Ondansetron 2 mg/ml Solution for Injection or Infusion

Each ml of solution for injection or infusion contains 2mg ondansetron (as ondansetron hydrochloride dihydrate)

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

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

1 ml solution for injection or infusion contains 3.62 mg of sodium as sodium citrate, sodium chloride and sodium hydroxide.

For a full list of excipients, see section 6.1

Solution for Injection or Infusion

Clear colourless solution

Adults:

Management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, Prevention and treatment of post-operative nausea and vomiting (PONV).

Paediatric Population:

Management of chemotherapy-induced nausea and vomiting in children aged 6 months.

Prevention and treatment of post-operative nausea and vomiting in children aged 1 month.

For intravenous injection or intramuscular injection or intravenous infusion after dilution.

For instructions on dilution of the product before administration, see section 6.6

Prescribers intending to use ondansetron in the prevention of delayed nausea and vomiting associated with chemotherapy or radiotherapy in adults, adolescents or children should take into consideration current practice and appropriate guidelines.

Chemotherapy and radiotherapy induced nausea and vomiting:

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 should be flexible in the range of 8-32 mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy:

For patient receiving Emetogenic chemotherapy and radiotherapy, ondansetron can be given either by intravenous or intramuscular or other routes of administration. However this product is for injection or infusion only.

For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron 8 mg should be administered as a slow intravenous or intramuscular injection or as a short-time intravenous infusion over 15 immediately before treatment, followed by 8 mg orally twelve hourly.

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with ondansetron associated with dexametasone should be continued for up to 5 days after a course of treatment. Ondansetron treatment with other dosage forms than intravenous should be continued for up to 5 days after a course of treatment.

Highly emetogenic chemotherapy: For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given either by intravenous or intramuscular administration. Ondansetron has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy:

• A single dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy.

• A dose of 8 mg by slow intravenous or intramuscular injection or as a short-time intravenous infusion over 15 minutes immediately before chemotherapy, followed by two further intravenous or intramuscular doses of 8 mg two to four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours.

• Doses of greater than 8mg and up to 32 mg of ondansetron may only be given by intravenous infusion diluted in 50-100 ml of saline (0.9% w/v) or other compatible infusion fluid (see section 6.6) and over not less than 15 minutes immediately before chemotherapy.

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

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

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment.

Paediatric Population:

Chemotherapy-induced nausea and vomiting in children aged 6 months and adolescents:

The dose of chemotherapy-induced nausea and vomiting 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 - see 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 Injection in the prevention of chemotherapy-induced delayed or prolonged nausea and vomiting. There are no data from controlled clinical trials on the use of Ondansetron Injection for radiotherapy-induced nausea and vomiting in children.

Dosing by BSA:

Ondansetron 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. See Table 1 below.

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

^a The intravenous dose must not exceed 8 mg.

^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 - see sections 4.4 and 5.1. Ondansetron 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. See Table 2 below.

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

^a The intravenous dose must not exceed 8 mg.

^b The total daily dose must not exceed adult dose of 32 mg.

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

Please refer also to 'Special Populations.'

Post-operative nausea and vomiting (PONV):

Prevention of PONV

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

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

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

Paediatric population:

Post-operative nausea and vomiting 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 0.1 mg/Kg up to a maximum of 4 mg 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 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 Injection for the treatment of postoperative vomiting in children under 2 years of age.

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

Please refer also to “Special Populations”.

Special populations

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

Patients with hepatic impairment: Clearance of ondansetron 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 8 mg should not be exceeded.

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 are required.

Hypersensitivity to ondensetron or to other selective 5HT₃ receptor antagonists (e.g. granisetron, dolasetron) or to any of the excipients.

The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron.

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 hypersensitive reactions.

Very rarely and predominantly with intravenous Ondansetron, transient ECG changes including QT interval prolongation have been reported. Caution is advised if patients have received cardiotoxic agents and in patients with a history or family history of prolonged QT syndrome (see section 4.8).

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

This medicinal product contains 2.5 mmol (or 57.9 mg) sodium per maximum daily dose of 32 mg. To be taken into consideration by patients on a controlled sodium diet.

Paediatric Population:

Paediatric population receiving ondansetron with hepatotoxic chemotherapeutical agents should be monitored closely for impaired hepatic function.

Chemotherapy-induced nausea and vomiting:

When calculating the dose on a mg/Kg basis and administering three doses at 4 hourly intervals, the total daily dose will be higher than if one single dose of 5 mg/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 comparing indicate similar efficacy for both regimens - see section 5.1

Effects of ondansetron on other medicinal products

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

Tramadol

Data from small studies indicate that ondansetron may reduce the analgestic effect of tramadol.

Effects of other medicinal products on ondansetron

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.

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.

Apomorphine: Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with ondansetron is contradindicated [see Contraindications (4)].

Use of Ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of Ondansetron with cardiotoxic drugs (e.g. anthracyclines) may increase the risk of arrhythmias (See section 4.4).

Pregnancy

The safety of ondansetron for use in human pregnancy has not been established. Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo, or fetus, the course of gestation and pre- and post-natal development. However as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended. If it is absolutely necessary that Ondansetron be given caution should be exercised when prescribing to pregnant women especially in the first trimester. A careful risk/benefit assessment should be performed.

Lactation

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.

Ondansetron 2mg/ml has no or negligible influence on the ability to drive and use machines.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (1/10), common (1/100 and <1/10), uncommon (1/1000 and <1/100), rare (1/10,000 and <1/1000) and very rare (<1/10,000) not known (cannot be estimated from the available data).

The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation.

Symptoms and Signs

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

Treatment

In all instances, the events resolved completely. There is no specific 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.

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.

In a pharmaco-psychological study in volunteers, ondansetron has not shown a sedative effect.

Ondansetron does not alter plasma prolactin concentrations.

The role of ondansetron in opiate-induced emesis is not yet established.

Paediatric Population:

Chemotherapy-induced nausea and vomiting

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 i.v. + after 8-12 hrs ondansetron 4 mg p.o. or ondansetron 0.45 mg/Kg i.v. + after 8-12 hrs placebo p.o. 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 % (5mg/m² i.v. + ondansetron 4 mg p.o.) and 41 % (0.45 mg/Kg i.v. + placebo p.o.). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. A double-blind randomise 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 5mg/m² i.v. together with 2-4 mg dexamethasone p.o. and in 71% of the patients when ondansetron was administered as a syrup at a dose of 8 mg + 2-4 mg dexamethasone p.o. 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). All children receive three 0.15 mg/Kg doses of intravenous ondansetron, administered at 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-operative, single-arm study investigated the efficacy of one intravenous dose of 0.15 mg/Kg ondansetron followed by two ondansetron doses of 4mg for children aged < 12 yrs and 8 mg for children aged 12yrs (total no. of children n = 28). Complete control of emesis was achieved in 42% of patients.

Prevention of post-operative nausea and vomiting

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 effective surgery under general anaesthesia and had an ASA status III. 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

CR = no emetic episodes, rescue or withdrawal

The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

A direct correlation of plasma concentration and anti-emetic effect has not been established.

Absorption

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (Bioavailability is about 60%). Peak plasma concentrations of about 30ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher 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).

A 4mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65 ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/ml are attained within 10 minutes of injection.

Distribution

The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing 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 IM and IV administration of ondansetron.

Ondansetron is not highly protein bound (70-76%).

Metabolism

Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics.

Excretion

Less than 5% of the absorbed dose is excreted unchanged in the urine. Terminal half-life is about 3 hours.

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-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 persons

Studies in healthy elderly volunteers have shown slight age-related increases in both oral bioavailability (65%) and half-life (5 hours).

Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration.

Renal impairment

In patients with moderate 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.

Gender differences

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).

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenic potential.

Ondansetron and its metabolites accumulate in the milk of rats at a milk:plasma ratio of 5.2:1.

A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels.

Citric acid monohydrate

Sodium citrate

Sodium chloride

Sodium hydroxide (for pH adjustment)

Hydrochloric acid, concentrated (for pH adjustment)

Water for injections.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened

3 years

Injection

After first opening the medicinal product should be used immediately.

Infusion

Chemical and physical in-use stability has been demonstrated for 7 days at 25°C and 2-8°C with the solutions given in section 6.6.

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 normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

This medicinal product does not require any special temperature storage conditions.

Keep ampoules in the outer carton in order to protect from light.

For storage conditions of the diluted medicinal product, see section 6.3.

Type I clear glass ampoules

Not all pack sizes may be marketed.

The solution must not be sterilised in an autoclave.

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

The stability of Ondansetron Injection after dilution with the recommended infusion fluids have been demonstrated in concentrations 0.016 mg/ml and 0.64 mg/ml.

Compatibility studies have been undertaken in polyvinyl chloride infusion bags with polyvinyl chloride administration sets, polyethylene infusion bags, Type 1 glass bottles and polypropylene syringes. Dilutions of Ondansetron Injection in 10% mannitol injection, ringer's injection, 0.3% potassium chloride and 0.9% sodium chloride injection, 0.3% potassium chloride and 5% dextrose injection, 0.9% sodium chloride injection and 5% glucose injection have been demonstrated to be stable in polyvinyl chloride infusion bags and polyvinyl chloride administration sets, polyethylene infusion bags, Type 1 glass bottles and polypropylene syringes.

Compatibility with other drugs: Ondansetron Injection may be administered by intravenous infusion using 0.9% sodium chloride and 5% dextrose injection 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 Injection 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.

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

Etoposide: Concentrations in the range 0.14 mg/ml to 0.25 mg/ml (e.g. 72 mg in 500 ml 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. 2.5 ml for 250 mg and 10 ml for 2g ceftazidime) and given as an intravenous bolus injection over approximately five minutes.

Cyclophosphamide: Doses in the range 100 mg to 1g, reconstituted with Water for Injections BP, 5 ml per 100 mg 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, 5 ml per 10 mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately 5 minutes.

Dexamethasone: Dexamethasone sodium phosphate 20mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 32mg of ondansetron diluted in 50-100 ml 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 microgram - 2.5 mg/ml for dexamethasone sodium phosphate and 8 microgram - 0.75 mg/ml for ondansetron.

The solution is to be visually inspected prior to use (also after dilution). Only clear solutions practically free from particles should be used.

The diluted solutions should be stored protected from light.

Any unused product or waste material should be disposed of in accordance with local requirements.

Accord Healthcare Limited

Sage House

319, Pinner Road

North Harrow

Middlesex, HA1 4HF

UK

PL 20075/0082

11/12/2009

16/04/2012