anaphylaxis.

Nervous system disorders

Very common: Headache.

Uncommon: Seizures, movement disorders (including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia) (1).

Eye disorders

Rare: Transient visual disturbances (e.g. blurred vision), predominantly during intravenous administration.

Very rare: Transient blindness, predominantly during intravenous administration(2).

Cardiac disorders

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

Rare: QTc prolongation (including Torsade de Pointes).

Not known: Myocardial Ischaemia (see section 4.4)

Vascular disorders

Common: Sensation of warmth or flushing.

Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: Hiccups.

Gastrointestinal disorders

Common: Constipation.

Hepatobiliary disorders

Uncommon: Asymptomatic increases in liver function tests(3).

General disorders and administration site conditions

Common: Local intravenous injection site reactions.

• 1. Observed without definitive evidence of persistent clinical sequelae.

• 2. The majority of the blindness cases reported resolved within 20 minutes. Most patients had received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness were reported as cortical in origin.

• 3. These events were observed commonly in patients receiving chemotherapy with cisplatin.

Paediatric population

The adverse event profiles in children and adolescents were comparable to that seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at Website: or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is limited experience of ondansetron overdose. In the majority of cases, symptoms were similar to those already reported in patients receiving recommended doses (see section 4.8). Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block.

Ondansetron prolongs the 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.

Treatment

There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

The use of ipecacuanha to treat overdose with ondansetron is not recommended, as patients are unlikely to respond due to the anti-emetic action of ondansetron itself.

Paediatric population:

Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12 months to 2 years.

• 5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

ATC code:- A04 Antiemetics and antinauseants

ATC group:- A04AAO 1 Serotonin (5HT3) antagonist

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 probably 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.

Ondansetron does not alter plasma prolactin concentrations. The role of ondansetron in opiateinduced emesis is not yet established.

QT Prolongation

The effect of ondansetron on the QTc interval was evaluated in a double blind, randomised placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes.

At the highest tested dose of 32 mg, the maximum mean (upper limit of 90% Cl) difference in QTcF from placebo after baseline-correction was 19.6 (21.5)msec. At the lower tested dose of 8 mg, the maximum mean (upper limit of 90% Cl) difference in QTcF from placebo after baselinecorrection was 5.8 (7.8) msec. In this study, there were no QTcF measurements greater than 480 msec and no QTcF prolongation was greater than 60 msec. No significant changes were seen in the measured electrocardio­graphic PR or QRS intervals.

Paediatric population

CINV

The efficacy of ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a double-blind randomised trial in 415 patients aged 1 to 18 years (S3AB3006). On the days of chemotherapy, patients received either ondansetron 5 mg/m2 intravenous and ondansetron 4 mg orally after 8 to 12 hours or ondansetron 0.45 mg/kg intravenous and placebo orally after 8 to 12 hours. Post- chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m2 intravenous and ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous and placebo orally). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.

A double-blind randomised placebo-controlled trial (S3AB4003) in 438 patients aged 1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy in:

• 73% of patients when ondansetron was administered intravenously at a dose of 5 mg/m2 intravenous together with 2–4 mg dexamethasone o­rally
• 71% of patients when ondansetron was administered as syrup at a dose of 8 mg together with 2–4 mg dexamethasone orally on the days of chemotherapy.

Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.

The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an openlabel, non-comparative, single-arm study (S3A40320). All children received three 0.15 mg/kg doses of intravenous ondansetron, administered 30 minutes before the start of chemotherapy and then at four and eight hours after the first dose. Complete control of emesis was achieved in 56% of patients. Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron doses of 4 mg for children aged < 12 yrs and 8 mg for children aged > 12 yrs (total no. of children n= 28). Complete control of emesis was achieved in 42% of patients.

PONV

The efficacy of a single dose of ondansetron in the prevention of post-operative nausea and vomiting was investigated in a randomised, double-blind, placebo-controlled study in 670 children aged 1 to 24 months (post-conceptual age >44 weeks, weight >3 kg). Included subjects were scheduled to undergo elective surgery under general anaesthesia and had an ASA status <111. A single dose of ondansetron 0.1 mg/kg was administered within five minutes following induction of anaesthesia. The proportion of subjects who experienced at least one emetic episode during the 24-hour assessment period (ITT) was greater for patients on placebo than those receiving ondansetron ((28% vs. 11%, p <0.0001).

Four double-blind, placebo-controlled studies have been performed in 1469 male and female patients (2 to 12 years of age) undergoing general anaesthesia. Patients were randomised to either single intravenous doses of ondansetron (0.1 mg/kg for paediatric patients weighing 40 kg or less, 4 mg for paediatric patients weighing more than 40 kg; number of patients = 735)) or placebo (number of patients = 734). Study drug was administered over at least 30 seconds, immediately prior to or following anaesthesia induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these studies are summarised in Table 3.

Table 3 Prevention and treatment of PONV in Paediatric Patients – Treatment response over 24 hours

Study	Endpoint	Ondansetron %	Placebo	% p value
S3A380	CR	68	39	0.001
S3GT09	CR	61	35	0.001
S3A381	CR	53	17	0.001
S3GT11	no nausea	64	51	0.004
S3GT11	no emesis	60	47	0.004

CR = no emetic episodes, rescue or withdrawal

5.2. Pharmacokinetic properties

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 30ng/ml are attained approximately 1.5 hours after an 8mg dose. For doses above 8mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Mean bioavailability in healthy male subjects, following the oral administration of a single 8mg tablet, is approximately 55 to 65%. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (five hours) of ondansetron.

The disposition of ondansetron following oral, intramuscular and intravenous dosing in adults is similar with a terminal half life of about 3 hours and steady state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after intramuscular and intravenous administration of ondansetron.

A 4mg intravenous infusion of ondansetron given over five minutes results in peak plasma concentrations of about 65ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25ng/ml are attained within 10 minutes of injection.

Following administration of ondansetron suppository, plasma ondansetron concentrations become detectable between 15 and 60 minutes after dosing.

Concentrations rise in an essentially linear fashion, until peak concentrations of 20–30ng/ml are attained, typically six hours after dosing. Plasma concentrations then fall, but at a slower rate than observed following oral dosing due to continued absorption of ondansetron. The absolute bioavailability of ondansetron from the suppository is approximately 60% and is not affected by gender. The half life of the elimination phase following suppository administration is determined by the rate of ondansetron absorption, not systemic clearance and is approximately six hours. Females show a small, clinically insignificant, increase in half-life in comparison with males.

Ondansetron is not highly protein bound (70–76%). Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's phar­macokinetics.

The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

Special Patient Populations

Gender

Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).

Children and Adolescents (aged 1 month to 17 years)

In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight normalised clearance was approximately 30% slower than in patients aged 5 to 24 months (n=22) but comparable to the patients aged 3 to 12 years. The half-life in the patient population aged 1 to 4 month was reported to average 6.7 hours compared to 2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The differences in pharmacokinetic parameters in the 1 to 4 month patient population can be explained in part by the higher percentage of total body water in neonates and infants and a higher volume of distribution for water soluble drugs like ondansetron.

In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron were reduced in comparison to values with adult patients. Both parameters increased in a linear fashion with weight and by 12 years of age, the values were approaching those of young adults.

When clearance and volume of distribution values were normalised by body weight, the values for these parameters were similar between the different age group populations. Use of weight-based dosing compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients.

Population pharmacokinetic analysis was performed on 428 subjects (cancer patients, surgery patients and healthy volunteers) aged 1 month to 44 years following intravenous administration of ondansetron. Based on this analysis, systemic exposure (AUC) of ondansetron following oral or IV dosing in children and adolescents was comparable to adults, with the exception of infants aged 1 to 4 months. Volume was related to age and was lower in adults than in infants and children.

Clearance was related to weight but not to age with the exception of infants aged 1 to 4 months. It is difficult to conclude whether there was an additional reduction in clearance related to age in infants 1 to 4 months or simply inherent variability due to the low number of subjects studied in this age group. Since patients less than 6 months of age will only receive a single dose in PONV a decreased clearance is not likely to be clinically relevant.

Elderly

Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. However, wide inter-subject variability resulted in considerable overlap in pharmacokinetic parameters between young (< 65 years of age) and elderly subjects (> 65 years of age) and there were no overall differences in safety or efficacy observed between young and elderly cancer patients enrolled in CINV clinical trials to support a different dosing recommendation for the elderly.

Based on more recent ondansetron plasma concentrations and exposure-response modelling, a greater effect on QTcF is predicted in patients > 75 years of age compared to young adults. Specific dosing information is provided for patients over 65 years of age and over 75 years of age for IV dosing (see section 4.2).

Renal Impairment

In patients with renal impairment (creatinine clearance 15–60 ml/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's phar­macokinetics to be essentially unchanged following IV administration.

Hepatic Impairment

Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's sys­temic clearance is markedly reduced with prolonged elimination half-lives (15–32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.

The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.

5.3. Preclinical safety data

No additional data of relevance.

• 6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Citric acid monohydrate

Sodium citrate

Sodium chloride

Water for injections.

6.2. Incompatibilities

Ondansetron injection should not be administered in the same syringe or infusion as any other medication.

6.3. Shelf life

36 months (unopened).

After dilution, see section 6.4 Special precautions for storage.

6.4. Special precautions for storage

Do not store above 25°C.

Keep the ampoule in the outer carton

Keep out of the reach and sight of children

After dilution:-

Chemical and physical in use stability has been demonstrated for 24 hours at 25°C and 5°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2–8°C, unless opening and dilution has taken place in controlled and validated aseptic conditions.

• 6.5. Nature and contents of container

Type I Ph. Eur. amber glass 3ml capacity ampoules. Each pack contains one, five or ten ampoules. Type I Ph. Eur. amber glass 4ml capacity ampoules. Each pack contains one, five or ten ampoules.

6.6. Special precautions for disposal

For single use. Discard any unused product immediately after use.

Ondansetron injection should not be autoclaved.

Compatibility with intravenous fluids:

Ondansetron injection should only be admixed with those infusion solutions which are recommended-

Sodium Chloride Intravenous Infusion BP 0.9%w/v

Glucose Intravenous Infusion BP 5%w/v

Mannitol Intravenous Infusion BP 10%w/v

Ringers 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

In keeping with good pharmaceutical practice dilutions of Ondansetron Injection in intravenous fluids should be prepared at the time of infusion although chemical and physical in use stability after dilution has been demonstrated for 24 hours at 25°C and 5°C.

Compatibility with other drugs: Ondansetron may be administered by intravenous infusion at 1mg/hour, e.g. 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 micrograms/ml (e.g. 8 mg/500 ml and 8 mg/50 ml respectively):

Cisplatin: Concentrations up to 0.48 mg/ml (e.g. 240 mg in 500 ml) administered over one to eight hours.

5 -Fluorouracil: Concentrations up to 0.8 mg/ml (e.g. 2.4g in 3 litres or 400mg in 500ml) administered at a rate of at least 20ml per hour (500 ml per 24 hours). Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-fluorouracil infusion may contain up to 0.045%w/v magnesium chloride in addition to other excipients shown to be compatible.

Carboplatin: Concentrations in the range 0.18mg/ml to 9.9mg/ml (e.g. 90mg in 500ml to 990mg in 100ml), administered over ten minutes to one hour.

Etoposide: Concentrations in the range 0.14 mg/ml to 0.25 mg/ml (e.g. 72mg in 500ml to 250 mg in 1 litre), administered over thirty minutes to one hour.

Ceftazidime: Doses in the range 250 mg to 2000 mg reconstituted with Water for Injections BP as recommended by the manufacturer (e.g. 2.5ml for 250mg and 10ml for 2g ceftazidime) and given as an intravenous bolus injection over approximately five minutes.

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

Doxorubicin: Doses in the range 10–100mg reconstituted with Water for Injections BP, 5ml per 10mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes.

Dexamethasone: Dexamethasone sodium phosphate 20mg may be administered as a slow intravenous injection over two to five minutes via the Y-site of an infusion set delivering 8 or 16mg of ondansetron diluted in 50–100ml of a compatible infusion fluid over approximately 15 minutes. Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the same giving set resulting in concentrations in line of 32 micrograms to 2.5mg/ml for dexamethasone sodium phosphate and |8 micrograms to 1mg/ml for ondansetron.

• 7. MARKETING AUTHORISATION HOLDER

Wockhardt Uk Ltd, Ash Road North, Wrexham, LL13 9UF, UK

• 8. MARKETING AUTHORISATION NUMBER(S)

PL 29831/0154

PL 29831/0155

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Renewed: 06/11/2013

• 10. DATE OF REVISION OF THE TEXT