Ondansetron 2mg|Ml Solution For Injection
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ondansetron 2mg/ml Solution for Injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 2 mg Ondansetron as Ondansetron hydrochloride dihydrate.
Each glass ampoule of 2ml contains 4mg Ondansetron (as hydrochloride dihydrate)
Each glass ampoule of 5ml (containing 4 ml of solution) contains 8mg Ondansetron (as hydrochloride dihydrate)
Each ml of the solution contains 3.6 mg of Sodium.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Solution for Injection A clear, colourless solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Ondansetron 2mg/ml Solution for Injection is indicated for the prevention and treatment of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy and for the prevention and treatment of post-operative nausea and vomiting (PONV).
Paediatric Population:
Ondansetron 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
For intravenous injection, intravenous infusion after dilution or intramuscular administration.
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 dose range of Ondansetron 2mg/ml Solution for Injection or infusion is 8-32mg a day and selected as shown below.
Emetogenic chemotherapy and radiotherapy:
For patients receiving emetogenic chemotherapy or radiotherapy, 8mg of ondansetron should be administered as a slow intravenous injection, an intravenous infusion over 15 minutes, or intramuscular injection immediately before treatment, followed by 8mg orally twelve hourly.
To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8mg twice daily or 16mg rectally once daily.
For oral or rectal administration refer to the SPC of ondansetron tablets and suppositories, respectively.
Highly emetogenic chemotherapy:
For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, Ondansetron can be given either by rectal, intravenous or intramuscular administration. Ondansetron has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy:
Ondansetron 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 or as a short-time intravenous infusion over 15 minutes 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 intravenous dose of 16mg diluted in 50-100ml of saline or other compatible infusion fluid (see compatibility with solutions for infusion under section 6.6) 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)
Doses of greater than 8mg and up to 16mg of Ondansetron may only be given by intravenous infusion diluted in 50-100ml of saline or other compatible infusion fluid (see Pharmaceutical Precautions) and infused over not less than 15 minutes.
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, ondansetron treatment with dosage forms other than intravenous should be continued after a course of treatment. The recommended dose for oral administration is 8mg twice daily.
Pediatric 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 injection 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 in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of ondansetron 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 (Table 1).
Table 1: BSA-based dosing for Chemotherapy - Children aged >6 months and adolescents
|
BSA |
Day 1 (a,b) |
Days 2-6(b) |
|
<0.6 m2 |
5 mg/m2i.v. plus 2 mg syrup after 12 hrs |
2 mg syrup every 12 hrs |
|
>0.6 m2 |
5 mg/m2i.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 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).
Table 2: Weight-based dosing for Chemotherapy - Children aged >6 months and adolescents
|
Weight |
Day 1(a,b) |
Days 2-6(b) |
|
<10 kg |
Up to 3 doses of 0.15 mg/kg every 4 hrs |
2 mg syrup every 12 hrs |
|
>10 kg |
Up to 3 doses of 0.15 mg/kg every 4 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.
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 administered by intravenous or intramuscular injection or other dosage forms.
Ondansetron may be administered as a single dose of 4mg given by intramuscular or slow intravenous injection at induction of anesthesia.
Treatment of established PONV
A single dose of 4-8 mg given by intramuscular or slow intravenous injection is recommended.
Pediatric Population:
PONV in children aged > 1 month and adolescents
For prevention of PONV in pediatric patients having surgery performed under general anesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds)d at a dose of 0.1mg/kg up to a maximum of 4mg prior to, at or after induction of anesthesia.
For treatment of established 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.
There are no data on the use of ondansetron in the treatment of PONV in children below 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 are 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 8mg 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 frequencies of dosing are required.
4.3 Contraindications
Hypersensitivity to Ondansetron or to other selective 5HT3 receptor antagonists (e.g. granisetron, dolasetron) or to any of the excipients.
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.
The medicinal product should not be used for children younger than two years, as for these patients the experience is limited.
As Ondansetron is known to increase large bowel transit time, patients with signs of sub acute intestinal obstruction should be monitored following administration.
As there is little experience to date of the use of ondansetron in cardiac patients, caution should be exercised if ondansetron is coadministered with anaesthetics to patients with arrhythmias or cardiac conduction disorders or to patients who are being treated with antiarrhythmic agents or beta-blockers.
The benefit/risk balance of ondansetron prescription should be evaluated in patients having a previous alteration of the QT interval (see section 4.8). 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 agentsor beta-adrenergic blocking agents and in patients with significant electrolyte disturbances.
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.
Pediatric 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).
Ondansetron contains 2.52 mmol (57.6 mg) sodium per maximum daily dose of 32 mg. This has to be taken into consideration for patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
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 ondansetron does not interact with alcohol, temazepan, furosemide, tramadol, alfentanil, propofol and thiopental.
Tramadol
Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
Effects of other medicinal products on ondansetron
Ondansetron is metabolized by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolizing 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.
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 (section 4.4).
4.6 Pregnancy and lactation
Pregnancy
Data on a limited number of exposed pregnancies indicate no adverse effects of ondansetron on pregnancy or on the health of the fetus/newborn child. To date, no other relevant epidemiological data are available.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development. However, animal studies are not always predictive of human response. 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 (see section 5.3). It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies.
4.7 Effects on ability to drive and use machines
Ondansetron 2mg/ml Solution for Injection has no influence on the ability to drive and use machines.
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 (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (< 1/10,000 and isolated reports). Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data. The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation.
Immune system disorders:
Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis. Anaphylaxis may be fatal.
Hypersensitivity reactions have also been observed in patients who are hypersensitive to other selective 5HT3 antagonists.
Nervous system disorders:
Rare: There have been reports suggestive of involuntary movement disorders such as extrapyramidal reactions, e.g. oculogyric crisis/dystonic reactions without definitive evidence of persistent clinical sequelae and seizures have been rarely observed, although no known pharmacological mechanism can account for ondansetron causing these effects.
Cardiac disorders:
Rare: Chest pain with or without ST segment depression, cardiac arrhythmias, hypotension and bradycardia. Chest pain and cardiac arrhythmias may be fatal in individual cases.
Transitory changes in the electrocardiogram, including prolongation of the QT interval and Torsade de Pointes have been observed, predominantly after intravenous administration of ondansetron.
Gastrointestinal disorders:
Common: Ondansetron is known to increase the large bowel transit time and may cause constipation in some patients.
Hepatobiliary disorders:
Uncommon: Asymptomatic increases in liver function tests*. *These events were frequently observed in patients receiving chemotherapy with cisplatin.
Skin and subcutaneous tissue disorders:
Uncommon: Hypersensitivity reactions around the injection site (e.g. rash, urticaria, itching) may occur, sometimes extending along the drug administration vein.
General disorders and administration site conditions:
Common: Headache, sensations of flushing or warmth, hiccups.
Rare: Transient visual disturbances (e.g. blurred vision) and dizziness during rapid intravenous administration of ondansetron.
In individual cases, transitory blindness was reported in patients receiving chemotherapeutic agents including cisplatin. Most of the reported cases resolved within 20 minutes.
Paediatric population
The adverse event profile in children and adolescents was 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 (see details below).
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4.9 Overdose
Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely. There is no specific antidote for ondansetron; therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiemetics and antinauseants, serotonin (5HT3) antagonists, ATC code: A04A A01
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.
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% CI) 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% CI) 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
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 + ondansetron 4 mg orally after 8-12 hrs or ondansetron 0.45 mg/kg
intravenous + placebo orally after 8-12 hrs. 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 + ondansetron 4 mg orally) 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-controlled trial (S3AB4003) in 438 patients aged 1 to17 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 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 < 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
|
Study |
Endpoint |
Ondansetro n % |
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
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 30 ng/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.
A 4mg intravenous infusion of ondansetron given over 5 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.
Distribution
The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a 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.
Special Patient Populations
Children and Adolescents (aged 1 month to 17years)
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).
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.
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).
5.3 Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and carcinogenic potential.
Ondansetron and its metabolites accumulate in the milk of rats with 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Citric acid monohydrate Sodium citrate Sodium chloride Water for Injections
6.2 Incompatibilities
Ondansetron 2mg/ml Solution for Injection should not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
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 36 hours at 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.
6.4 Special precautions for storage
This medicinal product does not require any special storage temperature.
Keep ampoules in the outer carton, in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
2 ml type 1 clear glass ampoules containing 2 ml of solution. 5 ml type 1 clear glass ampoules containing 4 ml of solution.
Each pack contains 25 ampoules of 2 ml or 5ml capacity glass ampoule. Each pack contains 5 ampoules of 2 ml or 5ml capacity glass ampoule
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Compatibility with intravenous fluids: 0.08mg/ml concentration of Ondansetron with each diluents at the storage of 2-8 °C for 36 hours.
The solution must not be sterilised in an autoclave.
The solution is to be visually inspected prior to use (also after dilution). Only clear solutions practically free from particles should be used. Do not use if container is damaged.
The diluted solutions should be stored protected from light.
Any unused product or waste material should be disposed of in accordance with local requirements.
Ondansetron 2mg/ml Solution for Injection should only be admixed with those infusion solutions, which are recommended:
Sodium Chloride Intravenous Infusion 0.9%w/v
Glucose Intravenous Infusion 5%w/v
Mannitol Intravenous Infusion 10%w/v
Ringers Intravenous Infusion
Potassium Chloride 0.3%w/v and Sodium Chloride 0.9%w/v Intravenous Infusion
Potassium Chloride 0.3%w/v and Glucose 5%w/v Intravenous Infusion
Compatibility studies have been undertaken in polyvinyl chloride infusion bags, Non polyvinyl chloride infusion bags, Ph. Eur. Type I glass bottles and polyvinyl chloride administration sets.
Dilutions of Ondansetron in sodium chloride 0.9%w/v or in glucose 5%w/v have been demonstrated to be stable in polypropylene syringes. It is considered that Ondansetron injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.
Compatibility with other drugs:
Ondansetron 2mg/ml Solution for Injection 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 2mg/ml Solution for 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 litres), 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.
7 MARKETING AUTHORISATION HOLDER
CLARIS LIFESCIENCES UK LIMITED CREWE HALL, GOLDEN GATE LODGE,
CREWE,
CHESHIRE,
CW1 6UL,
UNITED KINGDOM.
8 MARKETING AUTHORISATION NUMBER(S)
PL 20568/0009
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/07/2009
10 DATE OF REVISION OF THE TEXT
12/05/2015