Ondansetron 8mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ondansetron 8 mg Film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 8mg ondansetron (as ondansetron hydrochloride dihydrate).
Excipient(s) with known effect:
Each tablet contains 169.0 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Pale yellow, round, biconvex film-coated tablets, embossed with identification marking “42” on one side.
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
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 8-32mg a day and selected as shown below.
Emetogenic chemotherapy and 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 or as a short-time intravenous infusion over 15 minutes 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 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 oral or intravenous administration.
The recommended oral dose is 24 mg taken together with 12 mg oral dexamethasone sodium phosphate, 1 to 2 hours before treatment.
(For specific recommendations pertaining to the mode of administration of parenteral forms of ondansetron please refer to the corresponding Summary of Product Characteristics).
To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Ondansetron associated with dexamethasone, 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 doing 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 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) |
Day 2-6(b) |
|
< 0.6 m2 |
5 mg/m2 IV plus 2 mg syrup after 12 hrs |
2 mg syrup every 12 hrs |
|
> 0.6 m2 |
5 mg/m2 IV plus 4 mg syrup or tablet after 12 hrs |
4 mg syrup or tablet every 12 hrs |
|
> 1.2 m2 |
5 mg/m2 or 8 mg IV plus 8 mg syrup or tablet after 12 hours. |
8 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
Dosing by bodyweight:
Weight-based dosing results in higher total daily doses compared to BSA based dosing (sections 4.4. and 5.1).
Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg.
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 (Table 2).
Table 2: Weight-based dosing for Chemotherapy - Children aged > 6 months and adolescents
|
Weight |
Day 1(a’b) |
Day 2-6 (b) |
|
< 10 Kg |
Up to 3 doses of 0.15 mg/kg every 4 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
Older people :
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
Prevention of PONV
For the prevention of PONV Ondansetron can be administered orally or by intravenous injection.
For oral administration: 16 mg one hour prior to anaesthesia. Alternatively, 8mg one hour prior to anaesthesia followed by two further doses of 8 mg at eight hourly intervals.
For the treatment of established PONV
Intravenous administration is recommended.
Paediatric Population
PONV 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 seconds) at a dose of 0.1mg/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 0.1mg/kg up to a maximum of 4mg.
There are no data on the use of ondansetron in the treatment of PONV in children below 2 years of age.
Older people
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.
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 and therefore parenteral or oral administration is recommended.
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.
Method of administration
For oral use
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 5HT3 receptor antagonists. Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.
QT prolongation
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, cardiac rhythm, conduction disturbances, in patients treated with antiarrhythmic agents, or beta-adrenergic blocking agents or other medicinal products that lead to QT prolongation or electrolyte abnormalities.
Hypokalaemia and hypomagnesaemia 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 (SSRIs) 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 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.
Paediatric Population
Paediatric population receiving ondansetron with hepatotoxic chemotherapeutic agents should be monitored closely for impaired hepatic function.
Chemotherapy-induced nausea and vomiting (CINV):
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 comparing indicates similar efficacy for both regimens (see section 5.1).
Excipient(s) of known effect:
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 pharmacokinetic interactions when ondansetron is administered with alcohol, temazepam, furosemide, tramadol, alfentanil, morphine, lidocaine, 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.
Caution should be exercised when ondansetron is co-administered with drugs that prolong the QT interval and/or cause electrolyte abnormalities (see section 4.4).
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), antifungals (such as ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of arrhythmias (see section 4.4).
Serotonergic drugs (e.g. SSRIs and SNRIs): 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. 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
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 (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000) and 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.
The following frequencies are estimated at the standard recommended doses for ondansetron according to indication and formulation.
|
Adverse Drug Reactions by System Organ Class and Frequency | |
|
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 administration2. |
|
Cardiac disorders | |
|
Uncommon: |
Arrhythmias, chest pain with or without ST segment depression, bradycardia. |
|
Rare: |
QTc prolongation (including torsades de pointes) |
|
Vascular disorders | |
|
Common: |
Sensation of warmth or flushing. |
|
Uncommon: |
Hypotension. |
|
Respiratory, thoracic and mediastinal disorders | |
|
Uncommon: |
Hiccups. |
|
Gastrointestinal disorders | |
|
Common: |
Constipation |
|
Hepatobiliary disorders | |
|
Uncommon: |
Asymptomatic increases in liver function tests3 |
|
General disorders and administration site conditions | |
|
Common: |
Local IV injection site reactions. |
'■ 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 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
Symptoms and Signs
There is limited experience of ondansetron overdose. 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants. serotonin (5-HT3) antagonists,ATC Code: A04A A01
Mechanism of action
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.
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.
QT Prolongation
The effect of ondansetron on the QTc interval was evaluated in a double blind, randomized, 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.
Paediatric Population
Chemotherapy-induced nausea and vomiting (CINV)
The efficacy of ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a double-blind randomised trial in 415 patients aged 1 to 18 years (S3AB3006). On the days of chemotherapy, patients received either ondansetron 5 mg/m2 intravenous + ondansetron 4 mg orally after 8-12 hours or ondansetron 0.45 mg/kg intravenous + placebo orally after 8-12 hours. 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 intravenous + 4 mg ondansetron 4mg orally) and 41 % (0.45 mg/kg intravenous + placebo orally). Post-chemotherapy, both groups received 4 mg ondansetron syrup twice daily for 3 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.
A double-blind randomised placebo-controlled trial (S3AB4003) in 438 patients aged 1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy in:
• 73% of patients when ondansetron was administered intravenously at a dose of 5 mg/m2 intravenous together with 2-4 mg dexamethasone orally
• 71% of the patients when ondansetron was administered as a syrup at a dose of 8 mg + 2-4 mg of dexamethasone orally on the days of chemotherapy.
Post-chemotherapy, both groups received 4 mg ondansetron syrup twice daily for 2 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.
The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, non-comparative, single-arm study (S3A40320). All children receive three 0.15 mg/kg doses of intravenous ondansetron, administered 30 minutes before the start of chemotherapy and then four and eight hours after the first dose. Complete control of emesis was achieved in 56% of patients.
Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two ondansetron doses of 4 mg for children aged < 12 years and 8 mg for children aged > 12 years (total no. of children n = 28). Complete control of emesis was achieved in 42% of patients.
Prevention of post-operative nausea and vomiting (PONV)
The efficacy of a single dose of ondansetron in the prevention of post-operative nausea and vomiting was investigated in a randomised, double-blind, placebo-controlled study in 670 children aged 1 to 24 months (post-conceptual age > 44 weeks, weight > 3 kg). Included subjects were scheduled to undergo elective surgery under general anaesthesia and had an ASA status < III. A single dose of ondansetron 0.1 mg/kg was administered within five minutes following induction of anaesthesia. The proportion of subjects who experienced at
least one emetic episode during the 24-hour assessment period (ITT) was greater for patients on placebo than those receiving ondansetron (28 % vs. 11%, p < 0.0001).
Four double-blind, placebo-controlled studies have been performed in 1469 male and female patients (2 to 12 years of age) undergoing general anaesthesia. Patients were randomised to either single intravenous doses of ondansetron (0.1 mg/kg for paediatric patients weighing 40 kg or less, 4 mg for paediatric patients weighing more than 40 kg; number of patients = 735) or placebo (number of patients = 734). Study drug was administered over at least 30 seconds, immediately prior to or following anaesthesia induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these studies are summarised in Table 3.
Table 3: Prevention and treatment of PONV in Paediatric Patients - Treatment response over 24 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 (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. Mean bioavailability in healthy male subjects, following the oral administration of a single 8 mg tablet, is approximately 55 to 60%. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 hours) of ondansetron. Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).
The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a terminal half life of about 3 hours and steady state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.
A 4 mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65 ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/ml are attained within 10 minutes of injection.
Ondansetron is not highly protein bound (70-76%). Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less
than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron’s pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
Special Patient Populations
Gender
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 to 17 years)
In paediatric patients aged 1 month 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 patients aged 3 to 12 years. The half-life in the patient population aged 1 to 4 months was reported to average 6.7 hours compared to 2.9 hours for patients in the 5 to 24 months and 3 to 12 years age range. The differences in the pharmacokinetic parameters in the 1 to 4 months patient population can be 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 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 428 subjects (cancer patients, surgery patients and healthy patients) 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.
Older people
Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. However, wide inter-subject variability resulted in considerable overlap in pharmacokinetic parameters between young (< 65 years of age) and elderly subjects (> 65 years of age) and there were no overall differences in safety or efficacy observed between young and elderly cancer patients enrolled in CINV clinical trials to support a different dosing recommendation for the elderly.
Based on more recent ondansetron plasma concentrations and exposure-response modelling, a greater effect on QTcF is predicted in patients > 75 years of age compared to young adults. Specific dosing information is provided for patients over 65 years of age and over 75 years of age for intravenous dosing.
Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. 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. The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.
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
Tablet Core Lactose monohydrate Cellulose, microcrystalline (E460) Maize starch, pregelatinised Magnesium stearate (E572)
Tablet Coat Hypromellose (E464)
Titanium dioxide (E171) Macrogol (E1520)
Sorbitan oleate (E494)
Sorbic acid (E200)
Vanillin
Quinoline yellow (E104) Hydroxypropyl cellulose (E463).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30oC.
6.5 Nature and contents of container
Blister packs of 3, 6, 10, 14, 15, 20, 30, 40, 50, 60, 90, 100, 200, 300, 500 tablets comprising PVC film and aluminium foil lidding.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Ltd. t/a Mylan Station Close,
Potters Bar,
EN61TL,
Hertfordshire
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0659
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/09/2009
10 DATE OF REVISION OF THE TEXT
30/03/2015