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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ondansetron 4 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ondansetron 4 mg Film-coated Tablets:

Each tablet contains ondansetron 4mg (as ondansetron hydrochloride dihydrate).

Excipients :Each tablet contains 74.25 mg lactose as lactose anhydrous and lactose monohydrate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet. Yellow, film-coated oval shaped tablets, plain on both sides.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults:

Management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, Prevention and treatment of post-operative nausea and vomiting (PONV).

Paediatric Population:

Management of chemotherapy -induced nausea and vomiting in children aged > 6 months. Prevention and treatment of post-operative nausea and vomiting in children aged > 1 month.

4.2 Posology and method of administration

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

Emetogenic Chemotherapy and Radiotherapy: Ondansetron can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration.

For oral administration: 8mg 1-2 hours before treatment, followed by 8mg 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 8mg twice daily.

Highly Emetogenic Chemotherapy: For 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 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 doing 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 5mg/m². The intravenous dose must not exceed 8mg.

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	Day1a,b	Days 2-6°
< 0.6m2	5 mg/m2 i.v. 2 mg syrup or tablet after 12 hours	2 mg syrup or tablet every 12 hours
> 0.6m2	5 mg/m2 i.v. 4 mg syrup or tablet after 12 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.

Dosing by bodyweight:

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 0.15mg/kg. The intravenous dose must not exceed 8mg.

Two further doses 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.

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

Weight	Day1a,b	Days 2-6b
<10kg	Up to 3 doses of 0.15mg/kg at 4-hourly intervals.	2 mg syrup or tablet every 12 hours
> 10kg	Up to 3 doses of 0.15mg/kg at 4-hourly intervals.	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.

Elderly:

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 can 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 8mg at eight hourly intervals.

For the treatment of established PONV: Intravenous administration is recommended.

Paediatric population

Post-operative nausea and vomiting in children aged > 1 month 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 0.1mg/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 postoperative 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 in the elderly.

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 8mg should not be exceeded.

Patients with poor sparteine/debrisoquine metabolism:

The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT₃ receptor antagonists (e.g. granisetron, dolasetron). 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.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.

Ondansetron is not indicated for prevention and treatment of post-operative nausea and vomiting in children after intra-abdominal surgery.

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.

Ondansetron film-coated tablets should not be used in children with the total body surface below 0.6m².

Paediatric Population:

Paediatric 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 5mg/m² followed by an oral dose is given. The comparative efficacy of these two different dosing regimens has not been investigated in clinical trials. Cross-trial comparison indicate similar efficacy for both regimens - see section 5.1.

This medicine contains lactose.

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

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 medicinal products 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, 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.

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.

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)

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.

Lactation:

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.

Ondansetron has no or negligible influence on the ability to drive and use machines.

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 (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), including isolated reports.

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 according to indication and formulation.

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 have been observed without definitive evidence of persistent clinical sequelae.

Rare: Dizziness during i.v. administration, which in most cases is prevented or resolved by lengthening the infusion period.

Eye disorders:

Rare: Transient visual disturbances (eg. blurred vision) predominantly during i.v. administration.

Very rare: Transient blindness predominantly during intravenous administration.

The majority of the blindness cases reported resolved within 20 minutes. Most patients had received chemotherapeutic agents, which included cisplatin.

Some cases of transient blindness were reported as cortical in origin.

Cardiac disorders:

Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia.

Vascular disorders:

Common: Sensation of warmth or flushing. Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders.

Uncommon: Hiccups.

Gastrointestinal disorders:

Common: Ondansetron is known to increase the large bowel transit time and may cause constipation in some patients. Patients with signs of subacute obstruction should be monitored.

Hepatobiliary disorders:

Uncommon: Asymptomatic increase in liver function tests.These events were observed commonly in patients receiving chemotherapy with cisplatin.

Paediatric population:

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

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. In all instances, the events resolved completely.

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 antiemetic 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. 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.). Postchemotherapy 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. Postchemotherapy 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 postoperative 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).

5.2 Pharmacokinetic properties

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 8mg dose. For doses above 8mg 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 a 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.

Following administration of ondansetron suppository, plasma ondansetron concentrations become detectable between 15 and 60 minutes after dosing. Concentrations rise in an essentially linear fashion, until peak concentrations of 20-30 ng/ml are attained, typically 6 hours after dosing. 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 effect on ondansetron’s pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

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 (3-7 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.

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.

Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. However, it is anticipated that the halflife of ondansetron after rectal administration in these populations will be similar to that seen in healthy volunteers, since the rate of elimination of ondansetron following rectal administration is not determined by systemic clearance.

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.

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.

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)

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

List of excipients

Core

lactose anhydrous, cellulose microcrystalline, starch pregelatinised (maize), magnesium stearate

Coat

hypromellose, lactose monohydrate, titanium dioxide (E171), triacetin,

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

PVC/PVDC//Aluminium blisters.

Pack sizes:

Blisters containing 6, 10, 15, 20, 30, 50, and 100 film-coated tablets. Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04416/0875

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

12/01/2010

10 DATE OF REVISION OF THE TEXT

18/05/2012