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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Teva Ondansetron 4 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 4 mg ondansetron as ondansetron hydrochloride dihydrate.

Excipient(s) with known effect:

Each film-coated tablet contains 88.8 mg of lactose monohydrate.

For the full list of excipients see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Yellow, oblong film coated tablet debossed "4" on one side and plain on the other.

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:

Ondansetron is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged > 6 months, and for the prevention and treatment of PONV in children aged > 1 month.

4.2 Posology and method of administration

Oral use.

4.2.1. Chemotherapy and Radiotherapy Induced Nausea and Vomiting (CINV and RINV):

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 regimen should be determined by the severity of the emetogenic challenge.

Emetogenic Chemotherapy and Radiotherapy:

For patients receiving emetogenic chemotherapy or 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.

The recommended oral dose is 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 oral dose is 8 mg to be taken twice daily.

Highly Emetogenic Chemotherapy e.g. high-dose cisplatin:

For patients receiving highly emetogenic chemotherapy e.g. high-dose cisplatin, ondansetron can be given by intravenous administration.

The recommended oral dose is 24 mg taken together with oral dexamethasone sodium phosphate 12 mg, 1 to 2 hours before treatment.

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 oral dose is 8 mg to be taken twice daily.

Paediatric population

Chemotherapy-induced nausea and vomiting (CINV) in children aged > 6 months and adolescents

The dose for CINV can be calculated based on body surface area (BSA) or weight -see below. In paediatric clinical studies, ondansetron was given by IV infusion diluted in 25 to 50 ml of saline or other compatible infusion fluid (see Instructions for Use and Handling) and infused over not less than 15 minutes. Weight-based dosing results in higher total daily doses compared to BSA-based dosing (see section 4.4).

Ondansetron injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid (see Use and Handling) and infused intravenously over not less than 15 minutes.

There are no data from controlled clinical trials on the use of ondansetron in the prevention of delayed or prolonged CINV. 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 1ab	Day 2-6b
< 0.6 m2	5 mg/m2 IV 2 mg syrup or tablet after 12 hours	2 mg syrup every 12 hours
> 0.6 m2	5 mg/m2 IV 4 mg syrup or tablet after 12 hours	4 mg syrup or tablet every 12 hours
> 1.2 m2	5 mg/m2 IV 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 8 mg. ^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 BSE-based dosing (see section 4.4)

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 dose 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 continues for up to 5 days (see Table 2 below).

Table 2: Weight-based dosing for chemotherapy - children agen > 6 months and adolescents

Weight	Day 1a,b	Days 2-6b
< 10 ks	Up to 3 doses of 0.15 mg/kg	2 mg syrup every 12 hours
	at 4-hourly intervals
> 10 kg	Up to 3 doses of 0.15 mg/kg at 4 hourly intervals	4 mg syrup or tablet every 12 hours.

^a The intravenous dose must not exceed 8 mg ^b The total daily dose must not exceed adult dose of 32 mg.

Elderly:

CINV and RINV

Ondansetron is well tolerated by patients over 65 years and no alterations of dosage, dosing frequency or route of administration are required.

Please refer also to 4.2.3 ‘Special populations’.

4.2.2. Post-Operative Nausea And Vomiting (PONV):

Prevention of PONV:

Adults:

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

Ondansetron may be administered as a single dose of 4 mg given by slow intravenous injection at induction of anaesthesia.

For prevention of PONV, the recommended oral dose is 16 mg given 1 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, administration by injection is recommended. Paediatric population

Post-operative nausea and vomiting in children aged > 1 month and adolescents No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of PONV; slow IV injection (in not less than 30 seconds) is recommended for this purpose.

There are no data on the use of ondansetron in the treatments of PONV in children below 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 4.2.3 ‘Special populations’.

4.2.3. Special populations:

Renal impairment:

No alterations of daily dosage or frequency of dosing, or route of administration are required.

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 dally 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.

4.3 Contraindications

Concomitant use with apomorphine (see section 4.5)

Hypersensitivity to ondansetron, or to other selective 5-HT3-receptor antagonists (e.g. granisetron, dolasetron), or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT₃- receptor antagonists. Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.

Ondansetron prolongs the QT interval in a dose-dependent manner. In addition, postmarketing 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 accult bleeding. Therefore, such patients should be followed carefully after ondansetron.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Paediatric population

Paediatric patients 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-hour 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 regimes has not been investigated in clinical trials. Cross-trial comparison indicate similar efficacy for both regimens.

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 interactions when ondansetron is administered with alcohol, temazepam, frusemide, tramadol, alfentanil, morphine, lignocaine, 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.

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 trastuzimab), antibiotics (such as erythromycin or ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol)) may increase the risk of arrhythmias (see section 4.4).

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

List of adverse reactions

The frequencies of adverce events are ranked according to the following: 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; including isolated reports), not known (cannot be estimated from the available date).

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. Anaphylaxis may be fatal.

Hypersensitivity reactions were also observed in patients who were sensitive to other selective 5-HT3 antagonists.

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 intravenous administration

Eye disorders:

Rare:    transient visual disturbances (e.g. blurred vision)

predominantly during intravenous administration Very rare:    transient blindness predominantly after intravenous

administration²

Cardiac disorders:

Uncommon:    chest pain (with or without ST segment depression),

arrhythmias, bradycardia.

Rare:    QTc prolongation (including Torsade de pointes)

Vascular disorders:

Common:    feeling of warmth, flushing

Uncommon:    hypotension

Respiratory, thoracic and mediastinal disorders:

Uncommon:    hiccups

Gastrointestinal disorders:

Common:    constipation

Hepato-biliary disorders:

Uncommon:    asymptomatic increases in    liver function tests³

General disorders and administration site conditions:

Common:    local intravenous injection    site reactions

¹    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 commonly observed 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. 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 (5HT3) antagonists.

ATC code: A04A A01

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 postoperative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.

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

Ondansetron does not alter plasma prolactin concentrations.

The role of ondansetron in opiate-induced emesis is not yet established.

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.

Clinical studies

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 randomized 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. Postchemotherapy 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 + ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous + placebo orally). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days.

A double-blind randomized placebo-controlled trila (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 patients when ondansetron was administered as syrup at a dose of 8 mg +

2-4 mg 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 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 (S3A239) 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 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.

PONV

The efficacy of a single dose of ondansetron in the prevention of post-operative nausea and vomiting was investigated in a randomizedm, 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 randomized 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 summarized in Table 3.

5.2 Pharmacokinetic properties

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (bioavailability is about 60%). Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases, in both oral bioavailability (65%) and half-life (5 hours) of ondansetron. Gender differences were shown in the disposition of ondansetron, with females having 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%). A direct correlation of plasma concentration and anti-emetic effect has not been established. Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on 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 normalized 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 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 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.

In a study of 21 paediatric patients aged between 3 and 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron following a single intravenous dose of 2 mg (37 years old) or 4 mg (8-12 years old) were reduced. The magnitude of the change was age-related, with clearance falling from about 300 ml/min at 12 years of age to 100 ml/min at 3 years. Volume of distribution fell from about 75 l at 12 years to 17 l at 3 years. Use of weight-based dosing (0.1 mg/kg up to 4 mg maximum) compensates for these 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 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 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.

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 (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.

Elderly

Studies in healthy elderly volunteers have shown slight age-related increases in both oral bioavailability (65%) and half-life (5 hours).

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.

5.3 Preclinical safety data

5.3.1. Acute toxicity:

Acute toxicity of ondansetron was assessed up to maximum non-lethal doses in rats (100 mg/kg BW orally and 15 mg/kg BW i.v.) and mice (10 mg/kg BW orally,

1 mg/kg BW i.v.). At high doses impairment of central nervous functions, identified as abnormal behaviour, has been observed. This effect was dose-limiting.

5.3.2. Repeated dose toxicity:

Oral application:

Studies were performed in rats (up to 18 month) and dogs (up to 12 month). Only at higher doses behavioural disturbances were observed. In rats a transient increase of alanin-aminotransferase levels were observed without any signs of hepatotoxicity. An observed binding to melanin- and specific elastin-containing tissues had no toxicological significance.

Intravenous application:

Studies were performed in rats and dogs. As after oral administration transient behavioural disturbances were detected. At high doses, markedly higher than human therapeutic doses, tremor was observed (rats: 12 mg/kg BW; dog: 6.75 mg/kg BW). In rats a transient minor increase of alanin-aminotransferase was detected. In dogs local irritation at the injection site was observed, which was dose dependent, and which only occurred at the high concentration of 6.75 mg/ml. With concentrations corresponding to that used in human therapy no irritation was observed in dogs.

5.3.3. Reproductive toxicity:

Studies were performed in rats and rabbits with oral and intravenous administration. No signs of a teratogenic effect of ondansetron were detected. Ondansetron passes into the placenta of rats and rabbits.

Undesirable effects on fertility and postnatal development were not observed. Ondansetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was

5.2.

5.3.4. Mutagenicity:

Ondansetron was subjected to extensive mutagenicity tests; no mutagenic potential was revealed.

5.3.5. Carcinogenicity:

Studies performed during the complete life span of rats (maximum dose 10 mg/kg BW) and mice (maximum dose 30 mg/kg BW) indicated no increase in tumour incidence.

5.3.6. Further studies:

Ondansetron in micromolar 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

Sodium starch glycolate - Type A

Microcrystalline cellulose

Pregelatinised starch (maize) Magnesium stearate

Coating:

Hypromellose Titanium dioxide (E171) Macrogol 400 Macrogol 6000 Iron oxide yellow(E172).

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Transparent & white opaque PVC/PVdC aluminium blisters. Blister packs of 2, 4, 5, 6, 10, 15, 30, 50, 100 & 500 tablets. Hospital packs of 10 x 1 and 50 x 1 Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road, Hampden Park Eastbourne, BN22 9AG England

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0542

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

9-06-2004

10 DATE OF REVISION OF THE TEXT

06/03/2014