Irinotecan EGIS 20 mg/ml concentrate for solution for infusion Irinotecan hydrochloride trihydrate

The name of the product is Irinotecan EGIS 20 mg/ml concentrate for solution for infusion and will be referred to as Irinotecan EGIS solution throughout this document.

Read all of this leaflet carefully before you start using this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, ask your doctor.

•    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 any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

In this leaflet:

1.    What Irinotecan EGIS solution is and what it is used for

2.    Before you are given Irinotecan EGIS solution

3.    How Irinotecan EGIS solution will be given to you

4.    Possible side effects

5.    How to store Irinotecan EGIS solution

6.    Further information

1. WHAT IRINOTECAN EGIS SOLUTION IS AND WHAT IT IS USED FOR

Irinotecan EGIS solution belongs to a group of medicines called cytostatics (anticancer medicines).

It is used for the treatment of advanced cancer of the colon and rectum in adults, either alone or in combination with other medicines.

Your doctor may use Irinotecan EGIS together with:

•    5-fluorouracil/folinic acid (5-FU/FA) and bevacizumab to treat cancer of the colon or rectum.

•    cetuximab to treat cancer of the large intestine that has epidermal growth factor receptors.

•    capecitabine with or without bevacizumab to treat cancer of the colon or rectum.

2. BEFORE YOU ARE GIVEN IRINOTECAN EGIS SOLUTION

You should not be given Irinotecan EGIS solution if any of the following apply to you:

Tell your doctor or hospital pharmacist if

•    you are allergic (hypersensitive) to irinotecan hydrochloride trihydrate or to any of the ingredients of Irinotecan EGIS solution (see list of ingredients in section 6 Further Information)

•    you have any other bowel disease or a history of bowel obstruction

•    you are pregnant or breast-feeding or if you think you might be pregnant

•    you have any liver problems

•    you have a problem with your bone marrow

•    you have been told by your doctor that you have an intolerance to some sugars, as this medicine contains sorbitol (E420)

•    you are taking St John’s Wort, a herbal remedy used for depression and sleep disorders

•    you are in a poor general health

Tell your doctor before you are treated with Irinotecan EGIS if you have any kidney problems.

If your doctor tells you that you will also be receiving cetuximab or bevacizumab or capecitabine with your Irinotecan EGIS please make sure you also read the patient information leaflet for cetuximab or bevacizumab or capecitabine.

Take special care with Irinotecan EGIS solution

This medicine is intended for adults only. Check with your doctor if this medicine has been prescribed for use in a child.

Special care is also needed for elderly patients.

As Irinotecan EGIS solution is an anti-cancer medicine it will be administered to you in a special unit and under the supervision of a doctor qualified in the use of anticancer medicines. The unit’s personnel will explain to you what you need to take special care of during and after the treatment. This leaflet may help you to remember that.

1. The first 24 hours after administration of Irinotecan EGIS solution

During administration of Irinotecan EGIS solution (30 - 90 min) and within 24 hours after administration you may experience some of the following symptoms: diarrhoea, abdominal pain, red, sore, itching or weeping eyes (conjunctivitis), running nose (rhinitis), low blood pressure, widening of the blood vessels, sweating, chills, a feeling of general discomfort and illness, dizziness, visual disturbance, pupil contraction, watering eyes and excessive mouth-watering. The medical term for these symptoms is acute cholinergic syndrome which can be treated (with atropine). If you have any of these symptoms immediately tell your doctor who will give you any treatment necessary.

1. From the day after treatment with Irinotecan EGIS solution until the next treatment

During this period you may experience various symptoms, which may be serious and require immediate treatment and close supervision.

Diarrhoea

If your diarrhoea starts more than 24 hours after administration of Irinotecan EGIS solution (“delayed diarrhoea”) it may be serious. It is often seen about 5 days after administration. The diarrhoea should be treated immediately and kept under close supervision. Immediately after the first liquid stools do the following:

1.    Immediately inform your doctor who is supervising the treatment and tell him/her about the diarrhoea. If you are not able to reach the doctor, contact the unit at the hospital supervising the Irinotecan EGIS solution treatment. It is very important that they are aware of the diarrhoea.

2.    Take any anti-diarrhoeal treatment that the doctor has given you exactly as he/she has told you. The treatment may not be changed without consulting the doctor. Recommended anti-diarrhoeal treatment is loperamide (4 mg for the first intake and then 2 mg every 2 hours, also during the night). This should be continued for at least 12 hours after the last liquid stools. The recommended dosage of loperamide may not be taken for more than 48 hours.

3. Drink large amounts of water and rehydration fluids immediately (such as water, soda

water, fizzy drinks, soup or oral rehydration therapy).

You must immediately tell the doctor, or the unit supervising the treatment, if:

•    you have nausea, vomiting or any fever as well as diarrhoea

•    you still have diarrhoea 48 hours after starting the diarrhoea treatment.

Note: Do not take any treatment for diarrhoea other than that given to you by your doctor and the fluids described above. Follow the doctor’s instructions. The anti-diarrhoeal treatment should not be used to prevent a further episode of diarrhoea, even if you have experienced delayed diarrhoea at previous cycles.

Fever

If the body temperature increases over 38°C it may be a sign of infection, especially if you also have diarrhoea. If you have any fever (over 38°C) contact your doctor or the unit immediately so that they can give you any treatment necessary.

Nausea and vomiting

If you have nausea and/or vomiting contact your doctor or the unit immediately. Neutropenia

Irinotecan EGIS solution 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. Neutropenia is often seen during treatment with irinotecan and is reversible. Your doctor should arrange for you to have regular blood tests to monitor these white blood cells. Neutropenia is serious and should be treated immediately and carefully monitored.

If you have any fever this may be an indication of infection associated with this neutropenia and requires immediate treatment.

Breathing Difficulties

If you have any breathing difficulties contact your doctor immediately.

Impaired Liver Function

Before treatment with Irinotecan EGIS solution is started and before every following treatment cycle the liver function should be monitored (by blood tests).

If you have one or more of the symptoms mentioned, after you have returned home from the hospital, you should immediately contact the doctor or the unit supervising the Irinotecan EGIS solution treatment.

Impaired Kidney Function

As this medicine has not been tested in patients with kidney problems, please check with your doctor if you have any kidney problems.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is also valid for herbal medicines, strong vitamins and minerals.

Some medicines may alter the effects of Irinotecan EGIS solution, for example, ketoconazole (for the treatment of fungal infections), rifampicin (for the treatment of tuberculosis) and some medicines for the treatment of epilepsy (carbamazepine, phenobarbital and phenytoin).

The herbal medicine St John’s Wort (Hypericumperforatum) may not be used at the same time as Irinotecan EGIS solution and not between treatments, as it may decrease the effect of irinotecan.

If you require an operation, please tell your doctor or anaesthetist that you are using this medicine, as it may alter the effects of some medicines used during surgery.

Pregnancy and Breast-feeding

Irinotecan EGIS solution must not be used during pregnancy. Women of child-bearing age should avoid becoming pregnant. Contraceptive measures must be taken by both male and female patients during and for at least three months after cessation of therapy. If you become pregnant during this period you must immediately inform your doctor.

Breast-feeding must be discontinued for the duration of Irinotecan EGIS solution therapy.

Driving and using machines

In some cases Irinotecan EGIS solution may cause side effects which affect the ability to drive and use tools and machines. Contact your doctor or pharmacist if you are unsure.

During the first 24 hours after administration of Irinotecan EGIS solution you may feel dizzy or have visual disturbances. If this happens to you do not drive or use any tools or machines.

Important information about the ingredients of Irinotecan EGIS solution

Irinotecan EGIS solution contains sorbitol. If you suffer from an intolerance to some sugars, tell your doctor before you are given Irinotecan EGIS solution.

This medicinal product contains less than 1 mmol sodium per dose, therefore it can be considered to be essentially “sodium-free”.

3. HOW IRINOTECAN EGIS SOLUTION WILL BE GIVEN TO YOU

Irinotecan EGIS solution will be given as an infusion into your vein over a period of 30 to 90 minutes.

The amount of Irinotecan EGIS solution you will be given depends on your age, height, weight and general medical condition. It will also depend on any other treatment you may have received for your cancer. Your doctor will decide what is the right amount to use (the dose).

•    If you have previously been treated with 5-fluorouracil, you will normally be treated with Irinotecan EGIS solution alone starting with a dose of 350 mg/m² every 3 weeks.

•    If you have not had previous chemotherapy, you will normally receive

180 mg/m² Irinotecan EGIS solution every 2 weeks. This will be followed by folinic acid and 5-fluorouracil.

•    If you are to receive Irinotecan EGIS in combination with cetuximab, irinotecan must not be given earlier than 1 hour after the end of the cetuximab infusion.

These dosages may be adjusted by your doctor depending on your condition and any side effects you may have.

If you receive more Irinotecan EGIS solution than you should

Tell your doctor or care provider if you think that you have been given too much Irinotecan EGIS solution. Acute overdosing worsens side effects like diarrhoea or neutropenia (a decrease in the number of white blood cells in the blood). Should this happen you will receive treatment to prevent dehydration. Your blood cell count will be monitored and any infections treated accordingly.

4. POSSIBLE SIDE EFFECTS

Like all medicines Irinotecan EGIS solution can cause side effects, although not everybody gets them.

Your doctor will discuss these side effects with you and explain the risks and benefits of your medicine.

Very common side effects (more than 1 in 10 patients):

•    Blood disorders: Neutropenia (decreased number of some white blood cells) , thrombocytopenia (decreased number of blood platelets which makes you bruise and bleed easily), anaemia

•    Delayed diarrhoea

•    Nausea, and vomiting

•    Hair loss (the hair grows again at the end of treatment).

•    In combination therapy transient serum levels of some enzymes (ALT, AST, alkaline phosphatase) or bilirubin

Common side effects (less than 1 in 10 patients):

•    Acute cholinergic syndrome: the main symptoms are defined as: early diarrhoea, and various other symptoms such as abdominal pain, red, sore, itching or weeping eyes (conjunctivitis), running nose (rhinitis), low blood pressure, widening of blood vessels, sweating, chills, a feeling of general discomfort and illness, dizziness, visual disturbances, pupil contraction, watering eyes and increased salivation occurring during or within the first 24 hours after the infusion of Irinotecan EGIS solution.

•    Fever, infections

■    Fever associated with a severe decrease in the number of some white blood cells

•    Loss of water (dehydration), commonly associated with diarrhoea and/or vomiting

•    Constipation

•    Fatigue

•    Increase in levels of liver enzymes and creatinine in the blood

Uncommon side effects (less than 1 in 100 patients):

•    Allergic reactions

•    Mild skin reactions, mild reactions at the infusion site

•    Early effects such as breathing difficulties

•    Lung disease (interstitial    pulmonary disease)

•    Intestinal blockage

•    Abdominal pain and inflammation causing diarrhoea (a condition known as pseudomembraneous colitis)

•    Infrequent cases of renal insufficiency, low blood pressure or cardio-circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting or sepsis.

Rare side effects (less than 1 in 1,000 patients):

•    Severe allergic reactions (anaphylactic/anaphylactoid reactions. If this happens you should tell your doctor immediately

•    Early effects such as muscular contraction or cramps and numbness (paraesthesia)

•    Gastrointestinal bleeding and inflammation of the colon including the appendix

•    Intestinal perforation, anorexia, abdominal pain, inflammation of the mucous membranes

•    Inflammation of the pancreas

■    Increased blood pressure during and following administration

•    Decreased levels of potassium and sodium in the blood, mostly related to diarrhoea and vomiting.

Very rare side effects (less than 1 in 10,000 patients):

•    Transient speech disorders

•    Increase in levels of some digestive enzymes which break down sugars and fats

If you receive Irinotecan EGIS in combination with cetuximab or bevacizumab, some of the side effects you may experience can also be related to these combinations.

These may include acne-like rash. Therefore, please make sure you also read the patient information leaflet for cetuximab or bevacizumab.

If you receive Irinotecan EGIS 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 for capecitabine.

If you receive Irinotecan EGIS in combination with capecitabine and 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.

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 pharmacist.

5. HOW TO STORE IRINOTECAN EGIS SOLUTION

Keep out of the reach and sight of children.

Do not use Irinotecan EGIS solution after the expiry date which is stated on the vial label and outer carton.

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

For single use only.

Do not freeze.

After reconstitution and dilution under strict aseptic conditions, Irinotecan EGIS solution must be used (infusion completed) immediately or within 24 hours if stored in a refrigerator (2°C- 8°C).

If any cloudiness (precipitate) is observed in the vials or after reconstitution, the product should be disposed of.

Your doctor must use the Irinotecan EGIS solution as soon as it has been made.

Vials that have already been used must be disposed of by your healthcare professional according to hospital standard procedures applicable to cytotoxic medicines.

FURTHER INFORMATION

What Irinotecan EGIS solution contains

•    The active substance is irinotecan hydrochloride trihydrate 20 mg/ml.

•    The other ingredients are sorbitol E420, lactic acid, sodium hydroxide (for pH adjustment), hydrochloric acid, concentrate (for pH adjustment) and water for injections.

What Irinotecan EGIS solution looks like and contents of the pack

Irinotecan EGIS 20 mg/ml concentrate for solution for infusionis a clear, yellow solution with pH at 3.0 - 4.0 and osmolarity at 265-320 mOsmol/kg. It must be diluted before infusion into the patient.

It comes in two sizes:

•    1 x 40 mg of irinotecan hydrochloride trihydrate in a 2 ml type I amber glass, rubber (bromobutyl, teflon-coated) stoppered vial

•    1 x 100 mg of irinotecan hydrochloride trihydrate in a 6 ml type I amber glass, rubber (chlorobutyl, teflon-coated) stoppered vial.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation Holder is:

EGIS Pharmaceuticals PLC H-1106 Budapest, Kereszturi ut 30-38.

Hungary

The Manufacturers are:

Thymoorgan GmbH

Schiffgraben, D-38690, Vieneburg, Germany

EGIS Pharmaceuticals PLC H-1106 Budapest, Kereszturi ut 30-38.

Hungary

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

Irinotecan EGIS 20mg/ml concentrate for solution for infusion Irinocol 20mg/ml KoH^mpar 3a HH^e^noHeH pa3TBop Irinocol 20mg/ml

Famagil 20mg/ml koncentratum oldatos infuziohoz Irinocol

Ludiradol 20mg/ml concentrat pentru solutie perfuzabila

This leaflet was last approved in 04/2011.

INFORMATION FOR HEALTHCARE PROFESSIONALS

Irinotecan EGIS 20 mg/ml concentrate for solution for infusion Irinotecan hydrochloride trihydrate

The following information is intended for medical or healthcare professionals only: Instructions for use - cytotoxic Handling of Irinotecan EGIS

As with all other antineoplastic agents, caution should be exercised when handling Irinotecan EGIS. 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 EGIS solution for infusion

1. 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.

2.    In the event of Irinotecan EGIS 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.

3.    In case of contact of Irinotecan EGIS with eyes, wash them thoroughly with plenty of water. Contact an ophthalmologist immediately.

4.    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.

5.    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 of as HAZARDOUS WASTE.

Preparation of the infusion solution

Irinotecan EGIS 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 EGIS 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 dilution, the product should be discarded according to standard procedures for cytotoxic agents.

This medicinal product must not be mixed with other medicinal products except those mentioned above.

Irinotecan EGIS solution for infusion should be infused into a peripheral or central vein.

Irinotecan EGIS should not be delivered as an intravenous bolus or an intravenous infusion shorter than 30 minutes or longer than 90 minutes.

After dilution: the solution should be used immediately as it contains no antibacterial preservative. If reconstitution and dilution are performed under strict aseptic conditions (e.g. on Laminar Air Flow bench) the solution should be used (infusion completed) immediately or within24 hours if stored at 2°-8°C after the first opening.

Disposal

All items used for preparation, administration or otherwise coming into contact with Irinotecan EGIS should undergo disposal according to local guidelines for the handling of cytotoxic compounds.