Ondansetron 8 Mg Orodispersible Tablets
SUMMARY 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.
Excipients:
Each orodispersible tablet contains 20 mg lactose monohydrate and 6 mg aspartame.
Also contains benzyl alcohol, ethanol, potassium, propylene glycol, sodium and sulphites.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Orodispersible tablet.
White to off-white, round tablets debossed with ‘7' on one side and ‘E' on the other side with an embossed circular edge.
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 PONV in children aged > 1 month.
4.2 Posology and method of administration
Posology
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:
Ondansetron can be given either by rectal, oral (as orodispersible tablets, tablets or syrup), intravenous or intramuscular administration.
For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron 8 mg should be administered as a slow intravenous or intramuscular injection 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 or rectal treatment with ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg 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 8 mg twice daily.
Paediatric population:
Chemotherapy induced nausea and vomiting in children aged >6 months and adolescents The dose for 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 5 mg/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 32 mg.
|
BSA |
Day1ab |
Days 2-6b |
|
< 0.6m2 |
5 mg/m2 i.v. 2mg syrup or tablet after 12 hours |
2 mg syrup or tablet every 12 hours |
|
> 0.6 m2 |
5 mg/m2 i.v. 4mg syrup or tablet after 12 hours |
4 mg syrup or tablet every 12 hours |
a: The intravenous dose must not exceed 8mg. b: The total daily dose must not exceed adult dose of 32mg.
Table 1: BSA-based dosing for chemotherapy - Children aged >6 months and adolescents
Dosing by body weight:
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 8mg.
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.
Table2: Weight-based dosing for chemotherapy - children aged >6 months and adolescents
|
Weight |
Day 1ab |
Days 2-6b |
|
< 10kg |
Up to 3 doses of 0.15mg/kg at 4-hourly intervals. |
2 mg syrup or tablet every 12 hours |
|
> 10kg |
Up to 3 doses of 0.15mg/kg at 4-hourly intervals. |
4 mg syrup or tablet every 12 hours |
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 (PONV):
Adults
For the prevention of PONV ondansetron may be administered orally or by intravenous injection.
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 the treatment of established PONV intravenous administration is recommended. Paediatric population:
Post-operative nausea and vomiting in children aged > 1 months and adolescents:
Oral formulations:
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 seconds) at a dose of 0.1 mg/kg up to a maximum of 4mg 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, at or after induction of anaesthesia.
There are no data on the use of ondansetron for the treatment of post-operative vomiting in children under 2 years of age.
Elderly
There is limited experience in the use of ondansetron in the prevention and treatment of postoperative 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 medicinal product exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.
The orodispersible tablets should be taken orally. The orodispersible tablets should be placed on top of the tongue where it will rapidly disperse and should then be swallowed with water.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Hypersensitivity to other selective 5-HT3 receptor antagonists (e.g. granisetron, dolasetron).
• 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 5-HT3 receptor antagonists.
As ondansetron is known to increase large bowel transit time, patients with signs of subacute 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.
Since there is little experience to date of the use of ondansetron in cardiac patients, caution should be exercised if ondansetron is co-administered 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 of prolonged QT syndrome.
Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.
Pediatric population:
Pediatric 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 an mg/kg basis and administering three doses at 4-hourly intervals, the total daily dose will be higher than if one single dose of 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 indicate similar efficacy for both regimens (see section 5.1).
This product contains 20 mg lactose monohydrate per tablet. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicinal product contains a source of phenylalanine. May be harmful for people with phenylketonuria.
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 medicinal products commonly co-administered with it. Specific studies have shown that ondansetron does not interact 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 metabolizing ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.
Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the 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.
Use of ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of Ondansetron with cardiotoxic drugs (e.g. anthracyclines) may increase the risk of arrhythmias (section 4.4).
Apomorphine: Based on of reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.
4.6 Fertility, 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 fetus, 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 has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Adverse events are listed below by system organ class and frequency. Frequencies are defined as:
Very common (>1/10)
Common (>1/100 to <1/10)
Uncommon (>1/1,000 to <1/100)
Rare (>1/10,000 to <1/1,000)
Very rare (<1/10,000), not known (cannot be estimated from the available data)
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.
Very rarely transient ECG changes including QT interval prolongation have been reported
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.
There may be cross-sensitivity with other selective 5-HT3- antagonists.
Nervous system disorders
Very common: Headache.
Uncommon: Extrapyramidal reactions (such as oculogyric crisis/dystonic reactions) have been observed without definitive evidence of persistent clinical sequelae; seizures.
Eye disorders
Rare: Transient visual disturbances (e.g. blurred vision) predominantly during rapid intravenous 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.
Cardiac disorders
Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia. Vascular disorders
Common: Sensation of warmth or flushing.
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.
Hepatobiliary disorders
Uncommon: Asymptomatic increases in liver function tests.
These events were observed commonly in patients receiving chemotherapy with cisplatin. Paediatric population
The adverse event profile in children and adolescents was comparable to that seen in adults. Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov .uk/yellowcard.
4.9 Overdose
Little is known at present about overdosage with ondansetron, 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 Undesirable Effects).
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: Antiemetics and antinauseants, Serotonin (5-HT3) antagonists
ATC Code: A04AA01
Ondansetron is a potent, highly selective 5-HT3 receptor-antagonist.
Its precise antiemetic and antinauseal mechanism of action is not known. Chemotherapeutic agents and radiotherapy may cause release of 5-HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5-HT3 receptors.
Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5-HT 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 5-HT3 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. 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 5 mg/m2 i.v. + after 8-12 hrs ondansetron 4 mg p.o. or ondansetron 0.45 mg/kg i.v. + after 8-12 hrs 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.). Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days.
A double-blind randomised placebo-controlled trial 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 i.v. together with 2-4 mg dexamethasone
p.o. and in 71% of patients when ondansetron was administered as 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 open-label, non-comparative, single-arm study. All children received 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 oral ondansetron doses of 4mg 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 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 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 Prevention and treatment of PONV in Paediatric Patients - Treatment response over 24 hours
|
Study |
Endpoint |
Ondansetron |
Placebo |
p value |
|
% |
% | |||
|
S3A380 |
CR |
68 |
39 |
s 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 (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. 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 given as a single dose.
The extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important.)
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.
The protein binding of ondansetron is 70-76%. A direct effect of plasma concentration and anti-emetic effect has not been established. 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 has no effect on ondansetron's pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
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 2mg (3-7 years old) or 4mg (8-12 years old) were reduced. The magnitude of the change was age-related, with clearance falling from about 300mL/min at 12 years of age to 100mL/min at 3 years. Volume of distribution fell from about 75L at 12 years to 17L at 3 years. Use of weight-based dosing (0.1mg/kg up to 4mg maximum) compensates for these changes and is effective in normalising systemic exposure in paediatric patients.
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.
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.
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 halflife in the patient population aged 1 to 4 month was reported to average 6.7 hours compared to 2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The differences in pharmacokinetic parameters in the 1 to 4 month patient population can be explained in part by the higher percentage of total body water in neonates and infants and a higher volume of distribution for water soluble drugs like ondansetron.
In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron were reduced in comparison to values with adult patients. Both parameters increased in a linear fashion with weight and by 12 years of age, the values were approaching those of young adults. When clearance and volume of distribution values were normalised by body weight, the values for these parameters were similar between the different age group populations. Use of weight-based dosing compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients.
Population pharmacokinetic analysis was performed on 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 weight 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 4 to 18 years), and surgical patients (aged 3 to 12 years), at 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. Pharmacokinetics in Paediatric Patients 1 Month to 18 Years of Age
|
Study |
Patient |
Age |
N |
AUC |
CL |
Vdss |
T1/2 |
|
population (Intravenous |
(ng.h/mL ) |
(L/h/kg ) |
(L/kg) |
(h) | |||
|
dose) |
Geometric mean |
Mean | |||||
|
S3A4031 |
Surgery |
1 to 4 |
1 |
360 |
0.401 |
3.5 |
6.7 |
|
91 |
(0.1 or 02mg/kg) |
months |
9 | ||||
|
S3A4031 |
Surgery |
5 to 24 |
2 |
236 |
0.581 |
2.3 |
2.9 |
|
91 |
(0.1 or 02mg/kg) |
months |
2 | ||||
|
S3A4032 |
Cancer/Surge |
1 to 48 |
1 |
257 |
0.582 |
3.65 |
4.9 |
|
0 & |
ry |
months |
1 | ||||
|
S3A4031 |
(0.15mg/kg |
5 | |||||
|
9 Pop PK2&3 |
q4h/ 0.1 or 02mg/kg) | ||||||
|
S3KG024 |
Surgery |
3 to 12 |
2 |
240 |
0.439 |
1.65 |
2.9 |
|
(2mg or 4mg) |
years |
1 | |||||
|
S3A-150 |
Cancer |
4 to 18 |
2 |
247 |
0.599 |
1.9 |
2.8 |
|
(0.15mg/kg q4h) |
years |
1 | |||||
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)
5.3 Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and carcinogenic potential.
Ondansetron and its metabolites accumulate in the milk of rats with a milk:plasma ratio of 5.2:1.
A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol (E421)
Crospovidone (Type A)
Lactose monohydrate Cellulose, microcrystalline Aspartame (E951)
Silica, colloidal anhydrous Magnesium stearate Strawberry guarana flavor contains Maltodextrin Propylene glycol
Artificial flavors containing amongst other ingredients [Benzyl alcohol, ethanol, potassium, propylene glycol, sodium, sulphites]
Acetic acid
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.
6.5 Nature and contents of container
Blister (PVC/ Polyamide/ Aluminium/ PVC/ Aluminium/ Polyester/ Paper) with peelable lidding foil.
Pack size: 6, 10, 30, 50 and 100 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Amneal Pharma Europe Limited 70 Sir John Rogerson’s Quay, Dublin 2,
Ireland.
8 MARKETING AUTHORISATION NUMBER(S)
PL 42357/0090
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 28/04/2012
10 DATE OF REVISION OF THE TEXT
07/06/2016