Ondansetron 8 Mg Orodispersible Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ondansetron 8 mg Orodispersible Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each orodispersible tablet contains: 8 mg ondansetron.
Excipient: Aspartame (E951) 1.76 mg per 8 mg tablet.
Sorbitol (E420) up to 16.884mg per 8 mg tablet.
Glucose and sulphur dioxide (E220).
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Orodispersible tablet.
White, flat, round, bevel-edged tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults:
The management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention of post-operative nausea and vomiting in adults.
Paediatric Population:
Management of chemotherapy-induced nausea and vomiting in children aged >6 months. Prevention and treatment of postoperative nausea and vomiting in children aged > 1 month.
4.2 Posology and method of administration
For oral use. Place the orodispersible tablet on top of the tongue, where it will disperse within seconds.
For the different dosage regimens appropriate strengths and formulations are available.
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 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 should initially be administered intravenously immediately before treatment, followed by 8 mg orally twelve hourly.
For oral administration: 8 mg 1-2 hours before treatment, followed by 8 mg 12 hours later.
To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Ondansetron orodispersible tablets should be continued for up to 5 days after a course of treatment.
The recommended dose for oral administration is 8mg twice daily.
Highly emetogenic chemotherapy:
For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given by intravenous administration.
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 8mg twice daily.
Children (aged 2 years and over) 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 minutes immediately before chemotherapy, followed by 4 mg orally twelve hours later. Oral treatment with a dose according to the body area should be continued for up to 5 days after a course of treatment. Children with a total body area between 0.6 and 1.2 m2 should receive a dosage schedule of 4
mg 2 times a day, while children with a body area above 1.2 m should receive 8 mg 2 times a day.
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
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 5mg/m2. The intravenous dose must not exceed 8mg.
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 32mg
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 |
2 5 mg/m i.v. plus 2 mg syrup after 12 hrs |
2 mg syrup every 12 hrs |
|
>0.6 m2 |
5 mg/m i.v. plus 4 mg syrup or tablet after 12 hrs |
4 mg syrup or tablet every 12 hrs |
a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg
Dosing by bodyweight:
Weight-based dosing results in higher total daily doses compared to BSA-based dosing - see sections 4.4 and 5.1.
Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15mg/Kg. The intravenous dose must not exceed 8mg.
Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32mg. 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 hrs |
2 mg syrup every 12 hrs |
|
> 10 kg |
Up to 3 doses of 0.15 mg/kg every 4 hrs |
4 mg syrup or tablet every 12 hrs |
a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg.
Elderly:
Ondansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required.
Please refer also to “Special populations”.
Post-operative nausea and vomiting
Adults:
Prevention of post-operative nausea and vomiting
For the prevention of post-operative nausea and vomiting ondansetron can be administered orally or by intravenous injection.
For oral administration:
16 mg one hour prior to anesthesia.
Alternatively, 8 mg one hour prior to anesthesia followed by two further doses of 8 mg at eight hourly intervals.
Treatment of established _ post-operative nausea and vomiting
For the treatment of established post-operative nausea and vomiting
intravenous administration is recommended.
Children (aged 2 years and over) and adolescents (< 18 years):
For the prevention and treatment of post-operative nausea and vomiting slow intravenous injection is recommended
Paediatric population:
Post-operative nausea and vomiting in children aged > 1 month and
adolescents
Oral Formulation:
No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post operative nausea and vomiting; slow i.v. injection is recommended for this purpose.
Injection:
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 secounds) at a dose 0.1mg/Kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia.
There are no data on the use of Ondansetron for the treatment of postoperative vomiting in children under 2 years of age.
Elderly:
There is limited experience in the use of Ondansetron in the prevention and treatment of post-operative nausea and vomiting in the elderly, however Ondansetron is well tolerated in patients over 65 years receiving
chemotherapy.
Please refer also to “Special populations”.
Special populations
Patients with renal impairment:
No alteration of daily dosage or frequency of dosing, or route of administration are required.
Patients with hepatic impairment:
Clearance of Ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg should not be exceeded.
Patients with poor sparteine/debrisoquine metabolism:
The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give medical product 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 5HT3 receptor antagonists.
As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.
Very rarely and predominantly with intravenous Ondansetron, transient ECG changes including QT interval prolongation have been reported. Therefore caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic agents or beta-adrenergic blocking agents and in patients with significant electrolyte disturbances.
Paediatric Population:
Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitive reactions. Paediatric population receiving ondansetron with hepatotoxic chemotherapeutical agents should be monitored closely for impaired hepatic function.
Chemotherapy-induced nausea and vomiting:
When calculating the dose on a mg/Kg basis and administering three doses at 4 hourly intervals, the total daily dose will be higher than if one single dose of 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 comparing indicate similar efficacy for both regimens - see section 5.1
Warnings on excipients:
Aspartame, which contains a source of phenylalanine. May be harmful for people with phenylketonuria because aspartame is metabolized to fenylalanine.
Patients with rare hereditary problems of fructose intolerance or glucose-galactose malabsorption should not take this medicine because it contains sorbitol, mannitol and dextrose.
Strawberry flavour contains sulphur dioxide (E220) which may rarely cause severe hypersensitivity reactions and bronchospasm.
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 pharamcokinetic interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, propofol and thiopental.
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 4-fold and ondansetron blood concentrations were significantly decreased. Dose adjustment of ondansetron is probably necessary.
Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
Use of Ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of Ondansetron with cardiotoxic drugs (e.g. anthracyclines) may increase the risk of arrhythmias (See section 4.4)
4.6 Pregnancy and lactation
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 the 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.
Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving Ondansetron orodispersible tablets should not breast-feed their babies.
4.7 Effects on ability to drive and use machines
In psychomotor testing Ondansetron orodispersible tablets do not impair performance nor cause sedation.
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 <1/1000) 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.
Cardiac disorders
Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia.
Very rarely transient ECG changes including QT-interval prolongation have been reported.
Nervous system disorders Very common: Headache.
Uncommon: Seizures, movement disorders including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia have been observed without definitive evidence of persistent clinical sequelae.
Respiratory, thoracic and mediastinal disorders Uncommon: Hiccups.
Gastrointestinal disorders Common: Constipation.
Vascular disorders
Common: Sensation of warmth or flushing. Uncommon: Hypotension.
Immune system disorders
Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.
Hepatobiliary disorders
Uncommon: Asymptomatic increases in liver function tests.
These events were observed commonly in patients receiving chemotherapy with cisplatin.
Rare: Dizziness during i.v. administration, which in most cases is prevented or resolved by lengthening the infusion period.
Eye disorders
Rare: Transient visual disturbances (eg. blurred vision) during i.v. administration.
Very rare: Transient blindness predominantly during intravenous
administration
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.
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.
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: 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.
Ondansetron does not alter plasma prolactin concentrations.
The role of ondansetron in opiate-induced emesis is not yet established.
Paediatric Population:
Chemotherapy-induced nausea and vomiting
The efficacy of Ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a doubleblind 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. Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49 % (5mg/m2 i.v. + ondansetron 4mg p.o.) and 41 % (0.45 mg/Kg i.v. + placebo p.o.). Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days.
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 5mg/m2 i.v. together with 2-4 mg dexamethasone p.o. and in 71% of the patients when ondansetron was administered as a syrup at a dose of 8mg + 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, singlearm study. All children receive three 0.15mg/Kg doses of intravenous ondansetron, administered at 30 minutes before the start of chemotherapy and then at four and eight hours after the first dose. Complete control of emesis was achieved in 56% of patients.
Another open-label, non-operative, single-arm study investigated the efficacy of one intravenous dose of 0.15mg/Kg ondansetron followed by two ondansetron doses of 4mg for children aged < 12 yrs and 8 mg for children aged >12yrs (total no. of children n = 28). Complete control of emesis was achieved in 42% of patients.
Prevention of post-operative nausea and vomiting
The efficacy of a single dose of Ondansetron in the prevention of postoperative nausea and vomiting was investigated in a randomised, double-blind, placebo-controlled study in 670children 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 0.1mg/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).”
5.2 Pharmacokinetic properties
Following oral administration of ondansetron, absorption is rapid with maximum peak plasma concentrations of about 30 ng/ml being attained and achieved in approximately 1.5 hours after an 8 mg dose. The syrup and tablet formulations are bioequivalent and have an absolute oral bioavailability of 60%. The disposition of ondansetron following oral, intravenous and intramuscular dosing is similar with a terminal elimination half-life of approximately 3 hours and a steady-state volume of distribution of about 140L. Ondansetron is not highly protein bound (70-76%) and 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 the pharmacokinetics of ondansetron. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
Studies in healthy elderly volunteers have shown a slight but clinically insignificant, age-related increases in both oral bioavailability (65%) and halflife (5h) 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).
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 (0.15mg/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, as shown in Table C. 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.
Table C. Pharmacokinetics in Paediatric Patients 1 Month to 18 Years of Age
|
Study |
Patient population (Intravenous Dose) |
Age |
N |
AUC (ng.h/mL ) |
CL (L/h/kg) |
Vdss (L/kg ) |
T % (h) |
|
Geometric Mean |
Mea n | ||||||
|
S3A403191 |
Surgery (0.1 or 0.2 mg/kg) |
1 to 4 months |
19 |
360 |
0.401 |
3.5 |
6.7 |
|
S3A403192 |
Surgery (0.1 or 0.2 mg/kg) |
5 to 24 months |
22 |
236 |
0.581 |
2.3 |
2.9 |
|
S3A40320 & S3A40319 Pop PK 2,3 |
Cancer/Surgery (0.15 mg/kg q4h/ 0.1 pr 0.2 mg/kg) |
1 to 48 months |
115 |
257 |
0.582 |
3.65 |
4.9 |
|
S3KG024 |
Surgery (2 mg or 4 mg) |
3 to 12 years |
21 |
240 |
0.439 |
1.65 |
2.9 |
|
S3A.150 |
Cancer (0.15 mg/kg q4h) |
4 to 18 years |
21 |
247 |
0.599 |
1.9 |
2.8 |
1 Ondansetron single intravenous dose: 0.1 or 0.2 mg/kg
2 Population PK Patients: 64% cancer patients and 36% surgery patients.
3 Population estimates shown; AUC based on dose of 0.15 mg/kg.
4 Ondansetron single intravenous dose: 2 mg (3 to 7 years) or 4 mg (8 to 12 years)
In patients with renal impairment (creatinine clearance>15 ml/min), systemic clearance and volume of distribution are reduced, 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.
In patients with severe hepatic impairment, systemic clearance is markedly reduced with prolonged elimination half-lives (15-32h) and an oral bioavailability approaching 100% because of reduced pre-systemic metabolism.
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.
Preclinical safety data
5.3
Preclinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and carcinogenic potential.
Ondansetron and its metabolites accumulate in the milk of rats, milk:plasma-ratio of 5.2:1.
A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Aspartame (E951)
Crospovidone type B Magnesium stearate Microcrystalline cellulose
Pharmaburst TM C1, (mannitol E421, sorbitol E420, crospovidone type A and colloidal silicon dioxide)
Strawberrry flavouring, (Dextrose, maltodextrin, gum araibc E414, 2.3% and sulphur dioxide E220)
Sodium stearyl fumarate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light.
Store below 30oC.
6.5 Nature and contents of container
Ondansetron Orodispersible tablets are packed in OPA/Alu/PVC-Alu unit-dose blister pack as 6x1, 10x1, 14x1, 20x1, 30x1, 50x1, 60x1, 100x1 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Bluefish Pharmaceuticals AB,
Torsgatan 11,
111 23 Stockholm,
Sweden.
8 MARKETING AUTHORISATION NUMBER(S)
PL31774/0005
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/12/2009
10 DATE OF REVISION OF THE TEXT
02/12/2009