1. Name Of The Medicinal Product
Ondansetron 2 mg/ml Solution for Injection
2. Qualitative And Quantitative Composition
1 ml solution for injection contains 2 mg ondansetron as ondansetron hydrochloride dihydrate.
Each ampoule with 2 ml contains 4 mg ondansetron.
Each ampoule with 4 ml contains 8 mg ondansetron.
1 ml solution for injection contains 3.34 mg of sodium as sodium citrate dihydrate and sodium chloride.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection
Clear and colourless solution
4. Clinical Particulars
4.1 Therapeutic Indications
Ondansetron 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).
4.2 Posology And Method Of Administration
For intravenous injection or for intravenous infusion after dilution.
For instructions on dilution of the product before administration, see section 6.6.
Prescribers intending to use ondansetron in the prevention of delayed nausea and vomiting associated with chemotherapy or radiotherapy in adults, adolescents or children should take into consideration current practice and appropriate guidelines.
Chemotherapy and radiotherapy induced nausea and vomiting
Adults
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The dose range of ondansetron solution for injection or infusion is 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 intravenous or other routes of administration, however this product is for intravenous use only.
The recommended intravenous dose of ondansetron is 8 mg administered as a slow injection or as an infusion over 15 minutes immediately before treatment, followed by treatment with dosage forms other than intravenous.
Treatment with dosage forms other than intravenous is recommended to protect against delayed or prolonged emesis after the first 24 hours.
Highly emetogenic chemotherapy
For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given by intravenous or other routes of administration, however this product is for intravenous use only.
Ondansetron has been shown to be equally effective in the following intravenous dose schedules over the first 24 hours of chemotherapy:
• A single dose of 8 mg by slow intravenous injection immediately before chemotherapy.
• A dose of 8 mg by slow intravenous injection or as a short-time intravenous infusion over 15 minutes immediately before chemotherapy, followed by two further intravenous doses of 8 mg two to four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours.
• A single dose of 32 mg diluted in 50-100 ml of sodium chloride 9 mg/ml (0.9 % w/v) solution 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.
Doses of greater than 8 mg and up to 32 mg of ondansetron may only be given by intravenous infusion 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.
Children (aged 2 years and above) and adolescents (< 18 years)
Experience in paediatric patients is limited.
In children older than two years ondansetron may be administered as a single intravenous dose of 5 mg/m2 over 15 min immediately before chemotherapy, followed by treatment with dosage forms other than intravenous. For children with a body surface area of greater than 1.5 m² an initial i.v. dose of 8mg is administered immediately before chemotherapy, followed by treatment with dosage forms other than intravenous.
Elderly
Ondansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration is required.
Please refer also to “Special Populations”.
Post-operative nausea and vomiting (PONV)
Prevention of PONV
Adults: For the prevention of PONV ondansetron can be administered by intravenous injection or other dosage forms.
Ondansetron may be administered as a single dose of 4 mg given by slow intravenous injection at induction of anaesthesia.
Treatment of established PONV
For treatment of established PONV a single dose of 4 mg given by slow intravenous injection is recommended.
Children (aged 2 years and above) and adolescents (< 18 years)
For the prevention of PONV in paediatric patients and adolescents having surgery performed under general anaesthesia, ondansetron may be administered by slow intravenous injection 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 established PONV in paediatric patients and adolescents, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg.
There is limited data on the use of ondansetron in the prevention and 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 post-operative nausea and vomiting (PONV) in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.
Please refer also to “Special Populations”.
Special Populations
Patients with renal impairment
No alteration of daily dosage or frequency of dosing, or route of administration is required.
Patients with hepatic impairment
Clearance of ondansetron is significantly reduced and serum half life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.
Patients with poor sparteine/debrisoquine metabolism
The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is 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.
4.4 Special Warnings And Precautions For Use
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 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 subacute 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.
Very rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. Caution is advised if patients have received cardiotoxic agents and in patients with a history or family history of prolonged QT syndrome.
In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron.
This medicinal product contains 2.3 mmol (or 53.5 mg) sodium per 32 mg dose. To be taken into consideration by 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 coadministered with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, 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 metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e. g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.
Phenytoin, carbamazepine and rifampicin: In patients treated with potent inducers of CYP3A4 (i. e. phenytoin, carbamazepine and rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.
4.6 Pregnancy And Lactation
Pregnancy:
To date, the safe use of ondansetron during 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 (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 2 mg/ml has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable Effects
The following frequency terminology is used:
very common:
common:
uncommon:
rare:
very rare: <1/10,000 and isolated reports.
Immune system disorders
Rare: Immediate hypersensitivity reactions, sometimes severe including anaphylaxis. Anaphylaxis may be fatal. Hypersensitivity reactions were also observed in patients, who were sensitive towards other selective 5-HT3 receptor antagonists.
Nervous system disorders
Very common: Headache.
Uncommon: There have been reports suggestive of involuntary movement disorders such as extrapyramidal reactions, e.g. oculogyric crisis/dystonic reactions and dyskinesia without definitive evidence of persistent clinical sequelae and seizures (e.g. epileptic spasms) have been observed although no known pharmacological mechanism can account for ondansetron causing these effects.
Rare: Dizziness during rapid intravenous administration.
Very rare: Depression.
Ophthalmic disorders
Rare: Transient visual disturbances (e.g. blurred vision) during rapid intravenous administration.
Very rare: In individual cases transitory blindness was reported in patients receiving chemotherapeutic agents including cisplatin. Most reported cases were resolved within 20 minutes.
Cardiac disorders
Uncommon: Chest pain with or without ST segment depression, cardiac arrhythmias and bradycardia. Chest pain and cardiac arrhythmias may be fatal in individual cases.
Very rare: Transitory changes in the electrocardiogram, including prolongation of the QT interval have been observed predominantly after intravenous application of ondansetron.
Vascular disorders
Common: Sensations of flushing or warmth.
Uncommon: Hypotension.
Respiratory, thoracic and mediastinal disorders
Uncommon: Hiccups.
Gastrointestinal disorders
Common: Ondansetron is known to increase the large bowel transit time and may cause constipation in some patients.
Hepato-biliary disorders
Uncommon: Asymptomatic increases in liver function tests were observed. These reactions were frequently observed in patients under 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: Local reactions at the I.V. injection site.
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: 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 post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.
Ondansetron does not alter plasma prolactin concentrations. The role of ondansetron in opiate-induced emesis is not yet established.
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 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.
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 groups
Children
In a study of 21 paediatric patients aged between 3 and 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
Based on the population pharmacokinetic parameters for subjects aged 1 month to 48 months, administration of a 0.15 mg/kg i.v. dose of ondansetron every 4 hours for 3 doses would result in a systematic exposure (AUC) comparable to that observed in paediatric surgery subjects aged 5 to 24 months and previous paediatric studies in cancer (aged 4 to 18 years) and surgical (aged 3 to 12 years) subjects, at similar doses.
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 (5.4 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.
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 safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.
Ondansetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was 5.2.
A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. The clinical relevance of this finding is uncertain.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride
Sodium citrate dihydrate
Citric acid monohydrate
Water for injections
6.2 Incompatibilities
This medicinal product must 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 48 hours at 25°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.
The diluted solutions should be stored protected from light.
6.4 Special Precautions For Storage
Keep the 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
Type I clear glass ampoules
2 ml:
Pack sizes: Carton containing 5 or 10 ampoules.
4 ml:
Pack sizes: Carton containing 5 or 10 ampoules.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
The solution is to be visually inspected prior to use (also after dilution). Only clear solutions practically free from particles should be used.
Any unused product or waste material should be disposed of in accordance with local requirements.
Ondansetron 2 mg/ml may be diluted with the following solutions for infusion to concentrations of ondansetron as stated in section 4.2:
Sodium chloride 9 mg/ml (0.9 % w/v) solution
Glucose 50 mg/ml (5 % w/v) solution
Mannitol 100 mg/ml (10 % w/v) solution
Ringer's lactate solution
The diluted solutions should be stored protected from light.
Note:
The solution for injection must not be sterilized in an autoclave!
7. Marketing Authorisation Holder
hameln pharma plus gmbh
Langes Feld 13
31789 Hameln
Germany
8. Marketing Authorisation Number(S)
PL 25215/0016
9. Date Of First Authorisation/Renewal Of The Authorisation
10/12/2007
10. Date Of Revision Of The Text
03/2009
