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 of solution contains 2 mg of ondansetron as ondansetron hydrochloride dihydrate.
Ondansetron 4 mg / 2 ml Solution for Injection:
Each 2 ml ampoule contains 4 mg of ondansetron as ondansetron hydrochloride dihydrate.
Excipient with known effect:
Each 2 ml ampoule contains 7.2 mg of sodium as sodium chloride and sodium citrate. For the full list of excipients, see section 6.1.
Ondansetron 8 mg / 4 ml Solution for Injection:
Each 4 ml ampoule contains 8 mg of ondansetron as ondansetron hydrochloride dihydrate.
Excipient with known effect:
Each 4 ml ampoule contains 14.4 mg of sodium as sodium chloride and sodium citrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection or infusion:
Clear, colourless solution, practically free of particles
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 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 post-operative nausea and vomiting (PONV) in children aged > 1 month.
4.2 Posology and method of administration
Ondansetron 4 mg / 2 ml Solution for Injection / Ondansetron 8 mg / 4 ml Solution for Injection:
For intravenous injection or after dilution for intravenous infusion.
4.2.1. 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 patients receiving emetogenic chemotherapy or radiotherapy Ondansetron can be given either by oral or intravenous administration.
For most patients receiving emetogenic chemotherapy or radiotherapy, Ondansetron 8 mg should be administered as a slow intravenous injection (in not less than 30 seconds) or as a short-time intravenous infusion over 15 minutes 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 should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg twice daily.
Highly emetogenic Chemotherapy
For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, Ondansetron can be given by oral, rectal or intravenous 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 injection (in not less than 30 seconds) immediately before chemotherapy.
• A dose of 8 mg by slow intravenous injection (in not less than 30 seconds) immediately before chemotherapy, followed by two further intravenous injections (in not less than 30 seconds) of 8 mg four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours.
• A maximum initial intravenous dose of 16 mg diluted in 50-100 ml of saline or other compatible infusion fluid (see section 6.6) and infused over not less than 15 minutes immediately before chemotherapy. The initial dose of Ondansetron may be followed by two additional 8 mg intravenous doses (in not less than 30 seconds) four hours apart.
A single dose greater than 16 mg must not be given due to dose dependent increase of QT-prolongation risk (see sections 4.4, 4.8 and 5.1).
The selection of dose regimen should be determined by the severity of the emetogenic challenge.
The efficacy of Ondansetron 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 or rectal 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 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 chemotherapy-induced delayed or prolonged nausea and vomiting. 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. 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
|
BSA |
Day 1 (a,b) |
Days 2-6 (b) |
|
< 0.6 m2 |
5 mg/m2 i.v. plus 2 mg oral liquid after 12 hours |
2 mg oral liquid every 12 hours |
|
> 0.6 m2 |
5 mg/m2 i.v. plus 4 mg oral liquid or tablet after 12 hours |
4 mg oral liquid or tablet every 12 hours |
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
|
Weight |
Day 1 (a’b) |
Days 2-6 (b) |
|
<10 kg |
Up to 3 doses of 0.15 mg/kg every 4 hours |
2 mg oral liquid every 12 hours |
|
> 10 kg |
Up to 3 doses of 0.15 mg/kg every 4 hours |
4 mg oral liquid or tablet every 12 hours |
a The intravenous dose must not exceed 8 mg. b The total daily dose must not exceed adult dose of 32 mg.
Elderly patients:
In patients 65 to 74 years of age, the dose schedule for adults can be followed. All intravenous doses should be diluted in 50-100 ml of saline or other compatible infusion fluid (see section 6.6) and infused over 15 minutes.
In patients 75 years of age or older, the initial intravenous dose of Ondansetron should not exceed 8 mg. All intravenous doses should be diluted in 50-100 ml of saline or other compatible infusion fluid (see section 6.6) and infused over 15 minutes. The initial dose of 8 mg may be followed by two further intravenous doses of 8 mg, infused over 15 minutes and given no less than four hours apart (see section 5.2).
Please refer also to 4.2.3 “Special Populations”.
4.2.2. Post-Operative Nausea and Vomiting (PONV)
Adults:
Prevention of PONV
For the prevention of PONV Ondansetron can be administered orally or by intravenous injection.
Ondansetron may be administered as a single dose of 4 mg given by slow intravenous injection at induction of anaesthesia.
For oral administration:
16 mg one hour prior to anaesthesia.
Alternatively, 8 mg one hour prior to anaesthesia followed by two further doses of 8 mg at eight hourly intervals.
Treatment of established PONV
For treatment of established PONV a single dose of 4 mg given by 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 of 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 0.1 mg/kg up to a maximum of 4 mg.
There are no data on the use of Ondansetron in the treatment of postoperative vomiting in children under 2 years of age.
Elderly patients:
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 4.2.3 “Special Populations”.
4.2.3. 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 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.
4.3 Contraindications
Hypersensitivity to Ondansetron or to other selective 5-HT3-receptor antagonists (e.g. granisetron, dolasetron) or to any of the excipients listed in section 6.1.
Concomitant use with apomorphine (see section 4.5).
4.4 Special warnings and precautions for use
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT3 receptor antagonists.
Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.
Rarely, transient ECG changes including QT interval prolongation have been reported in patients receiving ondansetron. Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). 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.
Caution should also be exercised in patients with cardiac rhythm or conduction disturbances and in patients treated with anti-arrhythmic agents or beta-adrenergic blocking agents.
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.
Chemotherapy-induced nausea and vomiting:
When calculating the dose on a mg/kg basis and administering three doses at 4-hour 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 comparison indicates similar efficacy for both regimens (see section 5.1).
Excipient:
This medicinal product contains 3.6 mg sodium per ml of solution for injection. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it. Specific studies have shown that there are no interactions when ondansetron is administered with alcohol, temazepam, 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 trastuzumab), 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.
Phenytoin, Carbamazepine and Rifampicin:
In patients treated with potent inducers of CYP3A4 (i.e. Phenytoin, Carbamazepine and Rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.
Tramadol:
Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
4.6 Fertility, 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 (see section 5.3).
However as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended.
Breast-feeding
Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving Ondansetron should not breast-feed their babies.
4.7 Effects on ability to drive and use machines
Ondansetron has no 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 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) and very rare (<1/10,000). Very common, common and uncommon events were generally determined from-clinical trial data. The incidence in placebo was taken into account. Rare and very rare-events were generally determined from post-marketing spontaneous data.
The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation.
Immune system disorders
Rare: immediate 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.
Eye Disorders
Rare: Transient visual disturbances (e.g. blurred vision) predominantly during 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 tests (3). 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. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov .uk/yellowcard.
4.9. Overdose
Symptoms and Signs
There is limited experience of ondansetron overdose, 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. In all instances, the events resolved completely.
Ondansetron prolongs QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose.
Treatment
There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
The use of ipecacuanha to treat overdose with Ondansetron is not recommended as patients are unlikely to respond due to the anti-emetic action of Ondansetron itself.
Paediatric population
Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12 months to 2 years.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT3) antagonists
ATC Code: A04AA01
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.
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 bind, 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 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. On the days of chemotherapy, patients received either ondansetron 5mg/m2 i.v. + after 8-12hrs ondansetron 4 mg p.o. or ondansetron 0.45 mg/kg i.v. + after 8-12hrs 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 % (5 mg/m2 i.v. + ondansetron 4 mg p.o.) and 41 % (0.45 mg/kg i.v. + placebo p.o.).
A double-blind randomise placebo-controlled trial in 438 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 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. 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-comparative, single-arm study investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two ondansetron doses of 4 mg 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 > 3kg). 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 |
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 8mg 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 140L. 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.
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.
Studies in healthy elderly volunteers have shown slight age-related increases in both oral bioavailability (65%) and half-life (5 hours).
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.
Paediatric population:
Children and adolescents (aged 1 month 17 years)
In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight normalised clearance was approximately 30% lower than in patients aged 5 to 24 months (n=22) but comparable to the patients aged 3 to 12 years. The halflife in the patient population aged 1 to 4 months was reported to average 6.7 hours compared to 2.9 hours for the patients in the 5 to 24 months and 3 to 12 year age range. The differences in the pharmacokinetic parameters in the 1 to 4 months patient population can de explained in part by a 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 the 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 of these parameters were similar between the different age group populations. Use of weight base dosing compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients.
Population pharmacokinetic analysis was performed on 74 paediatric cancer patients aged 6 to 48 months and 41 surgery patients aged 1 to 24 months following intravenous administration of ondansetron. Based on the population pharmacokinetic parameters for patients aged 1 month to 48 months, administration of the adult based dose (0.15 mg/kg intravenously every 4 hours for 3 doses) would result in a systemic exposure (AUC) comparable to that observed in paediatric surgery patients (aged 5 to 24 months), paediatric cancer patients (aged 3 to 12 years), at a similar doses. This exposure (AUC) is consistent with the exposure-efficacy relationship described previously in paediatric cancer subjects, which showed a 50% to 90% response rate with AUC values ranging from 170 to 250 ng.h/mL.
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.
5.3. Preclinical safety data
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, milk/plasma-ratio was 5.2.
Ondansetron in submicromolar 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 sodium chloride Water for Injections.
6.2. Incompatibilities
Ondansetron injection should not be administered in the same syringe or infusion as any other medication.
Ondansetron injection should only be mixed with those infusion solutions that are recommended.
6.3. Shelf life
3 years
Once opened use immediately.
Once diluted
Chemical and physical in-use stability has been demonstrated for 7 days at 5 °C and 25 °C, when the product is diluted to a concentration of 0.32 or 0.64 mg/ml and stored in the original plastic containers of the infusion fluids.
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 30°C.
Store in the original package. Protect from light. For storage of diluted solutions see Section 6.3
6.5. Nature and contents of container
Type I amber glass ampoules.
1, 2, 5 or 10 ampoules are packed in a carton.
Pack size: 2ml, 4ml.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
For single use only. Any unused solution should be discarded.
The solution should be visually inspected prior to use. Only clear and colourless solutions practically free from particles should be used.
Note: Ondansetron solution for injection should not be autoclaved.
6.6.1.Compatibility with solutions for infusion
Ondansetron solution for injection should only be admixed with those infusion solutions which are recommended:
Sodium Chloride 9 mg/ml (0.9%) solution for infusion Glucose 50 mg/ml (5%) solution for infusion Mannitol 100 mg/ml (10%) solution for infusion Ringers solution for infusion
Potassium Chloride 3 mg/ml (0.3%) and Sodium Chloride 9 mg/ml (0.9%) solution for infusion
Potassium Chloride 3 mg/ml (0.3%) and Glucose 50 mg/ml (5%) solution for infusion
In keeping with good pharmaceutical practice, dilutions of Ondansetron injection in intravenous fluids should be prepared at the time of infusion. From a microbiological point of view, the product should be used immediately. If not used immediately, inuse storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8oC, unless dilution has taken place in controlled and validated aseptic conditions.
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 I 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 injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.
6.6.2. Compatibility with other medicinal products Dexamethasone-21-dihydrogenphosphate disodium:
Dexamethasone sodium phosphate 20 mg 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 50-100 ml of a compatible infusion fluid (see 6.6.1 “Compatibility with solutions for infusion”) over approximately 15 minutes. Ondansetron may be administered by intravenous infusion by 1 mg/hour. The following medicinal products may be administered only via a Y-site of an infusion set in concentrations of ondansetron 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 not exceeding the range of 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.
5 -Fluorouracil:
Concentrations up to 0.8 mg/ml (e.g. 2.4 g in 3 litres or 400 mg in 500 ml) 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.
Etoposide:
Concentrations not exceeding the range of 0.144 mg/ml to 0.250 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 of 250 mg to 2000 mg reconstituted with water for injections as recommended by the manufacturer (e.g. 2.5 ml for 250 mg and 10 ml for 2 g ceftazidime) and given as an intravenous bolus injection over approximately five minutes.
Cyclophosphamide:
Doses in the range of 100 mg to 1 g, reconstituted with water for injections, 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 of 10 mg to 100 mg reconstituted with water for injections, 5 ml per 10 mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately 5 minutes.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom.
8. MARKETING AUTHORISATION NUMBER
PL 04569/0656
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29/10/2009
10 DATE OF REVISION OF THE TEXT
22/02/2016