Irinotecan Koanaa 20 mg/ml concentrate for solution for infusion

Ireland - English - HPRA (Health Products Regulatory Authority)

Active ingredient:
Irinotecan hydrochloride trihydrate
Available from:
Koanaa Healthcare Limited
ATC code:
L01XX; L01XX19
INN (International Name):
Irinotecan hydrochloride trihydrate
Dosage:
20 milligram(s)/millilitre
Pharmaceutical form:
Concentrate for solution for infusion
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Other antineoplastic agents; irinotecan
Authorization status:
Not marketed
Authorization number:
PA2041/004/001
Authorization date:
2017-07-07

Read the complete document

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Package leaflet: Information for the user

Irinotecan Koanaa 20 mg/ml, concentrate for solution for infusion

Irinotecan hydrochloride trihydrate

Read all of this leaflet carefully before you start using this medicine because it contains

important information for you.

Keep this leaflet. 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, pharmacist or nurse. This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Irinotecan Koanaa is and what it is used for

What you need to know before you use Irinotecan Koanaa

How to use Irinotecan Koanaa

Possible side effects

How to store Irinotecan Koanaa

Contents of the pack and other information

1.

What Irinotecan Koanaa is and what it is used for

Your medicine is called Irinotecan Koanaa. Irinotecan Koanaa belongs to a group of

medicines called

cytostatics (anti-cancer medicines).

Irinotecan Koanaa may be used alone or in combination with a number of other medicines

used to treat cancer. These combinations may be used to treat

cancer of the large intestine

(colon or rectum)

where the disease is at an

advanced stage.

Your doctor may use a combination of Irinotecan Koanaa with

5-flurouracil/folinic acid

(5FU/FA)

bevacizumab

to treat your

cancer of the large intestine (colon or rectum).

Your doctor may use a combination of Irinotecan Koanaa with

capecitabine

with or without

bevacizumab

to treat your

cancer of the colon or rectum.

Your doctor may use a

combination of Irinotecan Koanaa with

cetuximab

to treat a particular type of

cancer of the

large intestine (KRAS wild-type)

which expresses a protein called

EGFR.

2.

What you need to know before you use Irinotecan Koanaa

Do not use Irinotecan Koanaa

if you are allergic to

irinotecan hydrochloride

or any of the other ingredients of

Irinotecan Koanaa.

if you have or have had

cronic inflammatory bowel

disease or

bowel obstruction

if you are

Pregnant

breast feeding

or if you think you might be pregnant

if you have

severe liver disease

if you have

severe bone marrow failure

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if your general health status does not allow you to carry out general activities of daily

living

if you are taking

St Johns’ Wort

(a herbal suplement)

Take special care with Irinotecan Koanaa

Before treatment with Irinotecan Koanaa tell your doctor if any of the following apply to you:

You have

liver problems

jaundice

You have

Kidney problems

You have

asthma

You have ever received

radiation therapy

You experienced

severe diarrhoea

fever

after being treated with Irinotecan Koanaa

before.

You have

heart problems

smoke,

have

high blood pressure

high cholesterol

as these can increase the risk

of heart problems during treatment with Irinotecan Koanaa

You have had or are due to have any

vaccinations

You are taking any other medicines. Please see the section below “

Taking other

medicines”

As with all anti-cancer medicines the use of Irinotecan Koanaa is associated with a number of

side-effects with may be serious. These side-effects require special management to minimise

the risk of complications.

You will be treated by a specialist team experienced in using these kinds of treatments and

managing their side effects, which are usually temporary. However, it is essential that you

read the section “

POSSIBLE SIDE EFFECTS”

and follow the instructions carefully if you

get any of the symptoms described.

Taking other medicines:

Please tell your doctor if your taking or have recently taken any other medicines, including

medicines obtained with out a prescription.

If you received irinotecan koanaa in combination with either capecitabine, cetuximab or

bevacizumad, please make sure that you also read patient inforamtion laeflet for each

medicine.

Some medicines, when taken at the same time as Irinotecan Koanaa, may effect the way

Irinotecan Koanaa works or Irinotecan Koanaa may effect the way they work. Tell your

doctor if you are taking any of the following medicines:

St. John’s Wort (a herbal supplement)

Ketoconazole (an antibiotic)

Rifampicin (an antibiotic)

Carbamazepine (used to treat seizures)

Phenobarbital (used to treat seizures)

Warfarin (an anticoagulant used to thin the blood)

Atazanavir (used to treat HIV)

Ciclosporin or Tacrolimus (used to dampen down your body’s immune system)

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If you go into hospital to have an operation, tell the anaesthetist and the medical staff that you

are being treated with Irinotecan Koanaa and any other medicines your taking

Pregnancy and breast-feeding

You must

not use Irinotecan Koanaa if you are pregnant as it may harm your unborn

baby.

You should also

avoid becoming pregnant while you are being treated with Irinotecan

Koanaa,

Men and women should use adequate contraception while being treated with Irinotecan

Koanaa and for:

Up to 1 month after you receive your last dose of Irinotecan Koanaa if your female

Up to 3 months after your last dose of Irinotecan Koanaa if you are male.

If you do become pregnant while being treated with Irinotecan Koanaa you must inform your

doctor

IMMEDIATELY

Because Irinotecan Koanaa may be harmful to nursing infants, women

must not breast-feed

while being treated with

Irinotecan Koanaa.

Driving and Using Machines

Irinotecan Koanaa may make you feel dizzy or cause visual disturbances. If this happens to

do not drive or operate machinery

until this resolves.

Important information about some of the ingredientd of Irinotecan Koanaa

Warning:

This medicine contains sorbital, a type of sugar. If you have been told by your doctor that you

have an intolerance to some sugars tell your doctor or nurse before you are given Irinotecan

Koanaa

3.

How to use Irinotecan Koanaa

If you are prescribed Irinotecan Koanaa it will only be given to you by doctors or nurses

experienced in giving chemotherapy.

Method of administration:

Irinotecan Koanaa will be given as an infusion into your veins

over a period of 30 to 90 minutes.

If you receive Irinotecan Koanaa in combination with

cetuximab,

Irinotecan Koanaa must not

be administered earlier than 1 hour after the end of the

cetuximab

infusion.

Dosage and frequency of administration:

The amount of Irinotecan Koanaa you are given will depend on your age, size and general

medical condition. It will also depend on any other treatment you may have received for your

cancer.

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Your doctor will calculate your body surface area in square metres (m

If you have previously been treated with 5-fluorouracil you will normally be treated

with Irinotecan Koanaa alone starting with a dose of 350 mg/m

2

every three weeks.

If you have not had previous chemotherapy you will normally receive 180 mg/ m

2

Irinotecan Koanaa every two weeks. This will be followed by folinic acid and 5-

fluorouracil.

These dosages may be adjusted by your doctor depending on your condition and any side-

effects you may have.

Duration of treatment:

The number of infusions that you receive will depend on how you are responding to

treatment. Your doctor will discuss this with you.

Blood Monitoring

Whilst you are taking Irinotecan Koanaa and/or other similar medicines you will have regular

blood tests to monitor your treatment and to ensure that there are no untoward adverse effects.

4.

Possible side effects

Medicines like Irinotecan koanaa will cause side effects. Your doctor will discuss these side-

effects with you and explain the risks and benefits of your treatment.

Some of these side effects must be treated

IMMEDIATELY

Please read the following instructions carefully and follow them if you have any of the

side-effects listed.

Diarrhoea

Irinotecan Koanaa may cause you to have diarrhoea. There are two types of diarrhoea, which

can be distinguished when they start. “Early” diarrhoea starts less than 24 hours after the

infusion and “delayed” diarrhoea starts more than 24 hours after infusionIf you have

ANY

DIARRHOEA

it is

IMPORTANT

that you follow these instructions carefully.

Early diarrhoea

If your diarrhoea starts less than 24 hours after the infusion

(“early diarrhoea”) you

should contact your doctor or nurse

IMMEDIATELY

and they will give you a suitable

treatment.

This “early diarrhoea” may be accompanied by other symptoms such as

sweating

chills

abdominal cramps

watering eyes

stuffy nose

visual disturbance

dizziness

low blood pressure

feeling unwell

feeling weak

excessive mouth watering

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pupils of the eye get smaller

Tell your doctor or nurse about all symptoms.

Do not use any anti-diarrhoeal treatment that your doctor has given you for “delayed

diarrhoea”.

Delayed diarrhoea

If your diarrhoea starts more than 24 hours

after infusion (“delayed diarrhoea”)

you

should IMMEDIATELY

take any anti-diarrhoeal treatment that the doctor has

given you, EXACTLY as he has told you. If you are unsure of what it is, ask your

doctor or nurse

Drink large amounts of rehydration fluids

, IMMEDIATELY

(i.e. water, soda water, fizzy

drinks, soup or oral rehydration therapy).

You must tell your doctor if

you have nausea and vomiting as well as diarrhoea

you have any fever as well as the diarrhoea

you still have diarrhoea 48 hours after starting the diarrhoea treatment

Do not take any treatment for diarrhoea other than that given to you by your doctor or

nurse and only drink the fluids described above.

Decrease in white blood cells

Irinotecan Koanaa may cause a decrease in the number of some of your white blood cells,

which play an important role in fighting infections. This is called

neutropenia.

Your doctor

will probably arrange for you have regular blood tests to monitor these white blood cells.

If you have any fever this may be an indication of infection associated with

neutropenia

and requires immediate treatment.

If you have any

fever

and particularly if you also have

diarrhoea

, contact your doctor or

nurse

IMMEDIATELY

so that they can give you necessary treatment.

Nausea and vomiting

If you have nausea and/or vomiting contact your doctor or nurse

IMMEDIATELY

Breathing difficulties

If you have breathing difficulties contact your doctor or nurse

IMMEDIATELY.

Other side effects

All medicines can cause allergic reactions. If you experience any of the following conditions

please report it to a doctor or nurse

IMMEDIATELY

wheeziness

difficult in breathing

swelling

rash or itching (especially affecting the whole body)

dehydration

kidney problems

low blood pressure

heart problems

blockage or perforation (a ‘hole’) in the bowel

bleeding from the bowel

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inflammation in the bowel

inflammation of the pancreas

severe stomach pain

passing black or blood stained stools

vomiting blood

changes in laboratory tests

If you receive Irinotecan Koanaa in combination with

cetuximab

, some of the side effects

you may experience can also be related to this combination. Such side effects may include

a

acne-like rash.

Therefore, please make sure that you also read the package leaflet for

cetuximab

If you receive Irinotecan Koanaa in combination with

capecitabine

, some of the side effects

you may experience can also be related to this combination. Such side effects may include:

very common blood clots, common allergic reactions, heart attack and fever in patients with a

low white blood cell count. Therefore, please make sure that you also read the package leaflet

capecitabine

If you receive Irinotecan Koanaa in combination with

capecitabine

bevacizumab

, some

of the side effects you may experience can also be related to this combination. Such side

effects include: low white blood cell count, blood clots, high blood pressure and heart attack.

Therefore, please make sure that you also read the package leaflet for

capecitabine

bevacizumab

Other side effects which may occur when you are treated with Irinotecan Koanaa are

:

hair loss

fatigue

loss of appetite

mild allergic skin reactions

mild stomach pains

muscular cramps and twitches

pins and needles

constipation

inflammation at the injection site

mouth ulcers

temporary speech disorders

high blood pressure

If any of the side effects get serious, or if you notice any side effects not listed in this

leaflet, please tell your doctor or nurse immediately.

Reporting of side effects

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist immediately. You can also report side effects directly

via:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

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Website: www.hpra.ie

e-mail: medsafety@hpra.ie

By reporting side effects you can help provide more information on the safety of this

medicine.

5.

How to store Irinotecan Koanaa

Keep out of the reach and sight of children.

For single use only.

Do not use this medicinal product after the expiry date which is stated on the carton and on

the glass after EXP. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

After dilution

Chemical and physical in-use stability has been demonstrated for 24 hours at 5ºC and 25ºC in

LDPE containers. From a microbiological point of view, unless the method of dilutes

precludes the risk of microbiological contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

6. Contents of the pack and other information

What Irinotecan Koanaa contains

The active substance is

irinotecan hydrochloride

trihydrate.

One ml of concentrate contains 20 mg irinotecan hydrochloride trihydrate equivalent to

17.33 mg of irinotecan.

One 2ml vial contains 40 mg irinotecan hydrochloride trihydrate.

One 5ml vial contains 100 mg irinotecan hydrochloride trihydrate.

One 15ml vial contains 300 mg irinotecan hydrochloride trihydrate.

One 25ml vial contains 500 mg irinotecan hydrochloride trihydrate.

The other ingredients are sorbitol, lactic acid, sodium hydroxide, hydrochloric acid and

water for injections.

What Irinotecan Koanaa looks like and contents of the pack

Irinotecan Koanaa is a pale yellow color clear aqueous solution, free from visible particles.

pH 3.0 to 3.8.

40 mg/2 ml:

Type I flint amber colored glass vial, with a rubber stopper (bromo butyl omniflex plus coated

rubber stopper) and sealed with an aluminium flip-off Dark blue colour seals.

100 mg/5 ml:

Type I flint amber colored glass vial, with a rubber stopper (bromo butyl omniflex plus coated

rubber stopper) and sealed with an aluminium flip-off Light blue colour seals.

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300 mg/15 ml:

Type I flint amber colored glass vial, with a rubber stopper (bromo butyl omniflex plus coated

rubber stopper) and sealed with an aluminium flip-off Dark blue colour seals.

500 mg/25 ml:

Type I amber colored glass vial, with a rubber stopper (bromo butyl omniflex plus coated

rubber stopper) and sealed with an aluminium flip-off Dark blue colour seals.

Pack sizes:

40 mg/2 ml: 1 vial, 5 vials, 10 vials

100 mg/5 ml: 1 vial, 5 vials, 10 vials

300 mg/15 ml: 1 vial

500 mg/25 ml: 1 vial

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Koanaa Healthcare Limited

4th Floor Cavendish House, 369 Burnt Oak,

Broadway, Edgware

Middlesex HA85AW

United Kingdom

Manufacturer

Wave Pharma Limited

4th Floor Cavendish House, 369 Burnt Oak,

Broadway, Edgware

Middlesex HA85AW

United Kingdom

and/or

Drehm Pharma GmbH

Hietzinger Hauptstraße 37/2

1130 Vienna, Austria

This medicinal product is authorised in the Member States of the EEA under the

following names:

Austria

Irinotecan Koanaa 20 mg/ml Konzentrat zur Herstellung einer

Infusionslösung

Germany

Irinotecan Koanaa 20 mg/ml Konzentrat zur Herstellung einer

Infusionslösung

France

Irinotecan Koanaa 20 mg/ml solution à diluer pour perfusion

Ireland

Irinotecan Koanaa 20 mg/ml concentrate for solution for infusion

Malta

Irinotecan Koanaa 20 mg/ml concentrate for solution for infusion

Netherlands

Irinotecan HCl-3-water Koanaa 20 mg/ml concentraat voor oplossing

voor infusie

Romania

Irinotecan Koanaa 20 mg/ml concentrat pentru soluţie perfuzabilă

United Kingdom

Irinotecan hydrochloride 20 mg/ml concentrate for solution for infusion

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This leaflet was last revised in09/2019.

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The following information is intended for medical or healthcare professionals only:

Instructions for use

Cytotoxic

Handling of Irinotecan Koanaa

As with all antineoplastic agents, caution should be exercised when handling Irinotecan

Koanaa. Dilution should be carried out under aseptic conditions by trained personnel in a

designated area. Precautions should be taken to avoid contact with the skin and mucous

membranes.

Protection instructions for preparation of Irinotecan Koanaa solution for infusion

Protective chamber should be used and protective gloves as well as protective gown

should be worn. If there is no protective chamber available mouth cover and goggles

should be used.

Opened containers, like injection vials and infusion bottles and used cannulae, syringes,

catheters, tubes, and residuals of cytostatics should be considered as hazardous waste and

undergo disposal according to local guidelines for the handling of HAZARDOUS

WASTE.

Follow the instructions below in case of spillage:

protective clothing should be worn

broken glass should be collected and placed in the container for HAZARDOUS

WASTE

contaminated surfaces should be flushed properly with copious amounts of cold water

the flushed surfaces should then be wiped thoroughly and the materials used for

wiping should be disposed as HAZARDOUS WASTE

In the event of Irinotecan Koanaa contact with the skin, the area should be rinsed with

plenty of running water and then washed with soap and water. In case of contact with

mucous membranes, wash the contacted area thoroughly with water. If you have any

discomfort, contact a doctor.

In case of contact of Irinotecan Koanaa with eyes, wash them thoroughly with plenty of

water. Contact an ophthalmologist immediately.

Preparation of infusion solution

Irinotecan Koanaa concentrate for solution for infusion is intended for intravenous infusion

only after diluting prior to administration in the recommended diluents, either 0.9 % Sodium

chloride solution for infusion or 5% glucose solution for infusion. Aseptically withdraw the

required amount of Irinotecan Koanaa concentrate for solution from the vial with a calibrated

syringe and inject into a 250 ml infusion bag or bottle. The infusion should be thoroughly

mixed by manual rotation.

If any precipitate is observed in the vials or after reconstitution, the product should be

discarded according to standard procedures for cytotoxic agents.

Read the package leaflet for the shelf life of the diluted product.

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Irinotecan Koanaa should

not

be delivered as an intravenous bolus or an intravenous infusion

shorter than 30 minutes or longer than 90 minutes.

Disposal

items

used

preparation,

administration

otherwise

coming

into

contact

with

irinotecan should undergo disposal according to local guidelines for the handling of cytotoxic

compounds.

Read the complete document

Health Products Regulatory Authority

16 March 2020

CRN009DY8

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Irinotecan Koanaa 20 mg/ml concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml of concentrate contains 20 mg irinotecan hydrochloride trihydrate equivalent to 17.33 mg irinotecan.

Each vial of 2ml contains 40 mg of irinotecan hydrochloride trihydrate.

Each vial of 5ml contains 100 mg of irinotecan hydrochloride trihydrate.

Each vial of 15ml contains 300 mg of irinotecan hydrochloride trihydrate.

Excipients with known effect: Also includes sorbitol (45 mg/ml) and sodium (less than 1 mmol sodium (23 mg) per dose, i.e.

essentially ‘sodium- free’).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion

Pale yellow color clear aqueous solution, free from visible particles. pH 3.0 to 3.8.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Irinotecan is indicated for the treatment of patients with advanced colorectal cancer.

- in combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease,

- as a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.

Irinotecan in combination with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor

(EGFR)-expressing, KRAS wild-type metastatic colorectal cancer, who had not received prior treatment for metastatic disease or

after failure of irinotecan-including cytotoxic therapy (please see 5.1).

Irinotecan in combination with 5-fluorouracil, folinic acid and bevacizumab is indicated for first-line treatment of patients with

metastatic carcinoma of the colon or rectum.

Irinotecan in combination with capecitabine with or without bevacizumab is indicated for first-line treatment of patients with

metastatic colorectal carcinoma.

4.2 Posology and method of administration

For adults only. Irinotecan solution for infusion should be infused into a peripheral or central vein.

Recommended dosage

In monotherapy (for previously treated patient): The recommended dosage of Irinotecan is 350 mg/m² administered as an

intravenous infusion over a 30-to 90- minute period every three weeks (see section 6.6 and section 4.4).

In combination therapy (for previously untreated patient):Safety and efficacy of irinotecan in combination with

5-fluorouracil (5FU) and folinic acid (FA) have been assessed with the following schedule (see section 5.1):

Irinotecan plus 5FU/FA in every 2 weeks schedule

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The recommended dose of Irinotecan is 180 mg/m² administered once every 2 weeks as an intravenous infusion over a 30- to

90- minute period, followed by infusion with folinic acid and 5-fluorouracil.

For the posology and method of administration of concomitant Cetuximab, refer to the product information for this medicinal

product.

Normally, the same dose of Irinotecan is used as administered in the last cycles of the prior Irinotecan-containing regimen.

Irinotecan must not be administered earlier than 1 hour after the end of the Cetuximab infusion.

For the posology and method of administration of bevacizumab, refer to the bevacizumab summary of product characteristics.

For the posology and method of administration of capecitabine combination, please see section 5.1 and refer to the

appropriate sections in the capecitabine summary of product characteristics.

Dosage adjustments

Irinotecan should be administered after appropriate recovery of all adverse events to grade 0 or 1 NCI-CTC grading (National

Cancer Institute Common Toxicity Criteria) and when treatment-related diarrhoea is fully resolved.

At the start of a subsequent infusion of therapy, the dose of irinotecan, and 5FU when applicable, should be decreased

according to the worst grade of adverse events observed in the prior infusion. Treatment should be delayed by 1 to 2 weeks to

allow recovery from treatment-related adverse events.

With the following adverse events a dose reduction of 15 to 20 % should be applied for irinotecan and/or 5FU when applicable:

haematological toxicity (neutropenia grade 4, febrile neutropenia (neutropenia grade 3-4 and fever grade 2-4),

thrombocytopenia and leukopenia (grade 4)),

non haematological toxicity (grade 3-4).

Recommendations for dose modifications of cetuximab when administered in combination with irinotecan must be followed

according to the product information for this medicinal product.

In combination with capecitabine for patients 65 years of age or more, a reduction of the starting dose of capecitabine to 800

mg/m² twice daily is recommended according to the summary of product characteristics for capecitabine. Refer also to the

recommendations for dose modifications in combination regimen given in the summary of product characteristics for

capecitabine.

Treatment Duration:

Treatment with irinotecan should be continued until there is an objective progression of the disease or an unacceptable toxicity.

Special populations

Patients with impaired hepatic function: In monotherapy: Blood bilirubin levels (up to 3 times the upper limit of the normal

range (ULN) in patients with performance status ≤ 2, should determine the starting dose of irinotecan. In these patients with

hyperbilirubinemia and prothrombin time greater than 50%, the clearance of irinotecan is decreased (see section 5.2) and

therefore the risk of hematotoxicity is increased. Thus, weekly monitoring of complete blood counts should be conducted in

this patient population.

- In patients with bilirubin up to 1.5 times the ULN, the recommended dosage of irinotecan is 350 mg/m²,

- In patients with bilirubin ranging from 1.5 to 3 times the ULN, the recommended dosage of irinotecan is 200 mg/m²,

- Patients with bilirubin beyond 3 times the ULN should not be treated with irinotecan (see section 4.3 and section 4.4).

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No data are available in patients with hepatic impairment treated with irinotecan in combination.

Patients with impaired renal function:Irinotecan is not recommended for use in patients with impaired renal function, as studies

in this population have not been conducted. (See section 4.4 and section 5.2).

Elderly: No specific pharmacokinetic studies have been performed in elderly. However, the dose should be chosen carefully in

this population due to their greater frequency of decreased biological functions. This population should require more intense

surveillance (see section 4.4).

Method of administration:

The concentrate should be diluted before administration.

For instructions for dilution of the concentrate before administering the product, see section 6.6

4.3 Contraindications

-Chronic inflammatory bowel disease and/or bowel obstruction (see section 4.4).

-History of severe hypersensitivity to irinotecan hydrochloride trihydrate or to one of the excipients of Irinotecan Hydrochloride

Injection.

- Lactation (see section 4.6 and section 4.4).

- Bilirubin >3 times the upper limit of the normal range (see section 4.4).

- Severe bone marrow failure.

- WHO performance status > 2.

- Concomitant use with St John's Wort (see section 4.5).

For additional contraindications of cetuximab or bevacizumab or capecitabine, refer to the product information for these

medicinal products.

4.4 Special warnings and precautions for use

The use of irinotecan should be confined to units specialised in the administration of cytotoxic chemotherapy and it should

only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy.

Given the nature and incidence of adverse events, irinotecan will only be prescribed in the following cases after the expected

benefits have been weighted against the possible therapeutic risks:

- in patients presenting a risk factor, particularly those with a WHO performance status = 2.

- in the few rare instances where patients are deemed unlikely to observe recommendations regarding management of

adverse events (need for immediate and prolonged antidiarrhoeal treatment combined with high fluid intake at onset of

delayed diarrhoea). Strict hospital supervision is recommended for such patients.

When irinotecan is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, the

weekly-dosage schedule (see section 5.1) may be considered in patients who may need a closer follow-up or who are at

particular risk of severe neutropenia.

Delayed diarrhoea

Patients should be made aware of the risk of delayed diarrhoea occurring more than 24 hours after the administration of

irinotecan and at any time before the next cycle. In monotherapy, the median time of onset of the first liquid stool was on day

5 after the infusion of irinotecan. Patients should quickly inform their physician of its occurrence and start appropriate therapy

immediately.

Patients with an increased risk of diarrhoea are those who had a previous abdominal/pelvic radiotherapy, those with baseline

hyperleucocytosis, those with performance status ≥2 and women. If not properly treated, diarrhoea can be life-threatening,

especially if the patient is concomitantly neutropenic.

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As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and

an appropriate antidiarrhoeal therapy must be initiated immediately. This antidiarrhoeal treatment will be prescribed by the

department where irinotecan has been administered. After discharge from the hospital, the patients should obtain the

prescribed drugs so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their physician or the

department administering irinotecan when/if diarrhoea is occurring.

The currently recommended antidiarrhoeal treatment consists of high doses of loperamide (4mg for the first intake and then 2

mg every 2 hours). This therapy should continue for 12 hours after the last liquid stool and should not be modified. In no

instance should loperamide be administered for more than 48 consecutive hours at these doses, because of the risk of paralytic

ileus, nor for less than 12 hours.

In addition to the anti-diarrhoeal treatment, a prophylactic broad spectrum antibiotic should be given, when diarrhoea is

associated with severe neutropenia (neutrophil count < 500 cells/mm³).

In addition to the antibiotic treatment, hospitalisation is recommended for management of the diarrhoea, in the following

cases:

- Diarrhoea associated with fever,

- Severe diarrhoea (requiring intravenous hydration),

- Diarrhoea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.

Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea at previous cycles.

In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles (see section 4.2).

Haematology

In clinical studies, the frequency of NCI CTC grade 3 and 4 neutropenia has been significantly higher in patients who received

previous pelvic/abdominal irradiation than in those who had not received such irradiation. Patients with baseline serum total

bilirubin levels of 1.0 mg/dL or more have also had a significantly greater likelihood of experiencing first-cycle grade 3 or 4

neutropenia than those with bilirubin levels that were less than 1.0 mg/dL.

Weekly monitoring of complete blood cell counts is recommended during treatment with irinotecan. Patients should be aware

of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature >38°C and neutrophil count ≤1,000

cells/mm³) should be urgently treated in the hospital with broad-spectrum intravenous antibiotics.

In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration

(see section 4.2).

There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea. In patients with severe

diarrhoea, complete blood cell counts should be performed.

Liver impairment

Liver function tests should be performed at baseline and before each cycle.

Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging from 1.5 to 3 times ULN,

due to decrease of the clearance of irinotecan (see section 5.2) and thus increasing the risk of hematotoxicity in this population.

for patients with a bilirubin > 3 times ULN (see section 4.3).

Nausea and vomiting

A prophylactic treatment with antiemetics is recommended before each treatment with irinotecan. Nausea and vomiting have

been frequently reported. Patients with vomiting associated with delayed diarrhoea should be hospitalised as soon as possible

for treatment.

Acute cholinergic syndrome

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If acute cholinergic syndrome appears (defined as early diarrhoea and various other signs and symptoms such as sweating,

abdominal cramping, myosis and salivation), atropine sulphate ( 0.25 mg subcutaneously) should be administered unless

clinically contraindicated (see section 4.8).

These symptoms may be observed during or shortly after infusion of irinotecan, are thought to be related to the

anticholinesterase activity of the irinotecan parent compound, and are expected to occur more frequently with higher

irinotecan doses.

Caution should be exercised in patients with asthma. In patients who experienced an acute and severe cholinergic syndrome,

the use of prophylactic atropine sulphate is recommended with subsequent doses of irinotecan.

Respiratory disorders

Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Interstitial

pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include

the use of pneumotoxic drugs, radiation therapy and colony stimulating factors. Patients with risk factors should be closely

monitored for respiratory symptoms before and during irinotecan therapy.

Extravasation

While irinotecan is not a known vesicant, care should be taken to avoid extravasation and the infusion site should be

monitored for signs of inflammation. Should extravasation occur, flushing the site and application of ice is recommended.

Elderly

Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection

with irinotecan should be cautious in this population (see section 4.2).

Chronic inflammatory bowel disease and/or bowel obstruction

Patients must not be treated with irinotecan until resolution of the bowel obstruction (see section 4.3).

Renal function

Increases in serum creatinine or blood urea nitrogen have been observed. There have been cases of acute renal failure.

These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting, or

diarrhoea. Rare instances of renal dysfunction due to tumour lysis syndrome have also been reported.

Irradiation therapy

Patients who have previously received pelvic/abdominal irradiation are at increased risk of myelosuppression following the

administration of irinotecan. Physicians should use caution in treating patients with extensive prior irradiation (e.g.>25% of

bone marrow irradiated and within 6 weeks prior to start of treatment with irinotecan). Dosing adjustment may apply to this

population (see section 4.2).

Cardiac disorders

Myocardial ischaemic events have been observed following irinotecan therapy predominately in patients with underlying

cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy (see section 4.8).

Consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimize all

modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Vascular disorders

Irinotecan has been rarely associated with thromboembolic events (pulmonary embolism, venous thrombosis, and arterial

thromboembolism) in patients presenting with multiple risk factors in addition to the underlying neoplasm.

Immunosuppressant effects/increased susceptibility to infections

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Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including

irinotecan may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving

irinotecan. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Others

Since this medicinal contains sorbitol, it is unsuitable in hereditary fructose intolerance.

Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced

episodes of dehydration associated with diarrhoea and/or vomiting, or sepsis.

Contraceptive measures must be taken during and for at least three months after cessation of therapy.

Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine,

phenobarbital, phenytoin, St John's Wort) of CYP3A4 may alter the metabolism of irinotecan and should be avoided (see

section 4.5).

4.5 Interaction with other medicinal products and other forms of interactions

Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Since irinotecan has anticholinesterase

activity, drugs with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the

neuromuscular blockade of non-depolarising drugs may be antagonised.

Several studies have shown that concomitant administration of CYP3A-inducing anticonvulsant drugs (e.g., carbamazepine,

phenobarbital or phenytoin) leads to reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced

pharmacodynamic effects. The effects of such anticonvulsant drugs were reflected by a decrease in AUC of SN-38 and SN-38G

by 50% or more. In addition to induction of cytochrome P450 3A enzymes, enhanced glucuronidation and enhanced biliary

excretion may play a role in reducing exposure to irinotecan and its metabolites.

A study has shown that the co-administration of ketoconazole resulted in a decrease in the AUC of APC of 87% and in an

increase in the AUC of SN-38 of 109% in comparison to irinotecan given alone.

Caution should be exercised in patients concurrently taking drugs known to inhibit (e.g., ketoconazole) or induce (e.g.,

rifampicin, carbamazepine, phenobarbital or phenytoin) drug metabolism by cytochrome P450 3A4. Concurrent administration

of irinotecan with an inhibitor/inducer of this metabolic pathway may alter the metabolism of irinotecan and should be

avoided (see section 4.4).

In a small pharmacokinetic study (n=5), in which irinotecan 350 mg/m

was co-administered with St. John's Wort (Hypericum

perforatum) 900 mg, a 42% decrease in the active metabolite of irinotecan, SN-38, plasma concentrations was observed.

St. John's Wort decreases SN-38 plasma levels. As a result, St. John's Wort should not be administered with irinotecan (see

section 4.3).

Coadministration of 5-fluorouracil/folinic acid in the combination regimen does not change the pharmacokinetics of irinotecan.

Atazanavir sulphate.

Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor, has the potential to increase systemic exposure to

SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs.

Interactions common to all cytotoxic:

The use of anticoagulants is common due to increased risk of thrombotic events in tumoral diseases.

If vitamin K antagonist anticoagulants are indicated, an increased frequency in the monitoring of INR (International Normalised

Ratio) is required due to their narrow therapeutic index, the high intra-individual variability of blood thrombogenicity and the

possibility of interaction between oral anticoagulants and anticancer chemotherapy.

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Concomitant use contraindicated

- Yellow fever vaccine: risk of fatal generalised reaction to vaccines

Concomitant use not recommended

- Live attenuated vaccines (except yellow fever): risk of systemic, possible fatal disease (e.g. infections). This risk is increased in

subjects who are already immunosuppressed by their underlying disease.

Use an inactivated vaccine where this exists (poliomyelitis)

- Phenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic

drug or risk of toxicity enhancement due to increased hepatic metabolism by phenytoin.

Concomitant use to take into consideration

- Ciclosporine, Tacrolimus: Excessive immunosuppression with risk of lymphoproliferation

There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa.

Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the

pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not preclude any increase of toxicities due

to their pharmacological properties.

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential/Contraception in males and females

Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after

treatment respectively.

Pregnancy

There is no data from the use of irinotecan in pregnant women. Irinotecan has been shown to be embryotoxic and teratogenic

in animals. Therefore, based on results from animal studies and the mechanism of action of irinotecan, Irinotecan should not be

used during pregnancy unless clearly necessary.

Breast-feeding

In lactating rats, 14 C-irinotecan was detected in milk. It is not known whether Irinotecan is excreted in human milk.

Consequently, because of the potential for adverse reactions in nursing infants, breast-feeding should be discontinued for the

duration of irinotecan therapy (see section 4.3).

Fertility

There are no human data on the effect of irinotecan on fertility. In animals adverse effects of irinotecan on the fertility of

offspring has been documented (see section 5.3).

4.7 Effects on ability to drive and use machines

Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following

the administration of irinotecan, and advised not to drive or operate machinery if these symptoms occur.

4.8 Undesirable effects

CLINICAL STUDIES

Adverse reaction data have been extensively collected from studies in metastatic colorectal cancer; the frequencies are

presented below. The adverse reactions for other indications are expected to be similar to those for colorectal cancer.

The most common (≥1/10), dose-limiting adverse reactions of irinotecan are delayed diarrhoea (occurring more than 24 hours

after administration) and blood disorders including neutropenia, anaemia and thrombocytopenia.

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Neutropenia is a dose-limiting toxic effect. Neutropenia was reversible and not cumulative; the median day to nadir was 8 days

whatever the use in monotherapy or in combination therapy.

Very commonly severe transient acute cholinergic syndrome was observed.

The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, sweating, myosis

and increased salivation occurring during or within the first 24 hours after the infusion of Irinotecan. These symptoms

disappear after atropine administration (see section 4.4).

MONOTHERAPY

The following adverse reactions considered to be possibly or probably related to the administration of Irinotecan have been

reported from 765 patients at the recommended dose of 350 mg/m

in monotherapy. Within each frequency grouping,

adverse reactions are presented in order of decreasing seriousness. 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), and very rare (<1/10,000).

AdverseReactionsReportedwithIrinotecaninMonotherapy(350mg/m

2

every3weeksschedule)

MedDRASystemOrganClass

FrequencyCategory

PreferredTerm

Infectionsandinfestations

Common

Infection

Bloodandlymphaticsystemdisorders

Verycommon

Neutropenia

Verycommon

Anaemia

Common

Thrombocytopenia

Common

Febrileneutropenia

Metabolismandnutritiondisorders

Verycommon

Decreasedappetite

Nervoussystemdisorders

Verycommon

Cholinergicsyndrome

Gastrointestinaldisorders

Verycommon

Diarrhoea

Verycommon

Vomiting

Verycommon

Nausea

Verycommon

Abdominalpain

Common

Constipation

Skinandsubcutaneoustissuedisorders

Verycommon

Alopecia(reversible)

Generaldisordersandadministrationsiteconditions

Verycommon

Mucosalinflammation

Verycommon

Pyrexia

Verycommon

Asthenia

Investigations

Common

Bloodcreatinineincreased

Common

Transaminases(SGPTandSGOT)increased

Common

Bilirubinincreased

Common

Bloodalkalinephosphataseincreased

Description of selected adverse reactions (monotherapy)

Severe diarrhoea was observed in 20% of patients who follow recommendations for the management of diarrhoea. Of the

evaluable cycles, 14% have severe diarrhoea. The median time of onset of the first liquid stool was on day 5 after the infusion

of Irinotecan.

Nausea and vomiting were severe in approximately 10% of patients treated with antiemetics.

Constipation has been observed in less than 10% of patients.

Neutropenia was observed in 78.7% of patients and was severe (neutrophil count < 500 cells/mm

) in 22.6% of patients. Of

the evaluable cycles, 18 % had a neutrophil count below 1,000 cells/mm3 including 7.6% with a neutrophil count < 500

cells/mm

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Total recovery was usually reached by day 22.

Fever with severe neutropenia was reported in 6.2% of patients and in 1.7% of cycles.

Infectious episodes occurred in about 10.3% of patients (2.5% of cycles) and were associated with severe neutropenia in about

5.3% of patients (1.1% of cycles), and resulted in death in 2 cases.

Anaemia was reported in about 58.7% of patients (8% with haemoglobin < 8 g/dl and 0.9% with haemoglobin < 6.5 g/dl).

Thrombocytopenia (< 100,000 cells/mm

) was observed in 7.4 % of patients and 1.8% of cycles with 0.9% with platelets count

≤ 50,000 cells/mm

and 0.2% of cycles.

Nearly all the patients showed a recovery by day 22.

Acute cholinergic syndrome

Severe transient acute cholinergic syndrome was observed in 9 % of patients treated in monotherapy.

Asthenia was severe in less than 10 % of patients treated in monotherapy. The causal relationship to Irinotecan has not been

clearly established.

Fever in the absence of infection and without concomitant severe neutropenia, occurred in 12% patients treated in

monotherapy

Laboratory tests

Transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatase or bilirubin were

observed in 9.2 %, 8.1 % and 1.8 % of the patients, respectively, in the absence of progressive liver metastasis.

Transient and mild to moderate increases of serum levels of creatinine have been observed in 7.3 % of the patients.

COMBINATION THERAPY

Adverse reactions detailed in this section refer to irinotecan.

There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa. In combination with

cetuximab, additional reported adverse reactions were those expected with cetuximab (such as acneform rash 88%). For

information on adverse reactions on irinotecan in combination with cetuximab, also refer to their respective summary of

product characteristics.

Adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan in addition to those seen

with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Very

common, all grade adverse drug reactions: thrombosis/embolism; Common, all grade adverse drug reactions: hypersensitivity

reaction, cardiac ischemia/infarction; Common, grade 3 and grade 4 adverse drug reactions: febrile neutropenia. For complete

information on adverse reactions of capecitabine, refer to the capecitabine summary product of characteristics.

Grade 3 and Grade 4 adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan and

bevacizumab in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to

capecitabine monotherapy include: Common, grade 3 and grade 4 adverse drug reactions: neutropenia, thrombosis/embolism,

hypertension, and cardiac ischemia/infarction. For complete information on adverse reactions of capecitabine and

bevacizumab, refer to the respective capecitabine and bevacizumab summary of product characteristics.

Grade 3 hypertension was the principal significant risk involved with the addition of bevacizumab to bolus Irinotecan /5-FU/FA.

In addition, there was a small increase in the grade 3/4 chemotherapy adverse events of diarrhoea and leukopenia with this

regimen compared to patients receiving bolus Irinotecan /5-FU/FA alone. For other information on adverse reactions in

combination with bevacizumab, refer to the bevacizumab summary of product characteristics.

Irinotecan has been studied in combination with 5-FU and FA for metastatic colorectal cancer.

Safety data of adverse reactions from clinical studies demonstrate very commonly observed NCI Grade 3 or 4 possibly or

probably-related adverse events in the blood and the lymphatic system disorders, gastrointestinal disorders, and skin and

subcutaneous tissue disorders MedDRA System Organ Classes.

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The following adverse reactions considered to be possibly or probably related to the administration of Irinotecan have been

reported from 145 patients treated by Irinotecan in combination therapy with 5FU/FA in every 2 weeks schedule at the

recommended dose of 180 mg/m

AdverseReactionsReportedwithIrinotecaninCombinationTherapy(180mg/m

2

every2weeksschedule)

MedDRASystemOrganClass

FrequencyCategory

PreferredTerm

Infectionsandinfestations

Common

Infection

Bloodandlymphaticsystemdisorders

Verycommon

Thrombocytopenia

Verycommon

Neutropenia

Verycommon

Anaemia

Common

Febrileneutropenia

Metabolismandnutritiondisorders

Verycommon

Decreasedappetite

Nervoussystemdisorders

Verycommon

Cholinergicsyndrome

Gastrointestinaldisorders

Verycommon

Diarrhoea

Verycommon

Vomiting

Verycommon

Nausea

Common

Abdominalpain

Common

Constipation

Skinandsubcutaneoustissuedisorders

Verycommon

Alopecia(reversible)

Generaldisordersandadministrationsiteconditions

Verycommon

Mucosalinflammation

Verycommon

Asthenia

Common

Pyrexia

Investigations

Verycommon

Transaminases(SGPTandSGOT)increased

Verycommon

Bilirubinincreased

Verycommon

Bloodalkalinephosphataseincreased

Description of selected adverse reactions (combination therapy)

Severe diarrhoea was observed in 13.1 % of patients who follow recommendations for the management of diarrhoea. Of the

evaluable cycles, 3.9 % have a severe diarrhoea.

A lower incidence of severe nausea and vomiting was observed (2.1 % and 2.8 % of patients respectively).

Constipation relative to Irinotecan and/or loperamide has been observed in 3.4 % of patients.

Neutropenia was observed in 82.5% of patients and was severe (neutrophil count < 500 cells/mm

) in 9.8% of patients. Of the

evaluable cycles, 67.3% had a neutrophil count below 1,000 cells/mm

including 2.7% with a neutrophil count <500 cells/mm

Total recovery was usually reached within 7-8 days.

Fever with severe neutropenia was reported in 3.4% of patients and in 0.9% of cycles.

Infectious episodes occurred in about 2% of patients (0.5% of cycles) and were associated with severe neutropenia in about

2.1% of patients (0.5% of cycles), and resulted in death in 1 case.

Anaemia was reported in 97.2% of patients (2.1% with haemoglobin < 8 g/dl).

Thrombocytopenia (< 100,000 cells/mm

) was observed in 32.6% of patients and 21.8% of cycles. No severe

thrombocytopenia (< 50,000 cells/mm

) has been observed.

Acute cholinergic syndrome

Severe transient acute cholinergic syndrome was observed in 1.4 % of patients treated in combination therapy.

Asthenia was severe in 6.2 % of patients treated in combination therapy. The causal relationship to Irinotecan has not been

clearly established.

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Fever in the absence of infection and without concomitant severe neutropenia, occurred in 6.2 % of patients treated in

combination therapy.

Laboratory tests

Transient serum levels (grades 1 and 2) of either SGPT, SGOT, alkaline phosphatase or bilirubin were observed in 15%, 11%,

11% and 10% of the patients, respectively, in the absence of progressive liver metastasis. Transient grade 3 were observed in

0%, 0%, 0% and 1% of the patients, respectively. No grade 4 was observed.

Increases of amylase and/or lipase have been very rarely reported.

Rare cases of hypokalemia and hyponatremia mostly related with diarrhea and vomiting have been reported.

OTHER ADVERSE EVENTS REPORTED IN CLINICAL STUDIES WITH THE WEEKLY REGIMEN FOR IRINOTECAN

The following additional drug-related events have been reported in clinical studies with irinotecan: pain, sepsis, rectal disorder,

GI monilia, hypomagnesemia, rash, cutaneous signs, abnormal gait, confusion, headache, syncope, flushing, bradycardia,

urinary tract infection, breast pain, increased GGTP, extravasation, and tumour lysis syndrome, cardiovascular disorders (angina

pectoris, heart arrest, myocardial infarction, myocardial ischaemia, peripheral vascular disorder, vascular disorder), and

thromboembolic events (arterial thrombosis, cerebral infarction, cerebrovascular accident, deep thrombophlebitis, embolus of

the lower extremity, pulmonary embolus, thrombophlebitis, thrombosis, and sudden death). (See section 4.4.)

POST-MARKETING SURVEILLANCE

Frequencies from post-marketing surveillance are not known (cannot be estimated from available data).

MedDRASystemOrganClass

PreferredTerm

Infectionsandinfestations

Pseudomembranous colitis one of which has been documented

bacteriologically (Clostridium difficile)

Sepsis

Bloodandlymphaticsystemd

isorders

Peripheralthrombocytopeniawithantiplateletantibodies

Metabolismandnutritiondisorders

Dehydration(duetodiarrhoeaandvomiting)

Hypovolaemia

Immunesystemdisorders

Hypersensitivityreaction

Anaphylacticreaction

Nervoussystemdisorders

Speechdisordersgenerallytransientinnature,insomecases,theeventwas

attributedtothecholinergicsyndromeobservedduringorshortlyafterinfusionofiri

notecan

Paraesthesia

Cardiacdisorders

Hypertension(duringorafterinfusion)

Cardiocirculatoryfailure*

Respiratory,thoracicand

mediastinaldisorders

Interstitialpulmonarydiseasepresentingaspulmonaryinfiltratesisuncommon

duringirinotecantherapy;Earlyeffectssuchasdyspnoea have been reported (See

section 4.4).

Dyspnoea (see section 4.4)

Hiccups

Gastrointestinal disorders

Intestinal obstruction

Ileus: cases of ileus without preceding colitis have also been reported

Megacolon

Gastrointestinal haemorrhage

Colitis; In some cases, colitis was complicated by ulceration, bleeding, ileus, or

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infection.

Typhlitis

Ischemic colitis

Ulcerative colitis

Gastrointestinal bleeding

Symptomatic or asymptomatic elevated pancreatic enzymes

Intestinal perforation

Skin and subcutaneous tissue

disorders

Skin reactions

General disorders and

administration site conditions

Infusion site reactions

Investigations

Blood amylase increased

Lipase increased

Hypokalaemia

Hyponatraemia mostly related with diarrhoea and vomiting

Increases in serum levels of transaminases (i.e., AST and ALT) in the absence

of progressive liver metastasis have been very rarely reported.

Musculoskeletal and connective

tissue

disorders

Muscular contraction or cramps

Renal and urinary disorders

Renal impairment and acute renal failure generally in patients who become

infected and/or volume depleted from severe gastrointestinal toxicities.*

Renal insufficiency*

Vascular Disorders

Hypotension*

* Infrequent cases of renal insufficiency, hypotension or cardio circulatory failure have been observed in patients who

experienced episodes of dehydration associated with diarrhoea and/or vomiting, or sepsis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected

adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be

fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhoea. There is no known

antidote for irinotecan. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat

any infectious complications.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents, ATC Code: L01XX19

Experimental data

Irinotecan is a semi-synthetic derivative of camptothecin. It is an antineoplastic agent which acts as a specific inhibitor of DNA

topoisomerase I. It is metabolised by carboxylesterase in most tissues to SN-38, which was found to be more active than

irinotecan in purified topoisomerase I and more cytotoxic than irinotecan against several murine and human tumour cell lines.

The inhibition of DNA topoisomerase I by irinotecan or SN-38 induces single-strand DNA lesions which blocks the DNA

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replication fork and are responsible for the cytotoxicity. This cytotoxic activity was found time-dependent and was specific to

the S phase.

In vitro, irinotecan and SN-38 were not found to be significantly recognised by the P-glycoprotein MDR, and displays cytotoxic

activities against doxorubicin and vinblastine resistant cell lines.

Furthermore, irinotecan has a broad antitumor activity in vivoagainst murine tumour models (P03 pancreatic ductal

adenocarcinoma, MA16/C mammary adenocarcinoma, C38 and C51 colon adenocarcinomas) and against human xenografts

(Co-4 colon adenocarcinoma, Mx-1 mammary adenocarcinoma, ST-15 and SC-16 gastric adenocarcinomas). Irinotecan is also

active against tumors expressing the P-glycoprotein MDR (vincristine- and doxorubicin-resistant P388 leukaemia's).

Beside the antitumor activity of irinotecan, the most relevant pharmacological effect is the inhibition of acetylcholinesterase.

Clinical data:

In combination therapy for the first-line treatment of metastatic colorectal carcinoma

In combination therapy with Folinic Acid and 5-Fluorouracil

A phase III study was performed in 385 previously untreated metastatic colorectal cancer patients treated with either every 2

weeks schedule (see section 4.2) or weekly schedule regimens. In the every 2 weeks schedule, on day 1, the administration of

irinotecan at 180 mg/m² once every 2 weeks is followed by infusion with folinic acid (200 mg/m² over a 2-hour intravenous

infusion) and 5-fluorouracil (400 mg/m² as an intravenous bolus, followed by 600 mg/m² over a 22-hour intravenous infusion).

On day 2, folinic acid and 5-fluorouracil are administered at the same doses and schedules. In the weekly schedule, the

administration of irinotecan at 80 mg/m² is followed by infusion with folinic acid (500 mg/m² over a 2-hour intravenous

infusion) and then by 5-fluorouracil (2300 mg/m² over a 24-hour intravenous infusion) over 6 weeks.

In the combination therapy trial with the 2 regimens described above, the efficacy of irinotecan was evaluated in 198 treated

patients:

Combined regimens

(n=198)

Weekly schedule

(n=50)

Every 2 weeks

schedule (n=148)

IRINOTECAN

+5FU/FA

5FU/FA

IRINOTECAN

+5FU/FA

5FU/FA

IRINOTECAN

+5FU/FA

5FU/FA

Response rate (%)

40.8 *

23.1 *

51.2 *

28.6 *

37.5 *

21.6 *

p value

p<0.001

p=0.045

p=0.005

Median time to progression(months)

p value

p<0.001

p=0.001

Median duration of response (months)

p value

p=0.043

Median duration of response and stabilisation

(months)

p value

p<0.001

p=0.003

Median time to treatment failure (months)

p value

p=0.0014

p<0.001

Median survival (months)

16.8

14.0

19.2

14.1

15.6

13.0

p value

p=0.028

p=0.041

5FU : 5-fluorouracil

FA : folinic acid

NS : Non Significant

*: As per protocol population analysis

In the weekly schedule, the incidence of severe diarrhoea was 44.4% in patients treated by irinotecan in combination with

5FU/FA and 25.6% in patients treated by 5FU/FA alone. The incidence of severe neutropenia (neutrophil count < 500

cells/mm

) was 5.8% in patients treated by irinotecan in combination with 5FU/FA and in 2.4% in patients treated by 5FU/FA

alone.

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Additionally, median time to definitive performance status deterioration was significantly longer in irinotecan combination

group than in 5FU/FA alone group (p=0.046).

Quality of life was assessed in this phase III study using the EORTC QLQ-C30 questionnaire. Time to definitive deterioration

constantly occurred later in the irinotecan groups. The evolution of the Global Health Status/Quality of life was slightly better in

irinotecan combination group although not significant, showing that efficacy of irinotecan in combination could be reached

without affecting the quality of life.

In combination therapy with bevazicumab

A phase III randomised, double-blind, active-controlled clinical trial evaluated bevacizumab in combination with

IRINOTECAN/5FU/FA as first-line treatment for metastatic carcinoma of the colon or rectum (Study AVF2107g). The addition of

bevacizumab to the combination of IRINOTECAN/5FU/FA resulted in a statistically significant increase in overall survival. The

clinical benefit, as measured by overall survival, was seen in all pre-specified patient subgroups, including those defined by age,

sex, performance status, location of primary tumour, number of organs involved, and duration of metastatic disease. Refer also

to the bevacizumab summary of product characteristics. The efficacy results of Study AVF2107g are summarized in the table

below.

AVF2107g

Arm1

IRINOTECAN/5FU/FA +Placebo

Arm2

IRINOTECAN/5FU/FA +Avastin

NumberofPatients

Overallsurvival

Mediantime(months)

15.6

20.3

95%ConfidenceInterval

14.29–16.99

18.46–24.18

Hazard ratio

0.660

p-value

0.00004

Progression-freesurvival

Mediantime(months)

10.6

Hazardratio

0.54

p-value

<0.0001

Overallresponserate

Rate(%)

34.8

44.8

95%CI

30.2–39.6

39.9–49.8

p-value

0.0036

Durationofresponse

Mediantime(months)

10.4

25–75percentile(months)

4.7–11.8

6.7–15.0

5 mg/kg every 2 weeks.

Relative to control arm.

In combination therapy with cetuximab

EMR 62 202-013: This randomised study in patients with metastatic colorectal cancer who had not received prior treatment for

metastatic disease compared the combination of cetuximab and irinotecan plus infusional 5-fluorouracil/folinic acid (5-FU/FA)

(599 patients) to the same chemotherapy alone (599 patients). The proportion of patients with KRAS wild-type tumours from

the patient population evaluable for KRAS status comprised 64%.

The efficacy data generated in this study are summarised in the table below:

Overallpopulation

KRASwild-typepopul

ation

Variable/statistic

Ce

tu

xi

m

ab

+FOL

F

FOLFIRI (N=599)

Ce

tu

xi

m

ab+

FOL

F

FOLFIRI (N=176)

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IRI

(N=

5

99)

IRI

(N=

1

72)

ORR

%(95%CI)

46.9

(42.

51.0)

38.7

(34.8,42.8)

59.3

(51.

6, 6

6.7)

43.2

(35.8,50.9)

p-value

0.0038

0.0025

PFS

HazardRatio(95% CI)

0.85(0.726,0.998)

0.68(0.501,0.934)

p-value

0.0479

0.0167

CI = confidence interval, FOLFIRI = irinotecan plus infusional 5-FU/FA, ORR = objective response rate (patients with complete

response or partial response), PFS = progression-free survival time

In combination therapy with capecitabine

Data from a randomised, controlled phase III study (CAIRO) support the use of capecitabine at a starting dose of 1000 mg/m²

for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of patients with metastatic colorectal

cancer. 820 patients were randomized to receive either sequential treatment (n=410) or combination treatment (n=410).

Sequential treatment consisted of first-line treatment with capecitabine (1250 mg/m² twice daily for 14 days), second-line

irinotecan (350 mg/m² on day 1), and third-line combination of capecitabine (1000 mg/m² twice daily for 14 days) with

oxaliplatin (130 mg/m² on day 1). Combination treatment consisted of first-line treatment of capecitabine (1000 mg/m² twice

daily for 14 days) combined with irinotecan (250 mg /m² on day 1) (XELIRI) and second-line capecitabine (1000 mg/m² twice

daily for 14 days) plus oxaliplatin (130 mg/m² on day 1). All treatment cycles were administered at intervals of 3 weeks. In

first-line treatment the median progression-free survival in the intent-to-treat population was 5.8 months (95%CI, 5.1 -6.2

months) for capecitabine monotherapy and 7.8 months (95%CI, 7.0-8.3 months) for XELIRI (p=0.0002).

Data from an interim analysis of a multicentre, randomised, controlled phase II study (AIO KRK 0604) support the use of

capecitabine at a starting dose of 800 mg/m² for 2 weeks every 3 weeks in combination with irinotecan and bevacizumab for

the first-line treatment of patients with metastatic colorectal cancer. 115 patients were randomised to treatment with

capecitabine combined with irinotecan (XELIRI) and bevacizumab: capecitabine (800 mg/m² twice daily for two weeks followed

by a 7-day rest period), irinotecan (200 mg/m² as a 30 minute infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg

as a 30 to 90 minute infusion on day 1 every 3 weeks); a total of 118 patients were randomised to treatment with capecitabine

combined with oxaliplatin plus bevacizumab: capecitabine (1000 mg/m² twice daily for two weeks followed by a 7-day rest

period), oxaliplatin (130 mg/m² as a 2 hour infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute

infusion on day 1 every 3 weeks). Progression-free survival at 6 months in the intent-to-treat population was 80% (XELIRI plus

bevacizumab) versus 74 % (XELOX plus bevacizumab). Overall response rate (complete response plus partial response) was

45% (XELOX plus bevacizumab) versus 47 % (XELIRI plus bevacizumab).

In monotherapy for the second-line treatment of metastatic colorectal carcinoma

Clinical phase II/III studies were performed in more than 980 patients in the every 3 week dosage schedule with metastatic

colorectal cancer who failed a previous 5-FU regimen. The efficacy of irinotecan was evaluated in 765 patients with

documented progression on 5-FU at study entry.

PhasesIII

Irinotecanversussupportivecare

Irinotecanversus5FU

Irinotecann=183

supportivecare n=90

pvalues

Irinotecann=127

n=129

pvalues

ProgressionFree Survival

at6months(%)

33.5*

26.7

p=0.03

Survival at 12months (%)

36.2*

13.8

p=0.0001

44.8*

32.4

p=0.0351

Median survival (months)

9.2*

p=0.0001

10.8*

p=0.0351

NA: Not Applicable

*: Statistically significant difference

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In phase II studies, performed on 455 patients in the every 3-week dosage schedule, the progression free survival at 6 months

was 30 % and the median survival was 9 months. The median time to progression was 18 weeks.

Additionally, non-comparative phase II studies were performed in 304 patients treated with a weekly schedule regimen, at a

dose of 125 mg/m² administered as an intravenous infusion over 90 minutes for 4 consecutive weeks followed by 2 weeks rest.

In these studies, the median time to progression was 17 weeks and median survival was 10 months. A similar safety profile has

been observed in the weekly-dosage schedule in 193 patients at the starting dose of 125 mg/m², compared to the every

3-week-dosage schedule. The median time of onset of the first liquid stool was on day 11.

In combination with cetuximab after failure of irinotecan-including cytotoxic therapy

The efficacy of the combination of cetuximab with irinotecan was investigated in two clinical studies. A total of 356 patients

with EGFR-expressing metastatic colorectal cancer who had recently failed irinotecan-including cytotoxic therapy and who had

a minimum Karnofsky performance status of 60, but the majority of whom had a Karnofsky performance status of ≥80 received

the combination treatment.

EMR 62 202-007: This randomised study compared the combination of cetuximab and irinotecan (218 patients) with cetuximab

monotherapy (111 patients).

IMCL CP02-9923: This single arm open-label study investigated the combination therapy in 138 patients.

The efficacy data from these studies are summarised in the table below:

Study

PFS (months)

OS (months)

n (%)

95% CI

n (%)

95% CI

Median

95% CI

Median

95% CI

Cetuximab + Irinotecan

EMR 62 202- 007

(22.9)

17.5,

29.1

(55.5)

48.6,

62.2

2.8,

7.6, 9.6

IMCLCP02-

9923

(15.2)

9.7,

22.3

(60.9)

52.2,

69.1

2.6,

7.2,

10.3

Cetuximab

EMR 62 202-007

(10.8)

5.7, 18.1

(32.4)

23.9, 42.0

1.4, 2.0

5.6, 9.1

CI= confidence interval, DCR= disease control rate (patients with complete response, partial response, or stable disease for at

least 6 weeks), ORR= objective response rate (patients with complete response or partial response), OS= overall survival time,

PFS= progression-free survival

The efficacy of the combination of cetuximab with irinotecan was superior to that of cetuximab monotherapy, in terms of

objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). In the randomised trial, no effects

on overall survival were demonstrated (hazard ratio 0.91, p=0.48).

Pharmacokinetic/Pharmacodynamic data

The intensity of the major toxicities encountered with irinotecan (e.g., leukoneutropenia and diarrhoea) are related to the

exposure (AUC) to parent drug and metabolite SN-38. Significant correlations were observed between haematological toxicity

(decrease in white blood cells and neutrophils at nadir) or diarrhoea intensity and both irinotecan and metabolite SN-38 AUC

values in monotherapy.

Patients with Reduced UGT1A1 Activity:

Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) is involved in the metabolic deactivation of SN-38, the active

metabolite of irinotecan to inactive SN-38 glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in variable

metabolic capacities among individuals. One specific variation of the UGT1A1 gene includes a polymorphism in the promoter

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region known as the UGT1A1*28 variant. This variant and other congenital deficiencies in UGT1A1 expression (such as

Crigler-Najjar and Gilbert's syndrome) are associated with reduced activity of this enzyme. Data from a meta analysis indicate

that individuals with Crigler-Najjar syndrome (types 1 and 2) or those who are homozygous for the UGT1A1*28 allele (Gilbert's

syndrome) are at increased risk of haematological toxicity (grades 3 and 4) following administration of irinotecan at moderate

or high doses (>150 mg/m2). A relationship between UGT1A1 genotype and the occurrence of irinotecan induced diarrhea was

not established.

Patients known to be homozygous for UGT1A1*28 should be administered the normally indicated irinotecan starting dose.

However, these patients should be monitored for haematologic toxicities. A reduced irinotecan starting dose should be

considered for patients who have experienced prior haematologic toxicity with previous treatment. The exact reduction in

starting dose in this patient population has not been established and any subsequent dose modifications should be based on a

patient's tolerance of the treatment. (see sections 4.2 and 4.4).

There is at present insufficient data to conclude on clinical utility of UGT1A1 genotyping.

5.2 Pharmacokinetic properties

In a phase I study in 60 patients with a dosage regimen of a 30-minute intravenous infusion of 100 to 750 mg/m² every three

weeks, irinotecan showed a biphasic or triphasic elimination profile. The mean plasma clearance was 15 L/h/m² and the volume

of distribution at steady state (Vss): 157 L/m². The mean plasma half-life of the first phase of the triphasic model was 12

minutes, of the second phase 2.5 hours, and the terminal phase half-life was 14.2 hours. SN-38 showed a biphasic elimination

profile with a mean terminal elimination half-life of 13.8 hours. At the end of the infusion, at the recommended dose of 350

mg/m², the mean peak plasma concentrations of irinotecan and SN-38 were 7.7 μg/ml and 56 ng/ml, respectively, and the

mean area under the curve (AUC) values were 34μg.h/ml and 451 ng.h/ml, respectively. A large inter-individual variability in

pharmacokinetic parameters is generally observed for SN-38.

A population pharmacokinetic analysis of irinotecan has been performed in 148 patients with metastatic colorectal cancer,

treated with various schedules and at different doses in phase II trials. Pharmacokinetic parameters estimated with a three

compartment model were similar to those observed in phase I studies. All studies have shown that irinotecan (CPT-11) and

SN-38 exposure increase proportionally with CPT-11 administered dose; their pharmacokinetics are independent of the

number of previous cycles and of the administration schedule.

In vitro, plasma protein binding for irinotecan and SN-38 was approximately 65 % and 95 % respectively.

Mass balance and metabolism studies with 14 C-labelled drug have shown that more than 50% of an intravenously

administered dose of irinotecan is excreted as unchanged drug, with 33% in the faeces mainly via the bile and 22% in urine.

Two metabolic pathways account each for at least 12% of the dose:

Hydrolysis by carboxylesterase into active metabolite SN-38. SN-38 is mainly eliminated by glucuronidation, and

further by biliary and renal excretion (less than 0.5% of the irinotecan dose). The SN-38 glucuronite is subsequently

probably hydrolysed in the intestine.

Cytochrome P450 3A enzymes-dependent oxidations resulting in opening of the outer piperidine ring with

formation of APC (aminopentanoic acid derivate) and NPC (primary amine derivate) (see section 4.5).

Unchanged irinotecan is the major entity in plasma, followed by APC, SN-38 glucuronide and SN-38. Only SN-38 has significant

cytotoxic activity.

Irinotecan clearance is decreased by about 40% in patients with bilirubinemia between 1.5 and 3 times the ULN. In these

patients a 200 mg/m² irinotecan dose leads to plasma drug exposure comparable to that observed at 350 mg/m² in cancer

patients with normal liver parameters.

5.3 Preclinical safety data

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Irinotecan and SN-38 have been shown to be mutagenic in vitro in the chromosomal aberration test on CHO-cells as well as in

the in vivo micronucleus test in mice. However, they have been shown to be devoid of any mutagenic potential in the Ames

test.

In rats treated once a week during 13 weeks at the maximum dose of 150 mg/m² (which is less than half the human

recommended dose), no treatment related tumours were reported 91 weeks after the end of treatment.

Single- and repeated-dose toxicity studies with irinotecan have been carried out in mice, rats and dogs. The main toxic effects

were seen in the haematopoietic and lymphatic systems. In dogs, delayed diarrhoea associated with atrophy and focal necrosis

of the intestinal mucosa was reported. Alopecia was also observed in the dog. The severity of these effects was dose-related

and reversible.

Reproduction

Irinotecan was teratogenic in rats and rabbits at doses below the human therapeutic dose. In rats, pups born to treated animals

with external abnormalities showed a decrease in fertility. This was not seen in morphologically normal pups. In pregnant rats

there was a decrease in placental weight and in the offspring a decrease in fetal viability and increase in behavioural

abnormalities.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sorbitol (E420)

Lactic Acid (E270)

Sodium Hydroxide (E524) (for pH adjustment)

Hydrochloric acid (E507)(for pH adjustment)

Water for injections

6.2 Incompatibilities

This medicinal is not to be mixed with other medicinal products, except those mentioned in section 6.6.

6.3 Shelf life

Unopened vials: 2 years.

After dilution

Chemical and physical stability after dilution of the concentrate has been demonstrated for 28 days, when stored in LDPE or

PVC containers between 5°C and 30°C, protected from light. If stored not protected from light, physico-chemical stability has

been demonstrated for up to 3 days at room temperature.

From a microbiological point of view, the product should be used immediately. If not used immediately, storage times and

conditions after first opening and dilution are the responsibility of the user and would normally not be longer than 24 hours at

25°C, unless opening and dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

40 mg/2 ml:

Type I flint amber colored glass vial, with a rubber stopper (bromo butyl omniflex plus coated rubber stopper) and sealed with

an aluminium flip-off Dark blue colour seals.

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100 mg/5 ml:

Type I flint amber colored glass vial, with a rubber stopper (bromo butyl omniflex plus coated rubber stopper) and sealed with

an aluminium flip-off Light blue colour seals.

300 mg/15 ml:

Type I flint amber colored glass vial, with a rubber stopper (bromo butyl omniflex plus coated rubber stopper) and sealed with

an aluminium flip-off Dark blue colour seals.

Pack sizes:

40 mg/2 ml: 1 vial, 5 vials, 10 vials

100 mg/5 ml: 1 vial, 5 vials, 10 vials

300 mg/15 ml: 1 vial

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

As with other antineoplastic agents, Irinotecan Koanaa must be prepared and handled with caution. The use of glasses,

mask and gloves is required.

If Irinotecan Koanaa solution or infusion solution should come into contact with the skin, wash immediately and

thoroughly with soap and water. If Irinotecan Koanaa solution or infusion solution should come into contact with the

mucous membranes, wash immediately with water.

Preparation for the intravenous infusion administration:

As with any other injectable medicinal products, the Irinotecan Koanaa solution must be prepared aseptically (see

section 6.3).

If any precipitate is observed in the vials or after dilution, the product should be discarded according to standard

procedures for cytotoxic agents.

Aseptically withdraw the required amount of Irinotecan Koanaa solution from the vial with a calibrated syringe and

inject into a 250 ml infusion bag or bottle containing either 0.9% sodium chloride solution or 5% glucose solution. The

infusion should then be thoroughly mixed by manual rotation.

Disposal

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

7 MARKETING AUTHORISATION HOLDER

Koanaa Healthcare Limited

4th Floor Cavendish House

369 Burnt Oak

Broadway

Edgware

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HA85AW

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA2041/004/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 7

July 2017

10 DATE OF REVISION OF THE TEXT

March 2020

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