- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Adults:• Prophylaxis of acute nausea and vomiting induced by moderately emetogenic chemotherapy. • Prophylaxis and treatment of delayed nausea and vomiting induced by moderately to highly emetogenic chemotherapy. • Prophylaxis and treatment of acute and delayed nausea and vomiting induced by highly emetogenic radiotherapy. • Prophylaxis and treatment of post-operative nausea and vomiting (PONV).
Paediatric Population:• Management of chemotherapy-induced nausea and vomiting in children aged ≥6 months. • Prophylaxis and treatment of post-operative nausea and vomiting (PONV) in children aged ≥4 years.
4.2.1 Chemotherapy and radiotherapy induced nausea and vomiting
AdultsThe emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The selection of dose regimen should be determined by the severity of the emetogenic challenge. Emetogenic chemotherapy and radiotherapyOndansetron can be given either by rectal, oral, intravenous or intramuscular administration.SETOFILM is an oral formulation. The recommended oral dose is 8mg 1 to 2 hours before treatment, followed by 8mg orally 12 hours later.To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with SETOFILM should be continued for up to 5 days after a course of treatment. The recommended oral dosage is 8mg to be taken twice daily.Highly emetogenic chemotherapy (e.g. high dose cisplatin)Ondansetron can be given either by oral, rectal, intravenous or intramuscular administration.SETOFILM is an oral formulation. The recommended oral dose is 24 mg taken together with oral dexamethasone sodium phosphate 12mg, 1 to 2 hours before treatment.To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with SETOFILM should be continued for up to 5 days after a course of treatment. The recommended oral dosage is 8mg to be taken twice daily.
Chemotherapy induced nausea and vomiting (CINV)The dose for CINV can be calculated based on body surface area (BSA) or weight see table 1 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 delayed or prolonged CINV or on the use of ondansetron for radiotherapy-induced nausea and vomiting (RINV) in children. Ondansetron should be administered immediately before chemotherapy as a single intravenous dose. 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 and weight based dosing for Chemotherapy
5 mg/m2 i.v*plus
2 mg** orally after 12 hrs
2 mg** orally every 12 hrs
5 mg/m2 i.v* plus
4 mg orally after 12 hrs
4 mg orally every 12 hrs
Up to 3 i.v* doses of 0.15mg/kg every 4 hrs
2 mg** orally every 12 hrs
Up to 3 i.v* doses of 0.15mg/kg every 4 hrs
4 mg orally every 12 hrs
ElderlyOndansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration is required.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.
4.2.2 Post-operative nausea and vomiting (PONV)
Prevention of Post-operative nausea and vomiting (PONV)For the prevention of post-operative nausea and vomiting, the recommended oral dose is 16mg given 1 hour prior to anaesthesia.Alternatively, use 8 mg one hour prior to anaesthesia followed by two further doses of 8 mg at eight hourly intervals.
Treatment of established Post-operative nausea and vomiting (PONV)For the treatment of established PONV, intravenous or intramuscular administration is recommended.
Post-operative nausea and vomitingFor the prevention and treatment of PONV, slow intravenous injection is recommended. Alternatively, for administration in children weighing ≥ 40kg SETOFILM can be administered orally as a 4 mg dose, one hour prior to anaesthesia, followed by one further dose of 4 mg after 12 hours.There are no data on the use of ondansetron for the 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 PONV in the elderly; however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.
Special populations both indications:
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 drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.
Paediatric Population:Paediatric patients receiving ondansetron with hepatotoxic chemo-therapeutic 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 comparison indicates similar efficacy for both regimens; refer to section 5.1.
PregnancyThe 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.
BreastfeedingTests 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.
Immune system disordersRare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.
Nervous system disordersVery 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). Rare: Dizziness during rapid intravenous administration.
Eye disordersRare: Transient visual disturbances (e.g. blurred vision) predominantly during 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 disordersUncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia. Rare: QTc prolongation (including Torsade de Pointes)
Vascular disordersCommon: Sensation of warmth or flushing. Uncommon: Hypotension.
Respiratory, thoracic and mediastinal disordersUncommon: Hiccups.
Gastrointestinal disordersCommon: Constipation Hepatobiliary disordersUncommon: Asymptomatic increases in liver function tests. These events were observed commonly in patients receiving chemotherapy with cisplatin.
Paediatric PopulationThe adverse event profile in children and adolescents was comparable to that seen in adults.
Reporting of suspected adverse reactionsReporting 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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard.
Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12 months to 2 years
Chemotherapy-induced nausea and vomitingThe 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 intravenously + ondansetron 4 mg orally after 8-12 hrs; or ondansetron 0.45 mg/kg intravenous + placebo orally after 8-12 hrs. Post-chemotherapy both groups received 4 mg ondansetron orally twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m2 intravenously + ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenously + 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 in 438 patients aged 1 to 17 years demonstrated complete control of emesis on the 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 patients when ondansetron was administered orally at a dose of 8 mg + 2 - 4 mg dexamethasone orally on the days of chemotherapy. Post-chemotherapy both groups received 4 mg ondansetron orally 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. All children received three 0.15 mg/kg doses of intravenous ondansetron, administered 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 4 mg for children aged < 12 yrs and 8 mg for children aged ≥12 yrs (total number of children n= 28). Complete control of emesis was achieved in 42% of patients.
Prevention of post-operative nausea and vomitingThe 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 anaesthesic induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting.
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 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 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 between 3 and 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 normalized 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 normalizing systemic exposure in paediatric patients.Population pharmacokinetic analysis was performed on 428 subjects (cancer patients, surgery patients and healthy volunteers) aged 1 month to 44 years following intravenous administration of ondansetron. Based on this analysis, systemic exposure (AUC) of ondansetron following oral or IV dosing in children and adolescents was comparable to adults, with the exception of infants aged 1 to 4 months. Volume was related to age and was lower in adults than in infants and children. Clearance was related to weight but not to age with the exception of infants aged 1 to 4 months. It is difficult to conclude whether there was an additional reduction in clearance related to age in infants 1 to 4 months or simply inherent variability due to the low number of subjects studied in this age group. Since patients less than 6 months of age will only receive a single dose in PONV a decreased clearance is not likely to be clinically relevant.
ElderlyStudies in healthy elderly volunteers have shown a slight but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (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).
Renal impairmentIn 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.
Hepatic impairmentIn 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.
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