Adults: Ondansetron MédiS 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 MédiS 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.

Oral use.

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 MédiS should be flexible in the range of 8-32 mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy: For patients receiving emetogenic chemotherapy or radiotherapy ondansetron can be given either by intravenous or other routes of administration; however this product is for oral use only.

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 8 mg twice daily.

Highly emetogenic chemotherapy: or 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 MÉDIS 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 12 hours later and may be continued for up to 5 days (Table 1). The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Table 1: BSA-based dosing for Chemotherapy - Children aged ≥6 months and adolescents

^a The intravenous dose must not exceed 8 mg.
^b The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

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

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.
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 post-operative nausea and vomiting (PONV) in the elderly; however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.

Please refer also to”Special populations”.

Special populations:

Patients with Renal Impairment:

No alteration of daily dosage or frequency of dosing, or route of administration 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.

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.

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.

Ondansetron prolongs the QT interval in a dose-dependent manner. 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 or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalemia and hypomagnesemia 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 (SSRI) 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.

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 114 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental, or propofol.

Ondansetron is metabolised by multiplehepatic 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 coadministered with drugs that prolong the QT interval and/orcause 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 iscontraindicated.

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.

Pregnancy

The safety of ondansetron for use in human pregnancy has not been established. Pregnancy Category B. 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.

Fertility

There is no information on the effects of ondansetron on human fertility.

In psychomotor testing ondansetron does not impair performance nor cause sedation. No detrimental effects on such activities are predicted from the pharmacology of ondansetron.

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) and very rare (<1/10,000). 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.
The adverse event profiles in children and adolescents were comparable to that seen in adults.

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) Rare: Dizziness predominantly 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 administration. (2)

Cardiac disorders
Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia.
Rare: QTc prolongation (including Torsade 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 tests.

Paediatric population
The adverse event profile in children and adolescents was comparable to that seen in adults.

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. Ondansetron prolongs the QT interval in a dose-dependent fashion. 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.

Paediatric

population 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.

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT3) antagonists ATC Code: A04AA01

Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known.

Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system.

The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting. Ondansetron does not alter plasma prolactin concentrations. The role of ondansetron in opiate-induced emesis is not yet established.

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.). Post-chemotherapy 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 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

CR = no emetic episodes, rescue or withdrawal

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism.

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.

The disposition of ondansetron following oral, intramuscular and intravenous dosing in adults is similar with a terminal half life of about3 hours and steady state volume of distribution of about 140 L.

Equivalent systemic exposure is achieved after intramuscular and intravenous 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. Following administration of ondansetron suppository, plasma ondansetron concentrations become detectable between 15 and 60 minutes after dosing.

Concentrations rise in anessentially linear fashion, until peak concentrations of 20-30 ng/ml are attained, typically 6 hours after dosing.Concentrations rise in anessentially linear fashion, until peak.

Plasma concentrations then fall, but at a slower rate than observed following oral dosing due to continued absorption of ondansetron. The absolute bioavailability of ondansetron from the suppository is approximately 60% and is not affected by gender. The half life of the elimination phase following suppository administration is determined by the rate of ondansetron absorption, not systemic clearance and is approximately 6 hours. Females show a small, clinically insignificant, increase in half-life in comparison with males.

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 effecton ondansetron's pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

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

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)

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.

Ondansetron MédiS tablets:

• Lactose monohydrate,
• Microcrystalline cellulose,
• Pregelitinized starch,
• Magnesium stearate,
• Opadry orange

Tablet coating:

• Polyvinil Alcohol
• Talc
• Titanium Glycol/Macrogol
• Yellow Iron Oxide
• Lecithin
• Red Iron Oxide
• FD4C yellow w6/sunset yellow FCF Aluminium lake

Not applicable.

Store below 30 °C

Blister (PVC/ Aluminium)

Pack size of 10 film-coated tablets.

Any unused product or waste material should be disposed off in accordance with local requirements.