KYTRIL

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
GRANISETRON HYDROCHLORIDE
Available from:
Atnahs Pharma UK Limited
ATC code:
A04AA02
INN (International Name):
GRANISETRON HYDROCHLORIDE
Dosage:
3 Mg/Ml
Pharmaceutical form:
Solution for Injection
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
granisetron
Authorization status:
Marketed
Authorization number:
PA1967/003/002
Authorization date:
1991-12-16

Read the complete document

IE 735-1976 APIL 28051813

start taking this medicine because it contains

important information for you.

Keep this

You may need to read it again.

If you have any further questions, ask your doctor,

nurse or pharmacist.

This medicine has been prescribed for you. Do not

pass it on to others. It may harm them, even if

their symptoms are the same as yours.

If you get any side effects, talk to your doctor, nurse

or pharmacist. This includes any possible side

effects not listed in this

See section 4.

1. What Kytril is and what it is used for

What you need to know before you are given Kytril

3. How Kytril will be given

4. Possible side effects

5. How to store Kytril

6. Contents of the pack and information

1.

What Kytril is and what it

is used for

Kytril contains the active substance granisetron.

This belongs to a group of medicines called

‘5-HT

receptor antagonists’ or ‘anti-emetics’.

Kytril is used to prevent or treat nausea and vomiting

(feeling and being sick) caused by other medical

treatments, such as chemotherapy or radiotherapy for

cancer, and by surgery.

The solution for injection is for use in adults and

children from 2 years old.

2.

What you need to know before you

are given Kytril

Do not use Kytril

if you are allergic (hypersensitive) to granisetron

or any of the other ingredients of Kytril (listed in

Section 6: Further information).

If you are not sure, talk to your doctor, nurse or

pharmacist before having the injection.

Warnings and precautions

Talk to your doctor, nurse or pharmacist before using

Kytril, especially if you:

are having problems with your bowel movements

because of a blockage of your gut (intestines)

have heart problems, are being treated for cancer

with a medicine that is known to damage your

heart or have problems with levels of salts, such

as potassium, sodium or calcium, in your body

(electrolyte abnormalities)

are taking other ‘5-HT

receptor antagonist’

medicines. These include dolasetron, ondansetron

used like Kytril in the treatment and prevention of

nausea and vomiting.

Serotonin Syndrome is an uncommon but

potentially life-threatening reaction that can occur

with granisetron (see section 4). It can cause

serious changes in how your brain, muscles, and

digestive system work. The reaction

can occur if

you take Kytril alone but

it is more likely to occur

if you take Kytril with certain other medications

(in particular

paroxetine, sertraline,

citalopram, escitalopram,

venlafaxine, duloxetine). Be sure to tell your

doctor, nurse or pharmacist all the medicines you

are taking.

Other medicines and Kytril

Please tell your doctor, nurse or pharmacist if you are

taking or have recently taken or might take any other

medicines, including medicines obtained without a

prescription. This is because Kytril can affect the way

some medicines work. Also some other medicines can

affect the way this injection works.

In particular, tell your doctor or nurse if you are

taking or might have taken any other medicines:

medicines used to treat an irregular heartbeat other

‘5-HT

receptor antagonist’ medicines such as

dolasetron or ondansetron (see “Warnings and

precautions” above)

phenobarbital, a medicine used to treat epilepsy

a medicine called ketoconazole used in the

treatment of fungal infections

the antibiotic erythromycin used to treat bacterial

infections

SSRIs (selective serotonin reuptake inhibitors)

used to treat depression and/or anxiety. Examples

paroxetine, sertraline,

citalopram, escitalopram

SNRIs (serotonin noradrenaline reuptake

inhibitors) used to treat depression and/or anxiety.

Examples are venlafaxine, duloxetine.

Pregnancy and breast-feeding

You should not have this injection if you are

pregnant, trying to get pregnant or are breast-feeding,

unless your doctor has told you to.

If you are pregnant or breast-feeding, think you may

be pregnant or are planning to have a baby, ask your

doctor, nurse or pharmacist for advice before taking

this medicine.

Driving and using machines

Kytril is not likely to affect your ability to drive or

use any tools or machines.

Kytril contains

Kytril contains sodium.

3.

How Kytril will be given

The injection

will be given to you by a doctor or

nurse. The recommended dose of Kytril varies from

one patient to another. It depends on your age,

weight, and whether you are being given the

medicine to prevent, or treat, nausea and vomiting.

The doctor will work out how much to give you.

Kytril can be given as an injection into the veins

(intravenous).

Prevention of feeling or being sick following

radio- or chemotherapy

You will be given the injection before your radio- or

chemotherapy starts. The injection into your veins

will take between 30 seconds and 5 minutes and the

dose will usually be between 1 and 3 mg. The

medicine may be diluted before it is injected.

Treatment of feeling or being sick following

radio- or chemotherapy

The injection will take between 30 seconds and

5 minutes and the dose will usually be between

1 and 3 mg. The medicine may be diluted before it is

injected into your veins. You may be given more

injections to stop your sickness after the

dose.

There will be at least 10 minutes between each

injection. The most Kytril you will be given is 9 mg a

day.

Please turn over

PACKAGE LEAFLET: INFORMATION FOR THE USER

Kytril

1 mg/1 ml

solution for injection

Kytril

3 mg/3 ml

solution for injection

Granisetron

Please turn over

Technical approval

Date:.......................

Signed:...................

‘OK for printing PDF’

Date:.......................

Signed:...................

Special instructions:

Size: 148 x 297 mm

Colour PMS

Information: Kytril 1mg/1ml & 3mg/3ml ampoules

PAGE 1 of 2

B/code:

Date:

Update:

22.05.17

11.01.18

Notes:

Laetus:

Type size: 9pt.

© 2017

Miles Gray Road, Basildon,

Essex. SS14 3FR United Kingdom

00000000

Previous ref:

Black

10183009 IE

New code 28051813

IE 735-1976 PIL

Version 12

28051813

24.01.18

25.01.18

Technical approval

Date:.......................

Signed:...................

‘OK for printing PDF’

Date:.......................

Signed:...................

Special instructions:

Size: 148 x 297 mm

Colour PMS

Information: Kytril 1mg/1ml & 3mg/3ml ampoules

PAGE 1 of 2

B/code:

Date:

Update:

22.05.17

11.01.18

Notes:

Laetus:

Type size: 9pt.

© 2017

Miles Gray Road, Basildon,

Essex. SS14 3FR United Kingdom

00000000

Previous ref:

Black

10183009 IE

New code 28051813

IE 735-1976 PIL

Version 12

IE 735-1976 APIL 28051813

Combination with steroids

The effect of the injection

may be improved by the

use of medicines called adrenocortical steroids.

The steroid will be given either as a dose between

8 and 20 mg dexamethasone before your radio- or

chemotherapy or as 250 mg methyl-prednisolone,

which will be given both before and after your

radio- or chemotherapy.

Use in children in the prevention or

treatment of feeling or being sick following

radio- or chemotherapy

Children will be given Kytril by injections into the vein

as described above with the dose depending on the

child’s weight. The injections will be diluted and be

given before radio- or chemotherapy and will take

5 minutes. Children will be given a maximum of

2 doses a day, at least 10 minutes apart.

Treatment of feeling or being sick following

surgery

The injection into your veins will take between

30 seconds and 5 minutes and the dose will usually

be 1 mg. The most Kytril you will be given is

3 mg a day.

Use in children in the prevention or treatment

of feeling or being sick following surgery

Children should not be given this injection

to treat

sickness or the feeling of sickness after surgery.

If you are given too much Kytril

Because the injection

will be given to you by a

doctor or nurse, it is unlikely that you will be given

too much. However, if you are worried talk to your

doctor or nurse. Symptoms of overdose include mild

headaches. You will be treated depending on your

symptoms.

If you have any further questions on the use of this

medicine, ask your doctor, nurse or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side

effects, although not everybody gets them. If you

notice the following problem you must see a doctor

straight away:

allergic reactions (anaphylaxis). The signs may

include swelling of the throat, face, lips and

mouth,

in breathing or swallowing.

Other side effects that may be experienced while

taking this medicine are:

Very common: affects more than 1 user in 10

headache

constipation. Your doctor will monitor your

condition.

Common: may affect up to 1 in 10 people

problems sleeping (insomnia)

changes in how your liver is working shown by

blood tests

diarrhoea.

Uncommon: may affect up to 1 in 100 people

skin rashes or an allergic skin reaction or

“nettle-rash” or “hives” (urticaria). The signs may

include red, raised itchy bumps

changes in the heartbeat (rhythm) and changes seen

on ECG readings (electrical recordings of the heart)

abnormal involuntary movements, such as

shaking, muscle rigidity and muscle contractions

Serotonin Syndrome. The signs may include

diarrhoea,

nausea,

vomiting,

high

temperature and

blood pressure, excessive sweating and rapid

heartbeat, agitation, confusion, hallucination,

shivering, muscle shakes, jerks or stiffness, loss

of coordination and restlessness.

Reporting of side effects

If you get any side effects, talk to your doctor, nurse

or pharmacist. This includes any possible side effects

not listed in this

You can also report side

effects directly (see details below). By reporting side

effects you can help provide more information on the

safety of this medicine.

HPRA Pharmacovigilance

Earlsfort Terrace

IRL-Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

5.

How to store Kytril

Keep this medicine out of the reach and sight of

children.

Do not use this medicine after the expiry date which

is stated on the carton and/or ampoule after EXP. The

expiry date refers to the last day of that month. Kytril

should be stored protected from light.

Following dilution, the diluted solution should

be stored between 2°C and 8°C and used within

24 hours of dilution.

Do not throw away any medicines via wastewater or

household waste. Ask your pharmacist how to

dispose of medicines you no longer use. These

measures will help to protect the environment.

6.

Contents of the pack and

information

What Kytril contains

The active substance is granisetron.

Each ml solution for injection contains 1 mg of

granisetron (as hydrochloride).

The other ingredients are sodium chloride, water for

injections, citric acid monohydrate, hydrochloric acid

and sodium hydroxide for pH (acidity) adjustment.

What Kytril looks like and contents of the pack

Kytril solution is a clear, colourless liquid supplied in

1 and 3 ml nominal volume colourless glass

ampoules. Each pack contains either 1 or

5 ampoules. Not all pack sizes may be marketed.

Each 1 ml Kytril solution contains 1 mg of

granisetron (as the hydrochloride).

Each 1 ml ampoule contains 1mg of granisetron

(as the hydrochloride).

Each 3 ml ampoule contains 3 mg of granisetron

(as the hydrochloride).

Preparation of dilution

For single use only. Dilute before use. The product

requires dilution prior to delivery as either injection

or infusion

Marketing Authorisation Holder and

Manufacturer

Marketing Authorisation Holder

Manufacturer

This medicinal product is authorised in

the Member States of the EEA under the

following names:

Austria, Belgium, Czech Republic, Estonia,

France, Ireland, Italy, Netherlands, Slovenia,

Spain and United Kingdom: Kytril

Germany: Kevatril

October 2017.

Other sources of information.

Detailed information on this medicine is available on

the Health Products Regulatory Agency (HPRA)

website: http://www.hpra.ie

Atnahs Pharma UK Ltd

Sovereign House, Miles Gray Road

Basildon, Essex, SS14 3FR

United Kingdom

Cenexi

52, rue M. et J. Gaucher

94120 Fontenay-sous-Bois

France

28051813

24.01.18

25.01.18

Read the complete document

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Kytril 3 mg/3 ml solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The active substance is granisetron.

Each ml solution for injection contains 1 mg of granisetron (as the hydrochloride).

Excipient with known effect: sodium

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

The solution for injection is a clear, colourless liquid.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Kytril solution for injection is indicated in adults for the prevention and treatment of

- acute nausea and vomiting associated with chemotherapy and radiotherapy.

- post-operative nausea and vomiting.

Kytril solution for injection is indicated for the prevention of delayed nausea and vomiting associated with

chemotherapy and radiotherapy.

Kytril solution for injection is indicated in children aged 2 years and above for the prevention and treatment of acute

nausea and vomiting associated with chemotherapy.

4.2 Posology and method of administration

Posology

Chemo- and radiotherapy-induced nausea and vomiting (CINV and RINV)

Prevention (acute and delayed nausea)

A dose of 1-3 mg (10-40 µg/kg)

of Kytril solution for injection should be administered either as a slow intravenous

injection or as a diluted intravenous infusion 5 minutes prior to the start of chemotherapy. The solution should be

diluted to 5ml per mg.

Treatment (acute nausea)

A dose of 1-3 mg (10-40 µg/kg)

of Kytril solution for injection should be administered either as a slow intravenous

injection or as a diluted intravenous infusion and administered over 5 minutes. The solution should be diluted to 5ml

per mg. Further maintenance doses of Kytril solution for injection may be administered at least 10 minutes apart. The

maximum dose to be administered over 24 hours should not exceed 9 mg.

Combination with adrenocortical steroid

The efficacy of parenteral granisetron may be enhanced by an additional intravenous dose of an adrenocortical steroid

e.g. by 8-20 mg dexamethasone administered before the start of the cytostatic therapy or by 250 mg methyl-

prednisolone administered prior to the start and shortly after the end of the chemotherapy.

Paediatric population

The safety and efficacy of Kytril solution for injection in children aged 2 years and above has been well established for

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the prevention and treatment (control) of acute nausea and vomiting associated with chemotherapy and the prevention

of delayed nausea and vomiting associated with chemotherapy. A dose of 10-40 µg/kg body weight (up to 3 mg) should

be administered as an i.v. infusion, diluted in 10-30 ml infusion fluid and administered over 5 minutes prior to the start

of chemotherapy. One additional dose may be administered within a 24 hour-period if required. This additional dose

should not be administered until at least 10 minutes after the initial infusion.

Post-operative nausea and vomiting (PONV)

A dose of 1 mg (10 µg/kg) of Kytril solution for injection should be administered by slow intravenous injection. The

maximum dose of Kytril to be administered over 24 hours should not exceed 3 mg.

For the prevention of PONV, administration should be completed prior to induction of anaesthesia.

Paediatric population

Currently available data are described in section 5.1, but no recommendation on a posology can be made. There is

insufficient clinical evidence to recommend administration of the solution for injection to children in prevention and

treatment of Post-operative nausea and vomiting (PONV).

Special populations

Older people and renal impairment

There are no special precautions required for its use in either elderly patients or those patients with renal impairment.

Hepatic impairment

There is no evidence to date for an increased incidence of adverse events in patients with hepatic disorders. On the

basis of its kinetics, whilst no dosage adjustment is necessary, granisetron should be used with a certain amount of

caution in this patient group (see section 5.2).

Method of administration

Administration may be as either a slow intravenous injection (over 30 seconds) or as an intravenous infusion diluted in

20 to 50 ml of compatible infusion fluid and administered over 5 minutes.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

As granisetron may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be

monitored following its administration.

As for other 5-HT

antagonists, ECG changes including QT interval prolongation have been reported with granisetron.

In patients with pre-existing arrhythmias or cardiac conduction disorders this might lead to clinical consequences.

Therefore caution should be exercised in patients with cardiac co

morbidities, on cardiotoxic chemotherapy and/or

with concomitant electrolyte abnormalities (see section 4.5).

Cross-sensitivity between 5-HT

antagonists (e.g. dolasetron, ondansetron) has been reported.

Kytril is essentially ‘sodium free’ as it contains less than 1 mmol sodium (23 mg) per dose (3 mg).

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone, but mostly in

combination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRIs), and serotonin

noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like symptoms

is advised.

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4.5 Interaction with other medicinal products and other forms of interaction

As for other 5-HT

antagonists, cases of ECG modifications including QT prolongation have been reported with

granisetron. In patients concurrently treated with medicinal products known to prolong QT interval and/or which are

arrhythmogenic, this may lead to clinical consequences (see section 4.4).

In studies in healthy subjects, no evidence of any interaction has been indicated between granisetron and

benzodiazepines (lorazepam), neuroleptics (haloperidol) or anti-ulcer medicinal products (cimetidine). Additionally,

granisetron has not shown any apparent medicinal product interaction with emetogenic cancer chemotherapies.

No specific interaction studies have been conducted in anaesthetised patients.

Serotonergic medicinal products (e.g. SSRIs and SNRIs): there have been reports of serotonin syndrome following

concomitant use of 5-HT3 antagonists and other serotonergic medicinal products (including SSRIs and SNRIs) (see

section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

There is limited amount of data from the use of granisetron in pregnant women. Animal studies do not indicate direct or

indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is

preferable to avoid the use of granisetron during pregnancy.

Breastfeeding

It is unknown whether granisetron or its metabolites are excreted in human milk. As a precautionary measure, breast-

feeding should not be advised during treatment with Kytril.

Fertility

In rats, granisetron had no harmful effects on reproductive performance or fertility.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions for Kytril are headache and constipation which may be transient. ECG

changes including QT prolongation have been reported with Kytril (see sections 4.4 and 4.5).

Tabulated summary of adverse reactions

The following table of listed adverse reactions is derived from clinical trials and post-marketing data associated with

Kytril and other 5-HT

antagonists.

Frequency categories are as follows:

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)

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*Occurred at a similar frequency in patients receiving comparator therapy

Description of selected adverse reactions

As for other 5-HT

antagonists, ECG changes including QT prolongation have been reported with granisetron (see

sections 4.4 and 4.5).

As with other 5-HT3 antagonists, cases of serotonin syndrome (including altered mental status, autonomic dysfunction

and neuromuscular abnormalities) have been reported following the concomitant use of Kytril and other serotonergic

drugs (see sections 4.4 and 4.5).

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 to HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2.

Tel: +353 1 6764971, Fax

+353 1 6762517, website: www.hpra.ie, e-mail: medsafety@hpra.ie.

Immune system disorders

Uncommon

Hypersensitivity reactions e.g. anaphylaxis,

urticaria

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Very common

Headache

Uncommon

Extrapyramidal Reactions

Uncommon

Serotonin Syndrome (see also sections 4.4

and 4.5)

Cardiac disorders

Uncommon

QT prolongation

Gastrointestinal disorders

Very common

Constipation

Common

Diarrhoea

Hepatobiliary disorders

Common

Elevated hepatic transaminases*

Skin and subcutaneous tissue disorders

Uncommon

Rash

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4.9 Overdose

There is no specific antidote for Kytril. In the case of overdose with the injection, symptomatic treatment should be

given. Doses of up to 38.5 mg of Kytril as a single injection have been reported, with symptoms of mild headache but

no other reported sequelae.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT

) antagonists.

ATC code: A04AA02

Neurological mechanisms, serotonin-mediated nausea and vomiting

Serotonin is the main neurotransmitter responsible for emesis after chemo- or radio-therapy. The 5-HT

receptors are

located in three sites: vagal nerve terminals in the gastrointestinal tract and chemoreceptor trigger zones located in the

area postrema and the nucleus tractus solidarius of the vomiting center in the brainstem. The chemoreceptor trigger

zones are located at the caudal end of the fourth ventricle (area postrema). This structure lacks an effective blood-brain

barrier, and will detect emetic agents in both the systemic circulation and the cerebrospinal fluid. The vomiting centre

is located in the brainstem medullary structures. It receives major inputs from the chemoreceptor trigger zones, and a

vagal and sympathetic input from the gut.

Following exposure to radiation or cytotoxic substances, serotonin (5-HT) is released from enterochromaffine cells in

the small intestinal mucosa, which are adjacent to the vagal afferent neurons on which 5-HT

receptors are located. The

released serotonin activates vagal neurons via the 5-HT

receptors which lead ultimately to a severe emetic response

mediated via the chemoreceptor trigger zone within the area postrema.

Mechanism of action

Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5-HT

) receptors.

Radioligand binding studies have demonstrated that granisetron has negligible affinity for other receptor types

including 5-HT and dopamine D2 binding sites.

Chemotherapy- and radiotherapy-induced nausea and vomiting

Granisetron administered intravenously has been shown to prevent nausea and vomiting associated with cancer

chemotherapy in adults and children 2 to 16 years of age.

Post-operative nausea and vomiting

Granisetron administered intravenously has been shown to be effective for prevention and treatment of post-operative

nausea and vomiting in adults.

Pharmacological properties of granisetron

Interaction with neurotropic and other active substances through its activity on P 450-cytochrome has been reported

(see section 4.5).

In vitro studies have shown that the cytochrome P450 sub-family 3A4 (involved in the metabolism of some of the main

narcotic agents) is not modified by granisetron. Although ketaconazole was shown to inhibit the ring oxidation of

granisetron in vitro, this action is not considered clinically relevant.

Although QT-prolongation has been observed with 5-HT

receptors antagonists (see section 4.4), this effect is of such

occurrence and magnitude that it does not bear clinical significance in normal subjects. Nonetheless it is advisable to

monitor both ECG and clinical abnormalities when treating patients concurrently with drugs known to prolong the QT

(see section 4.5).

Paediatric use

Clinical application of granisetron was reported by Candiotti et al. A prospective, multicentre, randomized, double-

blind, parallel-group study evaluated 157 children 2 to 16 years of age undergoing elective surgery. Total control of

postoperative nausea and vomiting during the first 2 hours after surgery was observed in most patients.

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5.2 Pharmacokinetic properties

Pharmacokinetics of the oral administration is linear up to 2.5-fold of the recommended dose in adults. It is clear from

the extensive dose-finding programme that the antiemetic efficacy is not unequivocally correlated with either

administered doses or plasma concentrations of granisetron.

A fourfold increase in the initial prophylactic dose of granisetron made no difference in terms of either the proportion

of patient responding to treatment or in the duration of symptoms control.

Distribution

Granisetron is extensively distributed, with a mean volume of distribution of approximately 3 l/kg. Plasma protein

binding is approximately 65%.

Biotransformation

Granisetron is metabolized primarily in the liver by oxidation followed by conjugation. The major compounds are 7-

OH-granisetron and its sulphate and glycuronide conjugates. Although antiemetic properties have been observed for 7-

OH-granisetron and indazoline N-desmethyl granisetron, it is unlikely that these contribute significantly to the

pharmacological activity of granisetron in man.

In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole,

suggestive of metabolism mediated by the cytochrome P-450 3A subfamily (see section 4.5).

Elimination

Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged granisetron averages 12% of dose

while that of metabolites amounts to about 47% of dose. The remainder is excreted in faeces as metabolites. Mean

plasma half-life in patients by the oral and intravenous route is approximately 9 hours, with a wide inter-subject

variability.

Pharmacokinetics in special populations

Renal failure

In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are

generally similar to those in normal subjects.

Hepatic impairment

In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose

was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage

adjustment is necessary (see section 4.2).

Older people

In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-

elderly subjects.

Paediatric population

In children, after single intravenous doses, pharmacokinetics are similar to those in adults when appropriate parameters

(volume of distribution, total plasma clearance) are normalized for body weight.

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5.3 Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated

dose toxicity, reproductive toxicity and genotoxicity. Carcinogenicity studies revealed no special hazard for humans

when used in the recommended human dose. However, when administered in higher doses and over a prolonged period

of time the risk of carcinogenicity cannot be ruled out.

A study in cloned human cardiac ion channels has shown that granisetron has the potential to affect cardiac

repolarisation via blockade of HERG potassium channels. Granisetron has been shown to block both sodium and

potassium channels, which potentially affects both depolarization and repolarization through prolongation of PR, QRS,

and QT intervals. This data helps to clarify the molecular mechanisms by which some of the ECG changes (particularly

QT and QRS prolongation) associated with this class of agents occur. However, there is no modification of the cardiac

frequency, blood pressure or the ECG trace. If changes do occur, they are generally without clinical significance.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Citric acid, monohydrate

Hydrochloric acid

Sodium hydroxide

Water for injection

6.2 Incompatibilities

Other medicinal products

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Interaction problems

This product should be diluted using glass flasks and / or polypropylene syringes.

6.3 Shelf life

3 years.

From a microbiological point of view the diluted product should be used immediately. If not used immediately, in use

storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 h

at 2°C – 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

See also section 6.6.

6.4 Special precautions for storage

Keep container in the outer carton in order to protect from light.

For storage after dilution of the medicinal product see section 6.3.

6.5 Nature and contents of container

The solution for injection is primary packed in standard colourless glass ampoules with 3 ml nominal volume.

Each pack contains either 1 or 5 ampoules. Not all pack sizes may be marketed.

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6.6 Special precautions for disposal and other handling

Disposal

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

Preparation of dilution

For single use only. Dilute before use.

The product requires dilution prior to delivery as either injection or infusion.

For adults: The appropriate dose is diluted to a total volume of 5 to 15 ml (for slow intravenous injection) or 20 to 50ml

(for intravenous infusion) in any of the following solutions: 0.9% sodium chloride B.P., 0.18% sodium chloride and 4%

dextrose B.P., 5% dextrose, Hartmann's solution 1.85%, sodium lactate and 10 % mannitol.

For children: The appropriate dose is diluted (as for adults) to a total volume of 10 to 30ml.

The admixture has been shown to be stable for at least 24 hours when stored at room temperature in the recommended

diluents.

7 MARKETING AUTHORISATION HOLDER

Atnahs Pharma UK Limited

Sovereign House

Miles Gray Road

Basildon

Essex SS14 3FR

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA1967/003/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

16 December 1991

Date of last renewal:

16 December 2006

10 DATE OF REVISION OF THE TEXT

July 2017

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