Emizof 4mg & 8mg Film-coated Tablets

4.9 Overdose

Symptoms and Signs

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.

10. DATE OF REVISION OF THE TEXT

AugustMay 20165

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications 
 

Adults:

Emizof 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).

 

For treatment of established PONV, administration by injection is recommended.

 

Paediatric Population:

Emizof is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged ≥ 6 months.

and for the prevention and treatment of post-operative nausea and vomiting (PONV) in children aged ≥ 1 month

No studies have been conducted on the use of orally administered ondansetron in the prevention and treatment of PONV in children aged ≥ 1 month, administration by IV injection is recommended for this purpose.

 

4.2        Posology and method of administration

 

Posology

 

Chemotherapy and radiotherapy induced nausea and vomiting

 

Adults

 

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used.  The selection of dose regimen should be determined by the severity of the emetogenic challenge.The route of administration and dose of Emizof should be flexible in the range of 8-32mg a day and selected as shown below

Emetogenic chemotherapy and radiotherapy

 

 

Emizof can be given either by oral or intravenous administration. 

 

For most patients receiving emetogenic chemotherapy or radiotherapy, Emizof 8 mg should be administered as a slow intravenous injection or as a short-time intravenous infusion over 15 minutes immediately before treatment, followed by 8 mg orally twelve hourly.

For oral administration: 8 mg taken 1-2 hours before treatment, followed by 8 mg  every 12 hours for a maximum of 5 days to protect against delayed or prolonged emesislater.

 

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Emizof should be continued for up to 5 days after a course of treatment.

 

The recommended dose for oral administration is 8mg twice daily.

 

Highly emetogenic chemotherapy

 

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

 

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

 

(For specific recommendations pertaining to the mode of administration of parenteral forms of ondansetron please refer to the corresponding Summary of Product Characteristics).

 

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Emizof associated with dexamethasone, may shouldbe continued for up to 5 days after a course of treatment.

 

The recommended dose for oral administration is 8 mg to be taken 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. In paediatric clinical studies, ondansetron was given by IV infusion diluted in 25 to 50 ml of saline or other compatible infusion fluid and infused over not less than 15 minutes.

 

Weight-based doing results in higher total daily doses compared to BSA-based dosing – (see sections 4.4.).and 5.1.

Dosing by BSA:

Emizof should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m². The single intravenous dose must not exceed 8 mg.

The total daily 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

 

BSA	Day 1(a,b)	Day 2-6(b)
< 0.6 m2	5 mg/m2 IV plus 2 mg syrup after 12 hours	2 mg syrup every 12 hours
≥ 0.6 m2 to ≤1.2 m2	5 mg/m2 IV plus 4 mg syrup or tablet after 12 hours	4 mg syrup or tablet every 12 hours
> 1.2 m2	5 mg/m2 or 8 mg IV plus 8 mg syrup or tablet after 12 hours.	8 mg syrup or tablet every 12 hours.

 

^a The intravenous dose must not exceed 8mg.

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

 

Dosing by bodyweight:

Weight-based dosing results in higher total daily doses compared to BSA based dosing (sections 4.4. and 5.1).

 

Emizof should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg.

Two further intravenous doses may be given in 4-hourly intervals. The total daily dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Oral dosing can commence twelve hours later and may be continued for up to

5 days (Table 2).

 

Table 2: Weight-based dosing for Chemotherapy - Children aged ≥ 6 months and adolescents

 

Weight	Day 1(a,b)	Day 2-6 (b)
< 10 Kg	Up to 3 doses of 0.15 mg/kg IV every 4 hours	2 mg syrup every 12 hours
> 10 Kg	Up to 3 doses of 0.15 mg/kg IV every 4 hours	4 mg syrup or tablet every 12 hours

 

^a The intravenous dose must not exceed 8mg.

^b The total daily dose must not exceed adult dose of 32 mg

 

Older people:

 

No alteration of oral dose or frequency of administration is required.Emizof is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required.

Post-operative nausea and vomiting (PONV)
Adults

 

Prevention of PONV

 

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

 

For oral administration: 16 mg taken one hour prior to anaesthesia.  Alternatively, 8mg one hour prior to anaesthesia followed by two further doses of 8 mg at eight hourly intervals.

Oral formulation:

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting; slow i.v.I.V. injection (not less than 30 seconds) is recommended for this purpose.

 

Special Populations 

 

 

Patients with hepatic impairment: Clearance of Ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function.  In such patients a total daily dose of 8 mg should not be exceeded and therefore parenteral or oral administration is recommended.

4.4 Special warnings and precautions for use

 

QT prolongation

Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). In addition, post-marketing cases of Torsade de pointes 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 cardiac rhythm, conduction disturbances, in patients treated with anti-arrhythmic agents, or beta-adrenergic blocking agents or other medicinal products that lead to QT prolongation or electrolyte abnormalities.

Fertility

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

 

 

4.8 Undesirable effects

 

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and, very rare (<1/10,000) and not known (cannot be estimated from the available data). Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data.

General disorders and administration site conditions
Common:	Local IV injection site reactions.

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 sSection 4.8).

 

Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block.  In all instances, the events resolved completely.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mechanism of action
 

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

5.2        Pharmacokinetic properties

 

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (bioavailability is about 60%).  Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose.  For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses.  Mean bioavailability in healthy male subjects, following the oral administration of a single 8 mg tablet, is approximately 55 to 60%. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids.  Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 hours) of ondansetron.  Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).

Older people

Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. Studies in healthy elderly volunteers have shown slight age-related increases in both oral bioavailability (65%) and half-life (5 hours).

Hepatic impairment

 

Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron’s systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.

5.3        Preclinical safety data

 

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

 

Ondansetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was 5.2:1.

 

Ondansetron in submicromolar concentrations blocked cloned HERG Potassium channels of the human heart. The clinical relevance of this finding is not clear.

 

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

 

Ondansetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was 5.2.

 

Ondansetron in submicromolar concentrations blocked cloned HERG Potassium channels of the human heart. The clinical relevance of this finding is not clear.No additional data of relevance.

 

section 4.2:
added:
The recommended oral dose is 24 mg taken together with 12 mg oral dexamethasone sodium phosphate, 1 to 2 hours before treatment.

updated:

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

 

BSA	Day 1(a,b)	Day 2-6(b)
< 0.6 m2	5 mg/m2 IV plus 2 mg syrup after 12 hrs	2 mg syrup every 12 hrs
≥ 0.6 m2	5 mg/m2 IV plus 4 mg syrup or tablet after 12 hrs	4 mg syrup or tablet every 12 hrs
> 1.2 m2	5 mg/m2 or 8 mg IV plus 8 mg syrup or tablet after 12 hours.	8 mg syrup or tablet every 12 hours.

Older people:

 

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

 

Please refer to “Special Populations”.

Method of administration

 

For oral use

section 4.4

QT prolongation

Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). In addition, post-marketing cases of torsade de pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc, including patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias, cardiac rhythm, conduction disturbances, in patients treated with anti-arrhythmic agents, or beta-adrenergic blocking agents or other medicinal products that lead to QT prolongation or electrolyte abnormalities.

section 4.5

Caution should be exercised when ondansetron is co-administered with drugs that prolong the QT interval and/or cause electrolyte abnormalities (see section 4.4).

Serotonergic drugs (e.g. SSRIs and SNRIs): There

section 4.8
and not known (cannot be estimated from the available data).

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

section 5.1

Mechanism of action

 

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.

There was no difference in the overall incidence or nature of adverse events between the two treatment groups.

There was no difference in the overall incidence or nature of adverse events between the two treatment groups.

section 5.2
Mean bioavailability in healthy male subjects, following the oral administration of a single 8 mg tablet, is approximately 55 to 60%

Gender

 

Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).

Older people

Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. However, wide inter-subject variability resulted in considerable overlap in pharmacokinetic parameters between young (< 65 years of age) and elderly subjects (≥ 65 years of age) and there were no overall differences in safety or efficacy observed between young and elderly cancer patients enrolled in CINV clinical trials to support a different dosing recommendation for the elderly.

 

Based on more recent ondansetron plasma concentrations and exposure-response modelling, a greater effect on QTcF is predicted in patients ≥ 75 years of age compared to young adults. Specific dosing information is provided for patients over 65 years of age and over 75 years of age for intravenous dosing.

Renal impairment

 

In patients with renal impairment (creatinine clearance 15-60 ml/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4 h).  A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron’s pharmacokinetics to be essentially unchanged following IV administration.

.The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.

section 6.1

 

Tablet Core

Lactose monohydrate

Cellulose, microcrystalline  (E460)

Maize starch, pregelatinised

Magnesium stearate (E572)

 

Tablet Coat

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol (E1520)

Sorbitan oleate (E494)

Sorbic acid (E200)

Vanillin

Quinoline yellow (E104)

Hydroxypropyl cellulose (E463).

section 4.4section 4.5section 4.8section 5.1section 5.2

section 4.4section 4.5section 4.8section 5.1section 5.2

section 4.4section 4.5section 4.8section 5.1section 5.2

The following sections updated

4.3,4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.1,

section 4.1-added
Paediatric Population

section 4.2-added
Paediatric Population

section 4.4-added

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

 

Very rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. Therefore caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic agents or beta-adrenergic blocking agents and in patients with significant electrolyte disturbances.

Paediatric Population -added

section 4.5-added

The use of ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines) may increase the risk of arrhythmias (see section 4.4).

section 4.6-added

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.

 

section 4.7-added

In psychomotor testing ondansetron does not impair performance nor cause sedation.

 

section 4.8-table of adverse drug reactions added

section 4.9-added

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 Undesirable effects).

Treatment

section 5.1-added
Paediatric Population

section 5.2-added
Special Patient Population

section 4.8-added

Eye disorders

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.

section 4.9-typo correction
The use of ipecacuanha to treat overdose with Emizof is not recommended as patients are unlikely to respond due to the anti-emetic action of Emizof itself.

section 6.3
36 months rewritten as 3 years

section 6.6-added
Any unused product or waste material should be disposed of in accordance with local requirements.