Ondansetron 8mg tablets

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Public Assessment Report Public Assessment Report (PAR)

30-11--0001

Active ingredient:
Ondansetron hydrochloride
Available from:
Ennogen Healthcare Ltd
ATC code:
A04AA01
INN (International Name):
Ondansetron hydrochloride
Dosage:
8mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04060000; GTIN: 05060254923000

Product:

Ondansetron 4mg & 8mg Tablets

Item Code:

P1412T

Size:

240 x 400 mm

Min. Point size:

O. Artwork:

06/04/20

Proof No.

Amendment Date:

07/04/20

Process Black

Keyline - Does not print

Colours Used

ONDANSETRON 4mg and 8mg TABLETS

Ondansetron hydrochloride dihydrate

PACKAGE LEAFLET: INFORMATION FOR THE USER

you have a blockage in your gut

you have problems with the levels of salts in your blood, such as

potassium, sodium and magnesium.

you have liver problems

you have an uneven heart beat (arrhythmias)

you are allergic to medicines similar to ondansetron, such as

granisetron (known as 'Kytril') or palonosetron.

Other medicines and Ondansetron tablets

Tell your doctor, nurse or pharmacist if you are taking, have recently taken

or might take any other medicines. This includes medicines that you buy

without a prescription and herbal medicines.This is because Ondansetron

can affect the way some medicines work. Also some other medicines can

affect the way Ondansetron works.

The liver function for persons under 18 years of age taking Ondansetron

Tablets should be regularly checked.

There are known interaction between the following medications and

Ondansetron therefore there use with Ondansetron Tablets is not

recommended.

If you are not sure if any of the above apply to you, talk to your doctor,

nurse or pharmacist before taking Ondansetron Tablets

rifampicm used to treat infections such as tuberculosis (TB), it lowers

the concentration of ondansetron,

Children and Adolescents

carbamazepine or phenytoin used to treat epilepsy, as it lowers the

concentration of ondansetron,

antibiotics such as erythromycin and antifungals such as ketoconazole

anti-arrhythmic medicines used to treat an uneven heartbeat, as

ondansetron prevents medication from working,

This medicine has been prescribed for you only. Do not pass it on

to others. It may harm them, even if their signs of illness are the

same as yours.

If you get any side effects, talk to your doctor, pharmacist or

nurse.Thls Includes any possible side effects not listed In this

leaflet. (See section 4).

Read all of this leaflet carefully before you start taking this medicine

because it contains important information for you.

If you have any further questions, ask your doctor, nurse or

pharmacist.

Keep this leaflet. You may need to read It again.

What is in this leaflet:

What Ondansetron Tablets are and what they are used for

What you need to know before you take Ondansetron Tablets

How to take Ondansetron Tablets

Possible side effects

How to store Ondansetron Tablets

Contents of the pack and other information

1. WHAT ONDANSETRON TABLETS ARE AND WHAT THEY ARE

USED FOR

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE

ONDANSETRON TABLETS

are allergic to ondansetron, or to any of the other ingredients or of this

medicines (listed in section 6).

are taking apomorphine (used to treat Parkinson's disease)

Do not take Ondansetron tablets if you:

preventing nausea and vomiting caused by chemotherapy (in adults

and children) or radiotherapy for cancer (adults only)

Talk to your doctor, nurse or pharmacist before taking Ondansetron tablets

Warnings and precautions

you have ever had heart problems (e.g. congestive heart failure which

causes shortness of breath & swollen ankles).

The active ingredient in your tablets is ondansetron. This belongs to a

group of medicines known as anti-emetics.

Ondansetron Tablets are used for:

preventing nausea and vomiting after surgery (adults only)

Ask your doctor, nurse or pharmacist if you would like any further

explanation about these uses.

There are no interactions with alcohol.

medicines that affect the heart (such as haloperidol or methadone),

Ondansetron tablets with food, drink and alcohol

Ondansetron Tablets are an oral medicine and the recommended dose you

are prescribed by your doctor will be dependent on your treatment.

SSRIs (selective serotonin reuptake inhibitors) used to treat depression

and/or anxiety including fluoxetine, paroxetine, sertraline, fluvoxamine,

citalopram, escitalopram

beta-blocker medicines used to treat certain heart or eye problems,

anxiety or prevent migraines as beta-blocker may not work properly,

The ondansetron in these tablets may pass into breast milk. Mothers taking

Ondansetron Tablets should not therefore breast-feed. Ask your doctor or

midwife for advice.

No data available.

tramadol, a pain killer, as tramadol may not work properly

Driving and using machines

Ondansetron can cause visual disturbances and dizziness. If you are

affected do not drive or operate machinery.

cancer medicines (especially anthracyclines and trastuzumab).

SNRIs (serotonin noradrenaline reuptake inhibitors) used to treat

depression and/or anxiety including venlafaxine, duloxetine.

If you are not sure if any of the above applies to you, talk to your doctor,

nurse or pharmacist before having Ondansetron tablets.

You can take your Ondansetron Tablets with or without food.

Pregnancy, breast-feeding and fertility

Only use during the first trimester of pregnancy after discussion with your

doctor of the potential benefits and risks to you and your unborn baby of the

different treatment options. This is because Ondansetron Tablets can

slightly increase the risk of a baby being born with cleft lip and/or cleft

palate (openings or splits in the upper lip and/or the roof of the mouth).

If you are already pregnant, think you might be pregnant or are planning to

have a baby, ask your doctor or pharmacist for advice before taking

Ondansetron Tablets. If you are a woman of childbearing potential you may

be advised to use effective contraception.

Pregnancy:

Breastfeeding:

Fertility:

Ondansetron Tablets contain lactose

If you have been told by your doctor that you have an intolerance to some

sugars, contact your doctor before taking this medicine.

3. HOW TO TAKE ONDANSETRON TABLETS

Always take this medicine exactly as your doctor or pharmacist has told

you. Check with your doctor, nurse or pharmacist if you are not sure.

To prevent Chemotherapy and radiotherapy induced nausea and

vomiting

On following days:

the usual adult dose is 8mg twice a day.

this may be given for up to 5 days.

the usual adult dose is 8mg one or two hours before treatment,

followed by another 8mg twelve hours later.

Children aged 6 months and adolescents:

The doctor will decide the dose depending on the child's size (body surface

area) or weight. Look at the label for more information.

This may be given for up to 5 days.

To prevention nausea and vomiting after an operation

The usual adult dose is 16mg before an operation or:

the usual dose for a child is up to 4mg twice daily.

On the day of chemotherapy or radiotherapy:

8mg before the operation, then

8mg after the operation, then

8mg after a further eight hours.

It is recommended that ondansetron be given as an injection.

Children aged over 1 month and adolescents:

Take Ondansetron tablets as soon as possible, then

Otherwise, do not take more Ondansetron tablets than the label says. If

you continue to feel sick, tell your doctor or nurse.

skin rash - red spots or lumps under the skin (hives) anywhere on your

body

sensation of warmth or flushing

Common (affects less than 1 In 10 people)

Other side effects Include

Do not take a double dose to make-up for a forgotten dose.

Take the next dose as shown on the label

If you stop taking Ondansetron tablets:

If you are sick (vomit) within one hour of taking a dose

collapse.

headache

Very common (affects more than 1 in 10 people)

constipation

Take the same dose again,

This medication has been prescribed by your doctor; you should not stop

taking Ondansetron tablets without discussing this with your doctor first.

swelling of the face, eyelids, lips mouth or tongue

If you have any further questions on the use of this medicine, ask

your doctor or pharmacist.

If you miss a dose but do not feel sick

Like all medicines, this medicine can cause side effects, although not

everybody gets them.

Allergic reactions:

If you miss a dose and feel sick or vomit:

Take your next tablet at the usual time (as shown on the label)

Do not take a double dose to make up for a forgotten dose.

If you take too many Ondansetron tablets:

It is important to take these tablets as directed - taking more than

prescribed can make you ill. If you do take more than you should, tell your

doctor or go to the nearest hospital casualty department straight away. If

you go to the hospital/doctor remember to take this leaflet and any

remaining tablets with you so the doctor knows what you have taken.

If you forget to take Ondansetron tablet

4. POSSIBLE SIDE EFFECTS

If you have an allergic reaction, stop taking Ondansetron tablets and see

your doctor straight away. The signs of an allergic reaction may include:

sudden wheezing, difficulty in breathing, chest tightness or chest pain,

changes to liver function test results (if you are taking with a medicine

called cisplatin, otherwise it's effect is uncommon).

fits,

Rare (affects less than 1 In 1,000 people)

hiccups,

feeling dizzy or light headed,

blurred vision,

disturbances in heart rhythm (sometimes causing a sudden loss of

consciousness).

Very rare (affects less than 1 in 10,000 people)

uneven heart beat,

poor vision or temporary loss of eyesight, which usually comes back

within 20 minutes.

unusual body movements or shaking.

5. HOW TO STORE ONDANSETRON TABLETS

Uncommon (affects less than 1 In 100 people)

Keep this medicine out of the sight and reach of children. Do not use this

medicine after the expiry date which is stated on the carton.

The expiry

P1412T

date refers to the last day of that month.

low blood pressure, which can make you feeling dizzy or faint,

Reporting of Side Effects:

chest pain,

If you get any side effects, talk to your doctor pharmacist or nurse. This

includes any possible side effects not listed in this leaflet. You can also

report side effects directly via the Yellow Card Scheme at

www.mhra.gov.uk/yellowcard. By reporting side effects you can help

provide more information on the safety of medicines.

Patients with moderate to severe liver problems:

The total daily dose should not be more than 8mg.

Ondansetron tablets should start to work within one or two hours of taking

a dose.

Crescent Pharma Limited, Units 3 and 4, Quidhampton Business Units,

Polhampton Lane, Overton, Hampshire, Basingstoke, RG25 3ED, UK.

(not all packs may be marketed)

The other ingredients include: lactose monohydrate, microcrystalline

cellulose, maize starch, magnesium stearate, hypromellose, titanium

dioxide (E171) and macrogol.

Ondansetron 4mg tablets are white, circular, biconvex, film-coated tablets

with a break line one side and plain on the other.

What Ondansetron tablets look like and contents of the pack:

Marketing Authorisation Holder:

Manufacturer responsible for batch release:

plain on both sides.

Ondansetron 8mg tablets are white, circular, biconvex, film-coated tablets

Cadila Pharmaceuticals (Europe) Limited, The Pavillion, 56 Rosslyn

Crescent, Harrow, Middlesex HA1 2SZ, UK

This leaflet was prepared in April 2020

Store the tablets in the original package. Keep the blister in the outer

carton.

Do not use this medicine if you notice any damage/discoloration to the

tablets.

Do not throw away any medicines via wastewater or household waste. Ask

your pharmacist how to throw away medicines you no longer need, these

measures will help protect the environment.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Ondansetron tablets contain:

The active substance is ondansetron (as ondansetron hydrochloride

dihydrate).

Crescent

F'HAr.llv'IA

LIMITED

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Ondansetron 8mg Orodispersible Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains ondansetron 8mg.

Excipient with known effect

Each orodispersible tablet contains 6mg aspartame.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Orodispersible tablets.

Round, white to off-white, flat, bevelled edged, tablets plain on both the surfaces,

having strawberry odour.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Adults:

Ondansetron orodispersible tablets are indicated for the management of nausea and

vomiting induced by cytotoxic chemotherapy and radiotherapy.

Ondansetron orodispersible tablets are indicated for the prevention of post-operative

nausea and vomiting (PONV).

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

Paediatric Population:

Ondansetron is indicated for the management of chemotherapy-induced nausea and

vomiting (CINV) in children aged

6 months.

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.

Emetogenic chemotherapy and radiotherapy: Ondansetron can be given either by

rectal, oral (as orodispersible tablet, tablets or syrup) intravenous or intramuscular

administration.

For oral administration: 8 mg taken 1 to 2 hours before chemotherapy or radiation

treatment, followed by 8 mg every 12 hours for a maximum of 5 days to protect

against delayed or prolonged emesis.

For highly emetogenic chemotherapy: a single dose of up to 24 mg ondansetron taken

with 12 mg oral dexamethasone sodium phosphate, 1 to 2 hours before chemotherapy,

may be used.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal

treatment with ondansetron may be 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

:

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 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.).

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/m

. The single intravenous dose must not exceed 8 mg.

Oral dosing can commence 12 hours later and may be continued for up to 5 days

(Table 1).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of

32 mg.

Table 1: BSA-based dosing for Chemotherapy - Children aged

6 months and

adolescents

Day 1

(a,b)

Days 2-6

<

0.6 m

5 mg/m

IV plus

2 mg syrup after

12 hours

2 mg syrup every

12 hours

0.6 m

1.2 m

5 mg/m

IV plus

4 mg syrup or

tablet after

12 hours

4 mg syrup or tablet

every 12 hours

>1.2 m

5 mg/m

or 8 mg

IV plus

8 mg syrup or

tablet after

12 hours

8 mg syrup or tablet

every 12 hours

The intravenous dose must not exceed 8 mg.

The total dose over 24 hours (given as divided doses) 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 0.15 mg/kg. The single intravenous dose must not exceed 8 mg.

Two further intravenous doses may be given in 4-hourly intervals.

Oral dosing can commence 12 hours later and may be continued for up to 5 days

(Table 2).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of

32 mg.

Table 2: Weight-based dosing for Chemotherapy - Children aged

6 months and

adolescents

Weight

Day 1

(a,b)

Days 2-6

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

The intravenous dose must not exceed 8 mg.

The total dose over 24 hours (given as divided doses) must not exceed adult

dose of 32 mg.

Elderly:

No alteration of oral dose or frequency of administration is required.

Post-operative nausea and vomiting (PONV):

Adults:

For the prevention of PONV: Ondansetron may be administered either orally (as

orodispersible tablet, tablets or syrup) or by intravenous or intramuscular injection.

For oral administration: 16 mg one hour prior to anaesthesia.

For the treatment of established PONV: Intravenous or intramuscular administration

is recommended.

Paediatric population:

PONV in children aged

1 month and adolescents

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 IV injection (not

less than 30 seconds) is recommended for this purpose.

There are no data on the use of ondansetron in the treatment 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 PONV in the elderly, however ondansetron is well tolerated in patients over 65

years receiving chemotherapy.

For both indications

Patients with renal impairment:

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

required.

Patients with hepatic impairment:

Clearance of ondansetron is significantly reduced and serum half-life significantly

prolonged in subjects with moderate or severe impairment of hepatic function. In

such patients a total daily dose of 8 mg should not be exceeded.

Patients with poor sparteine/debrisoquine metabolism:

The elimination half-life of ondansetron is not altered in subjects classified as poor

metabolisers of sparteine and debrisoquine. Consequently in such patients repeat

dosing will give drug exposure levels no different from those of the general

population. No alteration of daily dosage or frequency of dosing is required.

Method of administration

Place the orodispersible tablet on top of the tongue, where it will disperse quickly and

then swallow.

4.3

Contraindications

Concomitant use with apomorphine (see section 4.5).

Hypersensitivity to any component of the preparation.

4.4

Special warnings and precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited

hypersensitivity to other selective 5HT

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 (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 or patients taking other medicinal products

that lead to QT prolongation or electrolyte abnormalities.

Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron

administration.

There have been post-marketing reports describing patients with serotonin syndrome

(including altered mental status, autonomic instability and neuromuscular

abnormalities) following the concomitant use of ondansetron and other serotonergic

drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin

noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with

ondansetron and other serotonergic drugs is clinically warranted, appropriate

observation of the patient is advised.

As ondansetron is known to increase large bowel transit time, patients with signs of

subacute intestinal obstruction should be monitored following administration.

In patients with adenotonsillar surgery prevention of nausea and vomiting with

ondansetron may mask occult bleeding. Therefore, such patients should be followed

carefully after ondansetron.

Ondansetron orodispersible tablets formulation contains aspartame and therefore

should be taken with caution in patients with phenylketonuria.

Paediatric Population:

Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents

should be monitored closely for impaired hepatic function.

CINV: When calculating the dose on a 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/m

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

indicates similar efficacy for both regimens (see section 5.1).

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,

furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol.

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.

Caution should be exercised when ondansetron is coadministered with drugs that

prolong the QT interval and/or cause electrolyte abnormalities. (See section 4.4)

Use of ondansetron with QT prolonging drugs may result in additional QT

prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g.

anthracyclines (such as doxorubicin, daunorubicin) or trastuzumab), antibiotics (such

as erythromycin), antifungals (such as ketoconazole), antiarrhythmics (such as

amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of

arrhythmias. (See section 4.4).

Serotonergic Drugs (e.g. SSRIs and SNRIs): There have been post-marketing reports

describing patients with serotonin syndrome (including altered mental status,

autonomic instability and neuromuscular abnormalities) following the concomitant

use of ondansetron and other serotonergic drugs (including SSRIs and SNRIs). (See

section 4.4)

Apomorphine: Based on reports of profound hypotension and loss of consciousness

when ondansetron was administered with apomorphine hydrochloride, concomitant

use with apomorphine 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

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. It is

therefore recommended that mothers receiving ondansetron should not breast-feed

their babies.

Fertility

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

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

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

<

1/100), rare (

1/10,000 to

<

1/1000) and very rare (

<

1/10,000). Very common,

common and uncommon events were generally determined from clinical trial data.

The incidence in placebo was taken into account. Rare and very rare events were

generally determined from post-marketing spontaneous data.

The following frequencies are estimated at the standard recommended doses of

ondansetron. The adverse event profiles in children and adolescents were comparable

to that seen in adults

Immune system disorders

Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.

Nervous system disorders

Very common: Headache.

Uncommon: Seizures, movement disorders (including extrapyramidal reactions such

as dystonic reactions, oculogyric crisis and dyskinesia)

Rare: Dizziness predominantly during rapid IV administration.

Eye disorders

Rare: Transient visual disturbances (e.g. blurred vision) predominantly during IV

administration.

Very rare: Transient blindness predominantly during IV administration.

Cardiac disorders

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

bradycardia.

Rare: QTc prolongation (including Torsade de Pointes).

Vascular disorders

Common: Sensation of warmth or flushing.

Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: Hiccups.

Gastrointestinal disorders

Common: Constipation.

Hepatobiliary disorders

Uncommon: Asymptomatic increases in liver function tests.

Observed without definitive evidence of persistent clinical sequelae.

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.

These events were observed commonly in patients receiving chemotherapy

with cisplatin.

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 Google play or Apple App store.

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 the QT interval in a dose-dependent fashion. ECG monitoring

is recommended in cases of overdose.

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.

Treatment

There is no specific antidote for ondansetron, therefore in all cases of suspected

overdose, symptomatic and supportive therapy should be given as appropriate.

Further management should be as clinically indicated or as recommended by the

national poisons centre, where available.

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.

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 1 -

ONDANSETRON 4MG TABLETS (ONDANSETRON HYDROCHLORIDE)

PL 04543/0509

ONDANSETRON 8MG TABLETS (ONDANSETRON HYDROCHLORIDE)

PL 04543/0510

UKPAR

TABLE OF CONTENTS

Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 23

Steps taken after authorisation – summary

Page 24

Summary of Product Characteristics

Page 25

Product Information Leaflet

Page 41

Labelling

Page 44

ONDANSETRON 4MG TABLETS (ONDANSETRON HYDROCHLORIDE)

PL 04543/0509

ONDANSETRON 8MG TABLETS (ONDANSETRON HYDROCHLORIDE)

PL 04543/0510

LAY SUMMARY

The MHRA granted CP Pharmaceuticals Limited Marketing Authorisations (licences) for

the medicinal products Ondansetron 4mg Tablets (PL 04543/0508) and Ondansetron 8mg

Tablets (PL 04543/0510) on 21

March 2006. These prescription only medicines (POM)

are used for the management of nausea and vomiting caused by cancer chemotherapy and

radiotherapy, and for the prevention of post-operative nausea and vomiting in adults and

children.

Ondansetron Tablets contain the active ingredient ondansetron hydrochloride, which is an

anti-emetic, used to prevent nausea and vomiting.

The data presented to the MHRA, pre licensing, demonstrated that Ondansetron 4mg and

8mg Tablets are equivalent to the approved products, Zofran 4mg and 8mg Tablets.

Ondansetron Tablets can therefore be used interchangeably with Zofran Tablets.

No new or unexpected safety concerns arose from these applications. It was, therefore,

judged that the benefits of taking Ondansetron Tablets outweigh the risks. Hence

Marketing Authorisations have been granted.

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 2 -

ONDANSETRON 4MG TABLETS (ONDANSETRON HYDROCHLORIDE)

PL 04543/0509

ONDANSETRON 8MG TABLETS (ONDANSETRON HYDROCHLORIDE)

PL 04543/0510

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 16

Clinical assessment

Page 19

Overall conclusions and risk benefit assessment

Page 22

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 3 -

INTRODUCTION

Based on the review of the data on quality, safety and efficacy the UK granted marketing

authorisations for the medicinal products Ondansetron 4mg Tablets (PL 04543/0509) and

Ondansetron 8mg Tablets (PL 04543/0510) to CP Pharmaceuticals Limited on 21

March

2006. The products are prescription only medicines.

The applications were submitted as abridged applications according to article 10.1(a)(iii) of

Directive 2001/83/EC, claiming essential similarity to the original products Zofran 4mg

and 8mg Tablets.

The products contain the active ingredient ondansetron hydrochloride and are 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 in

adults and children.

Ondansetron hydrochloride, a carbazole, is a selective inhibitor of type 3 serotonin

(5-hydroxytryptamine) receptors (5-HT

) that exhibits anti-emetic activity.

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 4 -

PHARMACEUTICAL ASSESSMENT

1. INTRODUCTION

These are abridged applications for Marketing Authorisation in the UK submitted under

Article 10.1(a)(iii) of Directive 2001/83 (as amended), first paragraph so called generic

application.

The original products, Zofran 4mg Tablets, PL 00004/0376 and Zofran 8mg Tablets PL

00004/0377, were licensed in the UK on the 7

March 1990, to Glaxo. The licences have

undergone a change of ownership due to the mergers of GlaxoSmithKline, current licences

are PL 10949/0110 (4mg) and PL 10949/0111 (8mg).

The medicinal product used in the clinical studies is Zofron 8mg Tablets sourced from

Greece.

2.

COMMON TECHNICAL DOCUMENT SUMMARIES

2.1

INTRODUCTION

2.2

QUALITY OVERALL SUMMARY (QOS)

A satisfactory introduction and Quality Overall Summary have been provided.

3.

DRUG SUBSTANCE

3.1

GENERAL INFORMATION

3.1.1

Nomenclature

rINN: Ondansetron hydrochloride

Ph Eur name: Ondansetron hydrochloride dihydrate

USP name: Ondansetron hydrochloride

(3RS)-9-Methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2-3,9-tetrahydro-4H-

carbazol-4-one hydrochloride dihydrate

)-4-H-carbazol-4-one, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-

yl)methyl]-monohydrochloride dihydrate

)-2,3-Dihydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-carbazol-4(1H)-one

monohydrochloride dihydrate

3.1.2

Structure

0. HCl. 2H

MW: 365.86

3.1.3

General Properties

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 5 -

Ondansetron hydrochloride dihydrate is a white to off-white crystalline powder

sparingly soluble in water and alcohol, soluble in methanol, slightly soluble in

dichloromethane, very slightly soluble in acetone, chloroform and in ethyl acetate.

Solubility in water is 3.2% and 0.8% in 0.9% saline. The pH of a 1% w/v solution

in water is about 4.6. The pKa is 7.4 such that free base precipitates when the pH is

above the range 5.7-7.

Ondansetron hydrochloride dihydrate is more stable in acidic media than at neutral

Ondansetron contains a single asymmetric carbon and is used as the racemate.

There are no literature reports of polymorphism, although Module 3 refers to a

pseudo polymorph that melts at approximately 213

3.2

MANUFACTURE

3.2.1

Manufacturing process description and process controls

A letter of access dated 20

July 2004 and the open part of Drug Master File (DMF)

have been provided for the above source. The Applicant’s part is identical to the

version registered with the MHRA. No products have been authorised in the UK

using this source of active substance.

The synthetic route has been provided.

3.2.2

Control of materials

No materials of animal or human origin are used in manufacture of the drug

substance.

3.3

CHARACTERISATION

3.3.1

Impurities

Impurities A-H are described in the Ph Eur monograph.

Impurity A: (3RS)-3-[(dimethylamino)methyl]-9-methyl-1,2,3,9-tetrahydro-4H-

carbazol-4-one

Impurity B: 6,6

-methylenebis-[(3RS)- 9-methyl-3-[(2-methyl-1H-imidazol-1-

yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one]

Impurity C: 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one

Impurity D: 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one

Impurity E: 1H-imidazole

Impurity F: 2-methyl-1H-imidazole

Impurity G: (3RS)-3-[(1H-imidazol-1-yl)methyl(-9-methyl-1,2,3,9-tetrahydro-4H-

carbazol-4-one

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 6 -

Impurity H: (3RS)-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-

carbazol-4-one

Four of the above impurities (ondansetron impurities A-D) are also described in the USP

monograph for ondansetron hydrochloride.

3.4

CONTROL OF DRUG SUBSTANCE

3.4.1

Specification

Ondansetron hydrochloride dihydrate is the subject of Ph Eur monograph

01/2003:2016 corrected. The substance is also described in the USP/NF. Batches of

drug substance are controlled to the specifications provided. The specifications

provided satisfy the requirements of the Ph Eur monograph.

The proposed limits for residual solvents comply with ICH recommended limits.

3.4.2

Analytical procedures / validation

The active substance manufacturer uses the methods described in the Ph Eur

monograph except the methods used for determining water and heavy metals. The

active substance manufacturer has described alternative details for the preparation

of reference standards for the related substances methods that will be used until the

CRS reference standards for system suitability are available. A validated in-house

method has been described for determination of residual solvents. The method for

DSC analysis has been described. The methods are satisfactory.

The manufacturer of the finished product uses the methods described in the Ph Eur

monograph.

3.4.3

Batch analyses

Satisfactory Certificates of Analysis have been provided. Data from the active

substance manufacturer have been provided on 5 batches whilst data on 4 batches

have been provided by the finished product manufacturer.

3.4.4

Justification of specification

The applicant has provided a justification for the proposed specification. Impurity B

is considered qualified at a level of 0.4% on the basis of inclusion in the USP and

Ph Eur monographs. On the basis of the transparency statement in the Ph Eur

monograph, impurities A, C and E-H are considered qualified at a level of 0.2%.

3.5

REFERENCE STANDARDS OR MATERIALS

Satisfactory Certificates of Analysis have been provided for the current working

standard of ondansetron hydrochloride dihydrate. The reference standards are

provided by the active substance manufacturer.

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 7 -

3.6

CONTAINER CLOSURE SYSTEM

The drug substance is packed in sealed translucent polyethylene bags in HDPE

drums. The bags are stated as complying with Ph Eur requirements. Satisfactory

specifications and batch documentation have been provided for the above

packaging components.

3.7

STABILITY

3.7.1

Stability summary and conclusions

Ondansetron shows some sensitivity to temperature and moisture and should be

protected from light.

3.7.2

Post-approval stability protocol and stability commitment

A commitment has been provided in the DMF that the existing long term studies

will be continued and that an annual batch will be added to the programme.

4.

DRUG PRODUCT

4.1

DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT

Table 1: Qualitative composition and function of ingredients

Ingredient

Function

Reference

Standard

Core:

Ondansetron hydrochloride *

(equivalent to ondansetron)

Active ingredient

Ph Eur

Lactose monohydrate

Diluent

Ph Eur

Microcrystalline cellulose

Binder

Ph Eur

Pregelatinised starch

Disintegrant

Ph Eur

Magnesium stearate

Lubricant

Ph Eur

Film-coating (Opadry 20J22730

Yellow):

Hypromellose

Coating agent – binder

Ph Eur

Titanium dioxide

Opacifier

Ph Eur

Hydroxypropyl cellulose

Coating agent – binder

Ph Eur

Propylene glycol

Solubilizer

Ph Eur

Sorbitan Monooleate

Non-ionic surfactant

Sorbic acid

Coating preservative

Vanillin

Flavouring agent

Ph Eur

Quinoline yellow

Colouring agent

Ethanol 96%

Coating solvent

Ph Eur

Purified water

Coating solvent

Ph Eur

* dihydrate

4.2

PHARMACEUTICAL DEVELOPMENT

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4.2.1

Components of the drug product

The tablet cores and coating formulations are based on a common percentage formula.

The 8mg tablets used in the bioequivalence study were manufactured to the proposed

formula.

Excipients were selected with consideration to those included in the Greek reference

products. The function of each ingredient has been described. Levels of each

ingredient are typical for a product of this nature and have been optimised on the

basis of results from development studies. Satisfactory results of excipient-active

compatibility studies have been reported with no evidence of incompatibility seen

in the excipients selected for inclusion in the tablets. The tablets are film-coated to

protect the drug substance that is sensitive to light.

4.2.2

Formulation development

A satisfactory summary of the development of the product has been provided.

Satisfactory comparative in vitro dissolution profiles have been generated for

batches of originator products from UK, Greece, Belgium, Germany and Nordic

countries against the proposed 4mg and 8mg tablets.

4.2.3

Physicochemical and biological properties

A satisfactory summary of the physicochemical properties of the drug substance and

processing needs of the formulation has been provided.

4.2.4

Manufacturing process development

A satisfactory summary of the development and scale-up studies has been provided

that led to adoption of the direct compression process.

4.2.5

Container and closure system

Conventional PVC/Al blisters have been selected. This pack is suitable.

4.3

MANUFACTURE

4.3.1

Manufacturer(s)

A copy of the current Manufacturing Authorisation and GMP certificate has been

provided for the proposed manufacturing and assembly site.

QC testing and batch release site:

CP Pharmaceuticals Ltd, Ash Road North, Wrexham, LL13 9UF, UK.

A copy of the current manufacturing licence has been supplied.

4.3.2

Batch formula

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 9 -

Satisfactory formulae have been provided for the manufacture of a proposed

maximum batch size. This is acceptable as the biobatch (lot 11) and other batches

have been manufactured at a batch size greater than 10% of the proposed maximum

batch size.

4.3.3

Description of manufacturing process and process controls

A flow chart of the manufacturing process has been provided. The manufacturing

process is a standard direct compression method.

The maximum period for storage of the tablet cores prior to coating has been stated

together with details of the storage conditions and packaging.

4.3.4

Control of critical steps and intermediates

Critical steps have been identified and in-process controls have been proposed.

Satisfactory acceptance criteria have been established for the above tests.

4.3.5

Process validation and/or evaluation

The manufacturing process has been validated by manufacture of three batches of 4mg

tablets and three batches of 8mg tablets manufactured in December 2001 and April 2002

at the proposed commercial site. Four batches of active substance (as proposed for the

commercial products) were used. All in-process and end product test results meet the

protocol limits and finished product specification limits.

A commitment has been provided that further process validation studies will be

conducted on the first three commercial batches. Satisfactory acceptance criteria have

been provided for these studies.

4.4

CONTROL OF EXCIPIENTS

4.4.1

Specifications

All excipients used in manufacture of the tablet cores are said to comply with Ph

Eur monographs. Satisfactory specifications from the suppliers/finished product

manufacturer have been provided to demonstrate that lactose monohydrate,

pregelatinised starch, microcrystalline cellulose and ethanol 96% and purified water

are tested for compliance with relevant Ph Eur monographs. The applicant has

stated that between testing performed by the supplier and by the manufacturer of the

finished product it can be demonstrated whether a specific batch of magnesium

stearate complies with the requirements of the Ph Eur monograph. This is

acceptable.

Satisfactory supplier and finished product manufacturer specifications have been

provided for the commercial Opadry powder.

Satisfactory Certificates of Analysis have been provided.

4.4.2

Excipients of human or animal origin

MHRA PAR – Ondansetron 4mg & 8mg Tablets PL 04543/0509-10 - 10 -

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