Ondansetron

Ondansetron 8 mg orodispersible tablets

Each orodispersible tablet contains 8 mg ondansetron.

Excipients with known effect:

Each orodispersible tablet contains 19 mg lactose (as lactose monohydrate) and 6 mg aspartame (E951).

This medicine contains up to 100 microgram benzyl alcohol in each tablet.

For the full list of excipients, see section 6.1.

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.

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.

Posology

Chemotherapy and Radiotherapy induced nausea and vomiting

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. Selection of the dose and dosing regimen must therefore be guided by the emetogenic potential.

Adults

The recommended oral dose is 8 mg, taken 1-2 hours prior to chemotherapy or radiation, followed by 8 mg orally every 12 hours over a maximum of 5 days.

In highly emetogenic chemotherapy, a single oral dose up to a maximum of 24 mg ondansetron can be given orally together with 12 mg dexamethasone-21-dihydrogen phosphate disodium salt or equivalent 1 to 2 hours prior to chemotherapy. After the first 24 hours, ondansetron treatment can be continued orally for up to 5 days after a course of treatment. The recommended dose is 8 mg twice daily.

For the prevention of delayed or prolonged emesis, oral treatment is recommended.

Children and adolescents (aged 6 months to 17 years)

The dose for treatment of chemotherapy-induced nausea and vomiting can be calculated on the basis of body surface area (BSA) or based on body weight. In clinical studies with children and adolescents, ondansetron was given as an intravenous infusion, diluted in 25 to 50 mL saline solution or another compatible solution for infusion, over no less than 15 minutes. Posology based on body weight results in higher total daily doses compared with posology based on body surface area (see section 5.2).

No data are available from controlled clinical studies on the use of ondansetron for the prevention of delayed, prolonged (protracted) chemotherapy-induced nausea and vomiting. Similarly, no data are available from controlled clinical studies on the use of ondansetron in radiotherapy-induced nausea and vomiting in children.

Posology based on body surface area

Ondansetron should be intravenously administered immediately prior to chemotherapy as an initial dose of 5 mg/m². The single intravenous dose must not exceed 8mg.

Administration of oral doses can proceed 12 hours later and can be continued for up to 5 days (see table 1).

The total dose within 24 hours (as divided doses) must not exceed the adult dose of 32 mg.

Table 1: Posology based on body surface area in chemotherapy-induced nausea and vomiting (aged 6 months to 17 years)

Posology based on body weight

Posology based on body weight results in higher total daily doses compared to posology based on surface area (see section 5.2).

Ondansetron should be administered immediately prior to chemotherapy as an initial intravenous single dose of 0.15 mg/kg bodyweight. The single intravenous dose must not exceed 8mg.

If needed, two further intravenous doses can be administered at a 4-hourly interval.

Administration of oral doses can proceed 12 hours later and can be continued over a period of up to 5 days (see Table 2).

The total dose within 24 hours (as divided doses) must not exceed the adult dose of 32 mg.

Table2: Posology based on bodyweight for chemotherapy-induced nausea and vomiting (aged ≥6 months up to 17 years)

Elderly patients

No dose adjustment or change in the dosing frequency is required.

Patients with renal impairment

No alteration of dosage or frequency of dosing, or route of administration is required.

Patients with hepatic impairment

Clearance is significantly reduced and the serum half-life significantly prolonged in patients with moderate to severe impairment of hepatic function. In such patients, a total daily dose of 8 mg ondansetron (oral or intravenous) should not be exceeded.

Patients with poor sparteine/debrisoquine metabolism

The elimination half-life of ondansetron is not altered in patients classified as poor sparteine/debrisoquine metabolisers. Consequently, no difference in exposure after repeated administration is expected in such patients compared with the general population. No change in the dose or dosing frequency is required.

Post-operative nausea and vomiting (PONV):

Adults

For the prevention of PONV, ondansetron can be administered orally or by intravenous injection.

For the prevention of PONV, the recommended dose is 16 mg ondansetron orally 1 hour prior to anaesthesia.

For the treatment of established PONV, treatment with ondansetron as a slow intravenous injection is recommended.

Children and adolescents (aged 1 month up to 17 years)

No studies are available on the oral administration of ondansetron for the prophylaxis or treatment of postoperative nausea and vomiting; in this case, a slowly administered intravenous injection (over no less than 30 seconds) is recommended.

For children under 2 years of age, only limited data are available on the use of ondansetron for the treatment of postoperative nausea, nausea and vomiting.

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.

Patients with renal impairment

No alteration of dosage or frequency of dosing, or route of administration is required.

Patients with hepatic impairment

Clearance is significantly reduced and the serum half-life significantly prolonged in patients with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg (oral or intravenous) should not be exceeded.

Patients with poor sparteine/debrisoquine metabolism

The elimination half-life of ondansetron is not altered in patients classified as poor sparteine and debrisoquine metabolisers. Consequently, no difference in exposure after repeated administration is expected in such patients compared with the general population. No change in the dose or dosing frequency is required.

Method of administration

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.

Follow these instructions carefully:

Do not push the orodispersible tablet through the blister.

The tablet(s) must be taken as follows:

• Hypersensitivity to the active substance, benzyl alcohol, sulphites or to any of the excipients listed in section 6.1.

• Concomitant use with apomorphine (see section 4.5)

• Ondansetron 8 mg orodispersible tablets must not be used in children. For this patient group, more suitable dosage forms with a lower level of active substance are available.

Hypersensitivity reactions have been observed in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. If respiratory complaints occur, these should be treated symptomatically and monitored carefully by the physician, as respiratory complaints may be symptoms of an incipient hypersensitivity reaction.

Ondansetron dose-dependently prolongs the QT interval (see section 5.1). Furthermore, cases of torsade de pointes have been reported in post-marketing spontaneous reports among patients receiving ondansetron. In patients with congenital long QT syndrome, the use of ondansetron should be avoided. In patients with a prolonged QTc interval or who may develop a prolonged QTc interval, ondansetron should be used with caution. This group includes patients with electrolyte disturbances, congestive heart failure, bradyarrhythmias or patients taking other medicines that cause prolongation of the QT interval or electrolyte disturbances.

Cases of myocardial ischemia have been reported in patients treated with ondansetron. In some patients, especially in the case of intravenous administration, symptoms appeared immediately after administration of ondansetron. Patients should be alerted to the signs and symptoms of myocardial ischaemia.

Hypokalaemia or hypomagnesaemia should be corrected prior to administration of ondansetron.

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported in concomitant administration of ondansetron with other serotonergic agents (see section 4.5). If concomitant treatment with ondansetron and other serotonergic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs) and buprenorphine) is clinically warranted, careful observation of the patient is advised. Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, discontinuation of therapy should be considered depending on the severity of the symptoms.

As ondansetron slows colonic transit, patients with signs of subacute intestinal obstruction should be monitored following the administration of ondansetron.

Prophylaxis of nausea and vomiting with ondansetron may mask occult bleeding after adenotonsillar surgery. Therefore, affected patients should be monitored carefully after administration of ondansetron.

Paediatric population:

Children and adolescents receiving ondansetron together with hepatotoxic chemotherapy agents should be closely monitored for hepatic dysfunction.

Ondansetron orodispersible tablets contain lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ondansetron orodispersible tablets contain aspartame

Aspartame is a source of phenylalanine. It may be harmful for people with phenylketonuria. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

Ondansetron orodispersible tablets contain benzyl alcohol

Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called “gasping syndrome”) in neonates and young children. Therefore Ondansetron orodispersible tablets should not be used in neonates.

Due to increased risk of accumulation, Ondansetron orodispersible tablets should not be used for more than a week in young children (less than 3 years old).

High volumes of benzyl alcohol should be used with caution and only if necessary, especially in subjects with liver or kidney impairment and during pregnancy and lactation because of the risk of accumulation and toxicity (metabolic acidosis).

Benzyl alcohol may cause allergic reactions.

Ondansetron orodispersible tablets contain sulphites

May rarely cause severe hypersensitivity reactions and bronchospasm.

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, tramadol, morphine, lidocaine, thiopental and propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of cytochrome P450 isoenzymes capable of metabolising ondansetron, inhibition or reduced activity of any one isoenzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other isoenzymes. Thus, no significant change in ondansetron clearance or dose requirement should arise.

Administration of ondansetron with QT interval-prolonging medicines may further prolong the QT interval. Concomitant use of ondansetron with cardiotoxic medicines (e.g. anthracyclines) may increase the risk for the onset of arrhythmias. Concomitant use of ondansetron with medicinal products that induce prolongation of the QT interval and/or electrolyte disturbances should proceed with caution (see section 4.4).

Apomorphine

Due to reports of severe hypotension and loss of consciousness when ondansetron is used together 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), oral ondansetron clearance was increased and ondansetron blood concentrations were decreased.

Serotonergic medicinal products (e.g. SSRIs, SNRIs and buprenorphine)

The risk of serotonin syndrome, a potentially life-threatening condition, is increased with concomitant use of ondansetron and other serotonergic medicinal products, including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs) and buprenorphine (see section 4.4).

Tramadol

Data from smaller studies indicate that ondansetron may reduce the analgesic effect of tramadol.

Women of childbearing potential

Women of childbearing potential should consider the use of contraception.

Pregnancy

Based on human experience from epidemiological studies, ondansetron is suspected to cause orofacial malformations when administered during the first trimester of pregnancy.

In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10,000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)).

The available epidemiological studies on cardiac malformations show conflicting results. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Ondansetron should not be used during the first trimester of pregnancy.

Breast-feeding

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.

Ondansetron has no or negligible influence on the ability to drive and use machines. In psychomotor tests, it showed no performance-impairing or sedative effect. No adverse effect on these skills can be inferred from the pharmacological properties of the active substance ondansetron.

Adverse events are listed below by system organ class and absolute frequency (all reported events). 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 adverse reactions were generally determined from clinical trial data. The incidence of adverse events with placebo was taken into account. Rare and very rare adverse events were generally determined from post-marketing spontaneous data.

The following frequencies were determined with standard ondansetron dosing.

Paediatric population

The adverse reaction profile in children and adolescents was comparable to the adverse reaction profile observed 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms and signs

There is insufficient experience with ondansetron overdose. Symptoms were similar to those reported in patients after the recommended dosage (see section 4.8). Manifestations of an overdose included visual disturbances, severe constipation, low blood pressure and a vasovagal episode with transient second degree AV block.

Ondansetron dose-dependently prolongs the QT interval. In the event of an overdose, ECG monitoring is recommended.

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.

Therapy

There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

The further course of action should be as clinically indicated or in accordance with national poison centre recommendations.

The use of ipecac (ipecacuanha) to treat an overdose with ondansetron is not recommended, as patients are unlikely to respond due to the anti-emetic action of ondansetron itself.

Pharmacotherapeutic group: Serotonin (5-HT₃) antagonists

ATC Code: A04AA01

Mechanism of action

Ondansetron is a highly selective, competitive 5-HT₃ receptor-antagonist.

The exact pharmacological mechanism of action in the control of nausea and vomiting in humans is not yet elucidated. Animal studies show that both cytotoxic chemotherapy and radiotherapy elicit the release of 5-hydroxytryptamine (5-HT, serotonin) in the small intestine. 5-HT stimulates 5-HT₃ receptors on neurons in the periphery (visceral afferent vagus) and in the central nervous system (area postrema), thereby resulting in retching. Ondansetron antagonises the action of 5-HT directly at 5-HT₃ receptors and thus inhibits the biochemical/pharmacological process of emesis.

Clinical efficacy and safety

In a pharmaco-psychological study in volunteers ondansetron has not shown a sedative effect.

Prolongation of the QT interval

The effect of ondansetron on the QT interval was investigated in a double-blind, randomised, placebo and positive- (moxifloxacin) controlled, crossover study with 58 healthy adult men and women. Doses of 8 mg and 32 mg ondansetron were infused intravenously over 15 minutes. At the highest tested dose of 32 mg, the maximum mean change (upper limit of 90% CI) in the QTcF interval (Fridericia correction) versus placebo after baseline correction was 19.6 msec (21.5 msec). At the lower tested dose of 8 mg, the maximum mean change (upper limit of 90% CI) in the QTcF interval (Fridericia correction) versus placebo after baseline correction was 5.8 msec (7.8 msec). In this study, there were no QTcF intervals above 480 msec and no prolongation of the QTcF interval above 60 msec was measured. No significant changes occurred in PR- and QRS intervals, as measured by electrocardiogram.

Paediatric population

Chemotherapy -induced nausea and vomiting

The efficacy of ondansetron in the control of chemotherapy-induced vomiting and nausea was investigated in a double-blind, randomised clinical study in 415 patients aged 1 to 18 years (S3AB3006). On the treatment days, patients received either 5 mg/m² ondansetron intravenously and 4 mg ondansetron rally after 8 to 12 hours or 0.45 mg/kg body weights (BW) of ondansetron intravenously and an oral placebo dose after 8 to 12 hours. Complete control of emesis on thee treatment day with the most severe symptoms was 49% (5 mg/m² IV and ondansetron 4 mg p.o.) and 41% (0.45 mg/kg IV + placebo p.o.). Following chemotherapy, both groups received 4 mg ondansetron as a solution twice daily for three days. No difference was observed in the overall incidence or nature of adverse reactions between both treatment groups.

A double-blind randomised and placebo-controlled clinical study (S3AB4003) with 438 patients aged 1 to 17 years demonstrated,, on the treatment day with the most severe symptoms, complete control of emesis in

• 73% of patients receiving and intravenous dose of 5 mg/m² ondansetron with 2 to 4 mg dexamethasone orally and in

• 71% of patients receiving 8mg ondansetron as a solution with 2 to 4 mg dexamethasone orally on the treatment days.

Following chemotherapy, both groups received 4 mg ondansetron as a solution twice daily for two days. No difference was observed in the overall incidence or nature of adverse events between both treatment groups.

The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, uncontrolled, single-arm study (S3A40320). All children received three doses of ondansetron IV (0.15 mg/kg each), administered 30 minutes before the start of chemotherapy and then at 4 and 8 hours after the first dose. Complete control of emesis was achieved in 56% of patients.

Another open-label, uncontrolled, single-arm study (S3A239) with 28 children investigated the efficacy of an intravenous dose of 0.15 mg/kg BW ondansetron, followed by two oral ondansetron doses of 4mg for children under 12 years or with 8 mg ondansetron for children aged 12 years and older. Complete control of emesis was achieved in 42% of patients.

Prophylaxis of post-operative nausea and vomiting:

The efficacy of a single dose of ondansetron in the prophylaxis of post-operative nausea and vomiting was investigated in a randomised, double-blind and placebo-controlled study in 670 children aged 1 to 24 months (post-conceptual age ≥44 weeks, weight ≥ 3 kg). Elective surgery under general anaesthesia was scheduled for enrolled patients with an ASA status ≤ III. After induction of anaesthesia, a single dose of 0.1 mg/kg BW ondansetron was administered within 5 minutes. The proportion of patients experiencing at least one emetogenic episode during the 24-hour observation phase (ITT) was greater in the placebo group than for patients receiving ondansetron (28% vs. 11%, p <0.0001).

Four randomised, double-blind and placebo-controlled studies have been performed with 1,469 male and female patients aged 2 to 12 years of age undergoing general anaesthesia. Patients were randomised either to treatment with a single dose of ondansetron IV (0.1 mg/kg for children with a body weight of 40 kg or less, 4 mg for children with a body weight over 40 kg; number of patients = 735) or to treatment with placebo (number of patients = 734). The study medication was administered over at least 30 seconds shortly before or after induction of anaesthesia. The efficacy of ondansetron in the prophylaxis of postoperative nausea and vomiting was significantly greater compared with placebo. The results of these studies are summarised in Table 3.

Table 3. Prophylaxis and treatment of postoperative nausea and vomiting in paediatric patients –24 hour response to treatment

CR = no emetogenic episodes, emergency care or study discontinuation

Mean pharmacokinetic parameter values:

Absorption

Mean bioavailability in healthy volunteers, after administration of a single 8 mg tablet, is about 55 to 60%. There is no direct correlation between plasma levels and antiemetic effect.

Distribution

Plasma protein binding (in vitro) is 70 to 76%.

Biotransformation

Ondansetron is metabolised via several hepatic cytochrome P450 isoenzymes – CYP3A4, CYP2D6 and CYP1A2. Deficiency of the CYP2D6 enzyme (debrisoquine polymorphism) does not affect the pharmacokinetic behaviour of ondansetron. The pharmacokinetic properties of ondansetron are unchanged with repeated administration.

Elimination

The clearance of ondansetron mainly occurs via its hepatic metabolism. The metabolites are excreted in the urine and faeces.

Special populations

Paediatric population

In paediatric patients aged 1 to 4 months (n = 19) undergoing surgery, weight-normalised clearance was approximately 30% slower compared to clearance in patients aged between 5 and 24 months (n = 22), but was comparable to that in patients aged 3 to 12 years. The mean half-life in the patient population aged 1 to 4 months was 6.7 hours versus 2.9 hours in patients aged 5 to 24 months and 3 to 12 years, respectively. The differences in pharmacokinetic parameters in the 1- to 4-month-old patient population can be explained in part by the higher proportion of body water in newborns and infants and by the higher volume of distribution for water-soluble active substances such as ondansetron.

In paediatric patients aged 3 to 12 years undergoing elective surgery under general anaesthesia, the absolute values both for the clearance and volume of distribution of ondansetron were reduced in comparison to values in adult patients. Both parameters increased linearly in relation to body weight and, at 12 years of age, were close to those in young adults. After adjustment of clearance and volume of distribution for body weight, the values for these parameters were similar between the different age groups. Use of a weight-based dosage takes age-related changes into account and brings about normalisation of systemic exposure in paediatric patients.

The pharmacokinetic analysis was performed in a population of 428 patients (cancer patients, surgery patients and healthy volunteers) aged 1 month to 44 years after intravenous administration of ondansetron. Based on this analysis, systemic exposure (AUC) of ondansetron after oral or intravenous administration in children and adolescents was comparable to that in adults, with the exception of children aged 1 to 4 months. The volume was age-related and was lower in adults than in infants and children. Clearance was dependent on weight, but not on age, with the exception of children aged 1 to 4 months. It is difficult to conclude whether children aged 1 to 4 months underwent an additional reduction in age-related clearance or whether the cause is simply due to innate variability, owing to the low number of patients studied in this age group.

As patients under 6 months of age receive only a single dose of ondansetron in postoperative nausea and vomiting, decreased clearance is deemed not to be clinically relevant.

Elderly patients

Early phase I studies in healthy elderly volunteers showed an age-related decrease in clearance and an increase in the half-life of ondansetron. However, wide inter-individual variability led to a considerable overlap in pharmacokinetic parameters between younger (< 65 years) and elderly subjects (> 65 years) and, in the clinical studies on chemotherapy-induced nausea and vomiting, there were no overall differences in the safety or efficacy observed between younger and elderly cancer patients to support different dosage recommendations for elderly patients.

Based on more recent models regarding the relationship between ondansetron plasma concentrations and exposure response, a greater effect on the QTcF value is predicted in patients aged 75 years and older compared with younger adults. For intravenous administration, specific dose information is given for patients over 65 years and for patients over 75 years of age (see section 4.2).

Patients with renal impairment

In patients with moderate renal impairment (creatinine clearance 15 to 60 ml/min), both systemic clearance and volume of distribution are reduced after intravenous administration of ondansetron, resulting in a slight, but clinically insignificant, increase in the elimination half-life (to 5.4 hour). 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.

Patients with hepatic impairment

In patients with severe hepatic impairment, systemic clearance of ondansetron is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.

Preclinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and carcinogenic potential.

Reproductive toxicology studies

Reproductive toxicology studies with rats and rabbits revealed no indications of a harmful effect for the foetus when ondansetron was respectively administered during organogenesis at approximately 6-fold and 24-fold the maximum recommended human oral dose of 24 mg/day, based on body surface area.

In studies with rats and rabbits on embryofoetal development, pregnant animals received ondansetron at oral doses of up to 15 mg/kg/day and 30 mg/kg/day, respectively, during organogenesis. With the exception of a slight decrease in maternal body weight in rabbits, there were no significant effects of ondansetron on the mother animals or development of the offspring. Dosages of 15 mg/kg/day in rats and 30 mg/kg/day in rabbits were respectively equivalent to approximately 6-fold and 24-fold the maximum recommended human oral dose of 24 mg/day, based on body surface area.

In toxicity studies on pre- and postnatal development, pregnant rats received oral ondansetron doses of up to 15 mg/kg/day from day 17 of pregnancy up to parturition on day 21. With the exception of a slight decrease in maternal body weight, there were no toxic effects of ondansetron on the pregnant rats or on pre- and postnatal development of their offspring, including reproductive behaviour of the associated F1 generation. Dosages of 15 mg/kg/day in rats were equivalent to approximately 6-fold the maximum recommended human oral dose of 24 mg/day, based on body surface area.

Ondansetron and its metabolites accumulate in the milk of rats at a milk/plasma ratio of 5.2:1.

A study on cloned human cardiac ion channels has shown that ondansetron has the potential to affect cardiac repolarisation via blockade of hERG potassium channels. In a thorough QT study with healthy subjects, a dose-dependent prolongation of the QT interval was observed.

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

Not applicable.

3 years.

Store in the original package in order to protect from light.

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.

No special requirements for disposal.

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

Aristo Pharma GmbH

Wallenroder Straße 8-10

Berlin 13435

Germany

PL 40546/0115

23/06/2010

03/02/2023