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Package leaflet: Information for the patient ONDANSETRON 2 mg/ml SOLUTION FOR INJECTION OR INFUSION

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, please ask your doctor or your pharmacist.

•    This medicine has been prescribed for you only. Do not pass it on to others.

It may harm them, even if their signs of illness are the same as yours.

•    If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

In this leaflet:

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

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

3.    How to administer Ondansetron Solution for Injection

4.    Possible side effects

5.    How to store Ondansetron Solution for Injection

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 the active substance Ondansetron (as Ondansetron hydrochloride dihydrate).

Ondansetron belongs to the group of medicines known as antiemetics. Ondansetron is used to treat nausea and vomiting caused by cancer chemotherapy or radiotherapy (in adults and children).

It is also used to prevent and treat sickness that can sometimes occur after an operation (adults only)._

2. WHAT YOU NEED TO KNOW BEFORE ONDANSETRON SOLUTION FOR INJECTION IS ADMINISTERED

Do not administer Ondansetron Solution for Injection if any of the following apply to you.

•    you are allergic (hypersensitive) to ondansetron or any of the other ingredients of Ondansetron Solution for Injection (please refer to Section 6 for full list of ingredients). An allergic reaction may include rash, itching, swelling of face, lips, tongue or hands/feet,

or breathing difficulties

•    you are taking apomorphine (used to treat Parkinson's disease).

Warnings and precautions

Talk to your doctor or pharmacist before Ondansetron Solution for Injection is administered:

•    if you have symptoms of subacute intestinal obstruction (blockage in the bowel) such as stomach ache, nausea, vomiting, constipation or difficulty in passing wind

•    if you have undergone tonsil surgery. Prevention of nausea and vomiting with ondansetron may mask hidden bleeding. Therefore, such patients should

be monitored carefully after taking Ondansetron.

•    if you are taking any of the following medicines: tropisetron & granisetron.

•    if you are having cancer chemotherapy.

•    if you have an abnormal heart rhythm, suffer from palpitations, take drugs to control your heart rhythm, take betablocking drugs or if you have significant abnormalities of the electrolytes (sodium and potassium salts) in your blood

Please consult your doctor, even if these statements were applicable to you at any time in the past.

Other medicines and Ondansetron

Tell your doctor or pharmacist if you are taking, have recently taken or might have taken any other medicines.

In particular you should tell your doctor if you are taking any of the following:

•    phenytoin, used in the treatment of epilepsy

•    carbamazepine, used to treat epilepsy and bipolar disorder

•    rifampicin, an antibiotic used to treat bacterial infections

Ondansetron may reduce the effects of tramadol. The use of ondansetron with medicines that affect the heart (e.g. anthracyclines such as doxorubicin and idarubicin) may increase the risk of arrhythmias (changes in your heart beat).

In patients receiving cancer chemotherapy with medicines such as doxorubicin, the rhythm of the heart may be affected. Caution should be taken in patients who are being treated with medication that suppresses abnormal rhythms of the heart, such as beta blockers (e.g. atenolol) or antiarrhythmics (e.g. amiodarone).

Pregnancy and Breast-feeding

If you are pregnant or breast-feeding you should talk to your doctor or pharmacist before taking any medicine.

Driving and using machines Ondansetron does not affect your ability to drive or operate machines._

3. HOW TO ADMINISTER ONDANSETRON SOLUTION FOR INJECTION FOR INFUSION

The injection will usually be given by a doctor or nurse. For patients receiving chemotherapy or radiotherapy Ondansetron can be given either by oral, intravenous or intramuscular administration.

For most patients receiving chemotherapy or radiotherapy that causes nausea and vomiting: the recommended dose is 8 mg given by intravenous (into a vein) or intramuscular injection (into a muscle), immediately before chemotherapy, followed by 8 mg tablet after 12 hours.

For patients receiving chemotherapy that causes severe nausea and vomiting: any of the following dose schedules are recommended

•    8 mg by intravenous or intramuscular injection immediately before chemotherapy.

•    8 mg by intravenous or intramuscular injection immediately before chemotherapy, followed by two further intravenous or intramuscular doses of

8 mg 2 to 4 hours apart, or by a constant infusion of 1mg/hour for up to 24 hours.

•    16mg of ondansetron infused over not less than 15 minutes immediately before chemotherapy. After the initial ondansetron injection, you may be given ondansetron tablets for up to 5 days to prevent any further nausea & vomiting.

Use in children aged over 6 months and adolescents

The doctor will decide the dose. Look at the label for more information.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

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)

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, and for the prevention and treatment of postoperative nausea and vom ting (PONV).

Paediatric Population

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

4.2.    Posology and method of administration Chemotherapy and Radiotherapy

For intravenous use or for intramuscular use. Refer to Section 6.6 ‘Instructions for Use and Handling’, for information on compatibil ty with intravenous fluids and other drugs.

For single use. Discard any unused product immediately after use 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 w th 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 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 immediately before chemotherapy.

-    A dose of 8mg by slow intravenous or intramuscular injection immediately before chemotherapy, followed by two further intravenous or intramuscular doses of 8mg two to four hours apart, or by a constant infusion of 1mg/hour for up to 24 hours.

-    A single dose of 16mg diluted in 50-l00ml of saline or other compatible infusion fluid (see Pharmaceutical Precautions) and infused over not less than 15 minutes immediately before chemotherapy. 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 add tion 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 w th 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.

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 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 daily dose must not exceed adult dose of 32 mg.

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

BSA	Day 1 (ab	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	5 mg/m2 i.v. plus 4 mg syrup or tablet after 12 hrs	4 mg syrup or tablet every 12 hrs

a The intravenous dose must not exceed 8mg. b The total daily dose 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 intravenous dose must not exceed 8 mg.

Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32 mg.

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

Elderly: Ondansetron hydrochloride is well tolerated by patients over 65 years and no a teration of dosage, dosing frequency or route of administration are required.

Patients with Renal Impairment: No alteration of daily dosage or frequency of dosing, or route of administration are required. Patients wilh hepatic Impairment: Clearance of Ondansetron hydrochloride is significantly reduced and serum half-l fe 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.

Rost-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 wilh hepatic impairment: Clearance of ondansetron hydrochloride is significantly reduced and semm 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.

Patients wilh poor sparteine/debrisoquine metabolism:

The elimination half-life of ondansetron hydrochloride is not a tered 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 isted 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 5HTs receptor antagonists. Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersens tivity reactions.

Rarely, transient ECG changes including QT interval prolongation have been reported in patients receiving ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with electrolyte abnormalities, with congenital long QT syndrome, or patients taking other medicinal products that lead to QT prolongation. Therefore, caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with antiarrhythmic agents or beta-adrenergic blocking agents and in patients with significant electrolyte disturbances.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored fo lowing 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 c inical trials. Cross-trial comparison indicates similar efficacy for both regimens (section 5.1).

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 t. Specific studies have shown that there are no pharmacokinetic interactions when ondansetron is administered with alcohol, temazepam, furosemide, afentanil, tramadol, morphine, lidocaine, thiopental or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the mu tip icity 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.

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 w th 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.

Use of ondansetron with QT prolonging drugs may result in additional QT prolongation.

Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyc ines) may increase the risk of arrhythmias (see section 4.4).

4.6.    Fertility, pregnancy and lactation Pregnancy

The safety of ondansetron for use in human pregnancy has not been estab ished.

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 pre- 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.

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.

Immune system disorders

Rare: Immediate hypersens tivity 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), observed without defin tive evidence of persistent cinical 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.

Very rare: Transient ECG changes including QT interval prolongation predominantly w th intravenous administration of ondansetron.

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.

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

General disorders and administration site conditions Common: Local intravenous injection site reactions (e.g. rash, urticaria, itching), sometimes extending along the drug administration vein.

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 www.mhra.gov.uk/yellowcard.

4.9.    Overdose Symptoms and Signs

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). Manfestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block.

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 ch ldren aged 12 months to 2 years.

Treatment

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

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.

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 5HTs receptor-antagonist. ts 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 vomoting reflex by activating vagal afferents via 5HTs 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

On the day of chemotherapy or radiotherapy

•    the first dose is given by an injection into a vein, just before your child's treatment. After chemotherapy, your child's medicine will usually be given by mouth; the usual dose is a 4mg ondansetron tablet or 4mg ondansetron syrup twelve hours later.

On the following days

•    one 4mg tablet or 4mg syrup twice a day.

•    this can be given for up to five days.

To prevent nausea and vomiting after an operation: the usual adult dose is 4 mg given by intravenous or intramuscular injection before the operation.

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

To treat nausea and vomiting after an operation: the usual adult dose is 4 mg given as intravenous or intramuscular injection.

For children aged over 1 month and adolescents, the doctor will decide the dose. The maximum dose is 4mg given as an injection into the vein.

Patients with moderate or severe liver disease: the total daily dose should not be more than 8 mg.

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 may have missed a dose or had too much, let your doctor or nurse know immediately.

4. POSSIBLE SIDE EFFECTS

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

A few people can be allergic to some medicines; if any of the following rare side effects come on soon after having your injection, tell your doctor immediately:

•    Sudden chest tightness or wheezing

•    Swelling of eyelids, face or lips

•    Skin rash - red spots or hives (skin lumps)

•    Collapse

The following side effects are very rare but if you have them you should let your doctor know immediately:

•    Upward rolling of the eyes

•    Abnormal muscular stiffness, body movements or shaking

•    Fits

•    Blurring of vision

•    Temporary blindness

•    Yellowing of the skin or whites of the eyes caused by liver problems

•    Low blood pressure (symptoms may include dizziness, fainting and nausea)

Other possible side effects are:

•    Headache

•    Feeling of warmth in the head or stomach

•    Dizziness or lightheaded feeling

•    Slow or irregular heartbeat

•    Chest pain

•    Flushes of the face

•    Hiccups

•    Upset bowels - constipation

•    Irritation and redness at the site of injection

If you have any blood tests to check how your liver is working, this medicine may affect the results. If you feel unwell or have any other unusual discomfort you do not understand, tell your doctor as soon as possible.

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

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

5. HOW TO STORE ONDANSETRON SOLUTION FOR INJECTION OR 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, 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.

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

What Ondansetron solution for injection

or infusion

contains

•    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 Limited, Ash Road North, Wrexham, LL13 9UF, United Kingdom.

Manufacturer

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

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0800 198 5000 (UK Only)

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

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This leaflet was last revised in 09/2016

106938/3    Twvckhardt

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 opiate induced emesis is not yet established.

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 baseline correction 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 CNV

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 ether ondansetron 5 mg/m2 intravenous + ondansetron 4 mg orally after 8-12 hrs or ondansetron 0.45 mg/kg intravenous + placebo orally after 8-12 hrs. Rost- 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 + ondansetron 4 mg ora ly) and 41% (0.45 mg/kg intravenous + placebo orally). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days.

A double-blind randomised placebo-contro led 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 + 2-4 mg dexamethasone orally on the days of chemotherapy.

Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days.

The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open label, non-comparative, single-arm study (S3A40320). A l 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-b ind, placebo-controlled study in 670 ch ldren 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 < II. A single dose of ondansetron 0.1 mg/kg was administered wthin 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

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. 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. 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). The dispos tion of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a terminal half life of about three hours and steady state volume of distribution of about 140L. Equivalent systemic exposure is achieved after IM and IV 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 essentia ly 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 sma l, 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

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-lfe 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 d fferences 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 ch ldren 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.

t is d fficult 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.

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 sight, 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.

Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. However, t is anticipated that the ha f-life of ondansetron after rectal administration in these populations w ll be similar to that seen in healthy volunteers, since the rate of elimination of ondansetron following rectal administration is not determined by systemic clearance.

Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced w th prolonged e imination 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 suppos tory 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 monhydrate 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 d lution, 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 dlution:-

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. f not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not noma ly be longer than 24 hours at 2-8°C, unless opening and dilution has taken place in controlled and validated aseptic rand tions.

6.5.    Nature and contents of container

Type I Ph Eur amber glass 3ml 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):

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

5 -Fiuorouracii: Concentrations up to 0.8 mg/ml (e.g. 2.4g in 3 l tres 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.

Carbopiatin: 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. Compatib lity 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 18 micrograms to 1mg/ml for ondansetron.

7.    MARKETING AUTHORISATION HOLDER Wockhardt UK Ltd

Ash Road North Wrexham LL13 9UF U.K

8.    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0154

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Renewed: 06/11/2013

10.    DATE OF REVISION OF THE TEXT

09/2016

106938/3    Twockhardt