Ondansetron 2mg/Ml Solution For Injection
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ondansetron 2mg/ml Solution for Injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 2ml glass ampoule contains 2ml of aqueous solution containing 4mg ondansetron (as hydrochloride dihydrate). Each 5ml glass ampoule contains 4ml of aqueous solution containing 8mg ondansetron (as hydrochloride dihydrate).
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for Injection.
Ondansetron 2mg/ml Solution for Injection is a colourless, clear solution for injection.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults:
Ondansetron is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of post-operative nausea and vomiting (PONV).
Paediatric:
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
Chemotherapy and radiotherapy induced nausea and vomiting (CINV and RINV):
Adults: The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The selection of dose regimen should be determined by the severity of the emetogenic challenge. The route of administration and dose of ondansetron should be flexible in the range of 832mg a day and selected as shown below.
Emetogenic chemotherapy and radiotherapy: Ondansetron can be given either by oral (tablets), intravenous or intramuscular administration. The recommended intravenous (IV) or intramuscular (IM) dose of ondansetron is 8 mg administered as a slow injection in not less than 30 seconds immediately before treatment, followed by 8 mg orally twelve hourly.
Oral treatment is recommended to protect against delayed or prolonged emesis after the first 24 hours.
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.
Highly emetogenic chemotherapy e.g. high-dose cisplatin: 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:
Ondansetron may be administered as a single 8 mg IV or IM dose immediately before chemotherapy. Doses of greater than 8 mg and up to a maximum of 16 mg of ondansetron may only be given by IV infusion diluted in 50 to 100 ml of saline or other compatible infusion fluid and infused over not less than 15 minutes. A single dose greater than 16 mg should not be given (see section 4.4).
For management of highly emetogenic chemotherapy, a dose of 8 mg of ondansetron may be administered by slow IV in not less than 30 seconds, or slow IM injection immediately before chemotherapy, followed by 2 further IV or IM doses of 8 mg 2 to 4 hours apart, or by a constant infusion of 1 mg/h for up to 24 hours.
A single intravenous dose of 16 mg diluted in 50-100 ml 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 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.
Oral treatment is recommended to protect against delayed or prolonged emesis after the first 24 hours.
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:
CINV in children aged > 6 months and adolescents
The dose for CINV can be calculated based on body surface area (BSA) or weight -see below. In paediatric clinical studies, ondansetron was given by IV infusion diluted in 25 to 50 ml of saline or other compatible infusion fluid (see section 6.6) and infused over not less than 15 minutes.
Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4.and 5.1).
Ondansetron 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.
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(a’b) |
Day 2 - 6(b) |
|
< 0.6 m2 |
5mg/m2 IV plus 2 mg orally after 12 hours |
2 mg orally every 12 hours |
|
> 0.6 m2 |
5mg/m2 IV plus 4 mg orally after 12 hours |
4 mg orally every 12 hours |
|
> 1.2 m2 |
5 mg/m2 IV or 8 mg IV plus 8 mg syrup or tablet after 12 hours |
8 mg orally every 12 hours |
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.
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) |
Day 2 - 6(b) |
|
<10 kg |
Up to 3 doses of 0.15 mg/kg every 4 hours |
2 mg orally every 12 hours |
|
> 10 kg |
Up to 3 doses of 0.15 mg/kg every 4 hours |
4 mg orally every 12 hours |
|
a The intravenous c |
ose 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 are required..
Patients with Renal Impairment: No alteration of daily dosage or frequency of dosing, or route of administration are required.
PatiHepatic 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.
Post-operative nausea and vomiting (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 by IM or slow IV injection administered at induction of anaesthesia.
For treatment of established PONV a single dose of 4 mg given by IM or slow IV 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 IV injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia.
For 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 0.1 mg/kg up to a maximum of 4 mg.
There are no data on the use of ondansetron in the treatment of PONV 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.
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 active substance exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.
4.3 Contraindications
Concomitant use with apomorphine (see section 4.5) Hypersensitivity to the active substance 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. Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.
Ondansetron prolongs the QT interval in a dose-dependent manner (see Clinical Pharmacology). In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc, including patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalemia and hypomagnesemia should be corrected prior to ondansetron administration.
There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with ondansetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised.
As ondansetron is known to increase large bowel transit time, patients with signs of sub acute intestinal obstruction should be monitored following administration.
In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron.
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-hour 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 is not indicated for prevention and treatment of postoperative nausea and vomiting in children after intra-abdominal surgery.
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 most other medicinal products commonly co-administered with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepan, frusemide, alfentanil, tramadol, morphine, lignocaine, thiopental or propofol.
Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes:
CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes
and should result in little or no significant change in overall ondansetron clearance or dose requirement.
Use of ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines such as doxorubicin, daunorubicin or trastuzimab), antibiotics (such as erythromycin or ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of arrhythmias (see section 4.4).
There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including SSRIs and SNRIs). (see section 4.4)
Apomorphine
Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.
Tramadol
Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
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.
4.6 Pregnancy and lactation
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 foetus, the course of gestation and peri- and post-natal development. However as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended.
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.
4.7 Effects on ability to drive and use machines
Ondansetron has no or negligible influence on the ability to drive and use machines.
In psychomotor testing ondansetron does not impair performance nor cause sedation. No detrimental effects on such activities are predicted from the pharmacology of ondansetron.
4.8 Undesirable effects
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (^ 1/10), common ( ^ 1/100 and <1/10), uncommon (^ 1/1000 and <1/100), rare 1/10,000 and<l/1000) and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data.
The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation. . The adverse event profiles in children and adolescents were comparable to that seen in adults.
Immune system disorders
Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.
Nervous system disorders
Very common: Headache.
Uncommon: Seizures, movement disorders (including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia)1.
Rare: Dizziness during rapid IV administration, which in most cases is prevented or resolved by lengthening the infusion period.
Eye disorders
Rare: Transient visual disturbances (eg. blurred vision) predominantly during rapid IV administration.
Very rare: Transient blindness predominantly during intravenous administration.2 Cardiac disorders
Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia.
Rare: QTc prolongation (including Torsade de Pointes)
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 tests3.
General disorders and administration site conditions
Common: Local IV injection site reactions.
1 Observed without definitive evidence of persistent clinical sequelae.
2 The majority of the blindness cases reported resolved within 20 minutes. Most patients had received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness were reported as cortical in origin.
3 These events were observed commonly in patients receiving chemotherapy with cisplatin.
Paediatric population
The adverse event profiles in children and adolescents were comparable to that seen in adults.
4.9 Overdose
Symptoms and signs
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. Ondansetron prolongs QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose. In all instances, the events resolved completely.
Treatment
There is no specific antidote for ondansetron, therefore in cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
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
Pharmacotherapeutic group: 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 postoperative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.
The role of ondansetron in opiate-induced emesis is not yet established.
Ondansetron does not alter plasma prolactin concentrations.
QT prolongation
The effect of ondansetron on the QTc interval was evaluated in a double blind, randomised, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, the maximum mean (upper limit of 90% 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
Chemotherapy-induced nausea and vomitingCINV
The efficacy of ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a double-blind randomised trial in 415 patients aged 1 to 18 years (S3AB3006). On the days of chemotherapy, patients received either ondansetron 5 mg/m2 intravenous and ondansetron 4 mg orally after 8-12 hrs or ondansetron 0.45 mg/kg intravenous and placebo orally after 8-12 hrs. Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m2 intravenous and ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous and placebo orally). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.
A double-blind randomised placebo-controlled trial (S3AB4003) in 438 patients aged 1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy in:
• 73% of patients when ondansetron was administered intravenously at a dose of 5 mg/m2 intravenous together with 2-4 mg dexamethasone orally
• 71% of patients when ondansetron was administered as syrup at a dose of 8 mg + 2 - 4 mg dexamethasone orally on the days of chemotherapy.
Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.
The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, 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.
Prevention of post-operative nausea and vomitingPONV 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 |
lours | |||
|
Study |
Endpoint |
Ondansetron % |
Placebo % |
P value |
|
S3A380 |
CR |
68 |
39 |
< 0.001 |
|
S3GT09 |
CR |
61 |
35 |
<0.001 |
|
S3A381 |
CR |
53 |
17 |
< 0.001 |
|
S3GT11 |
no nausea |
64 |
51 |
0.004 |
|
S3GT11 |
no emesis |
60 |
47 |
0.004 |
CR = no emetic episodes, rescue or withdrawal
5.2 Pharmacokinetic properties
Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 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. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 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 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.
A 4 mg 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.
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-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 following a single intravenous dose of 2 mg (3-7 years old) or 4 mg (812 years old) 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. The magnitude of the change was age-related, with clearance falling from about 300 ml/min at 12 years of age to 100 ml/min at 3 years. Volume of distribution fell from about 75 l at 12 years to 17 l at 3 years. 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 (0.1 mg/kg up to 4 mg maximum) 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.
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 (5.4 h). 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.
Elderly
Specific studies in the elderly or patients with renal impairment have been limited to IV and oral 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.
5.3 Preclinical safety data
Non-clinical 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, milk/plasma-ratio was 5.2.
Ondansetron in micromolar concentrations blocked cloned HERG potassium channels of the human heart. The clinical relevance of this finding is not clear.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Citric acid monohydrate Sodium citrate
Hydrochloric acid for pH adjustment Sodium chloride Water for injections.
6.2 Incompatibilities
Ondansetron Solution for Injection must not be mixed with other medicinal products except those mentioned in 6.6.
6.3 Shelf life
Unopened product: 3 years.
Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°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 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
Do not store above 25°C.
Keep ampoule 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
Type I clear glass 2ml ampoules containing 2ml solution and type I clear glass 5ml ampoules containing 4ml solution. 1 or 5 ampoules are packed per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Ondansetron Solution for Injection should not be autoclaved.
Compatibility with intravenous fluids:
Ondansetron 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 Intravenous Infusion 5%w/v
In keeping with good pharmaceutical practice dilutions of ondansetron solution for injection in intravenous fluids should be prepared at the time of infusion or stored at 2-8°C for no more than 24 hours before the start of administration.
Compatibility studies have been undertaken in polyvinyl chloride infusion bags and polyvinyl chloride administration sets. It is considered that adequate stability would also be conferred by the use of polyethylene infusion bags or Type 1 glass bottles. 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 Solution for Injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.
Compatibility with other drugs: Ondansetron may be administered by intravenous infusion at 1mg/hour, e.g. from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the Ondansetron giving set for ondansetron concentrations of 16 to 160 micrograms/ml (e.g. 8 mg/500 ml and 8 mg/50 ml respectively);
Cisplatin: Concentrations up to 0.48 mg/ml (e.g. 240 mg in 500 ml) administered over one to eight hours.
5-Fluorouracil: Concentrations up to 0.8 mg/ml (e.g. 2.4g in 3 litres or 400mg in 500ml) administered at a rate of at least 20 ml per hour (500 ml per 24 hours). Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-fluorouracil infusion may contain up to 0.045%w/v magnesium chloride in addition to other excipients shown to be compatible.
Carboplatin: Concentrations in the range 0.18 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 16 mg of ondansetron diluted in 50-100ml of a compatible infusion fluid over approximately 15 minutes. Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the same giving set resulting in concentrations in line of 32 microgram - 2.5mg/ml for dexamethasone sodium phosphate and 8 microgram - 1mg/ml for ondansetron.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road Hampden Park Eastbourne
East Sussex BN22 9AG UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/1402
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30 June 2003
10 DATE OF REVISION OF THE TEXT
20/01/2014