Package leaflet: Information for the user Irinotecan Hydrochloride 20mg/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 or pharmacist

-    If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

The name of your medicine is Irinotecan hydrochloride 20mg/ml concentrate for solution for infusion, which will be called Irinotecan throughout this leaflet.

What is in this leaflet:

1.    What Irinotecan is and what it is used for

2.    What you need to know before you take Irinotecan

3.    How to use Irinotecan

4.    Possible side effects

5.    How to store Irinotecan

6.    Contents of the pack and other information

1. What Irinotecan is and what it is used for

Irinotecan belongs to a group of medicines called cytostatics (anti-cancer-medicines)

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

Your doctor may use a combination of irinotecan with 5-fluorouracil/folinic acid (5-FU/FA) and bevacizumab to treat your cancer of the colon and rectum.

Your doctor may use a combination of irinotecan with capecitabine with or without bevacizumab to treat your cancer of the colon and rectum.

Your doctor may use a combination of irinotecan with cetuximab to treat cancer of the large intestine (KRAS wild-type) that is of a certain type known to display cell markers referred to as epidermal growth factor receptors (EGFR) which are blocked by the monoclonal antibody.

If you need any further information on your condition, please ask your doctor.

2. What you need to know before you take Irinotecan

Do not use irinotecan if:

-    you are allergic (hypersensitive) to irinotecan or any of the other ingredients of this medicine (listed in section 6)

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

-    you are pregnant or breast feeding

-    you have increased levels of bilirubin in the blood (more than 3 times the upper limit of the normal range)

-    you have severe bone marrow failure (imbalance of your blood cells)

-    you are taking the natural remedy St. John’s Wort (Hypericum perforatum - used for depression)

-    you are in poor general health (this will be decided by your doctor using an international standard)

Warnings and precautions

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 in elderly patients.

As Irinotecan is an anti-cancer medicine it will be administered to you in a special unit and under supervision of a doctor qualified in the use of anti-cancer 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.

If you receive irinotecan in combination with cetuximab or bevacizumab or capecitabine, please make sure that you also read the package leaflet for these medicinal products.

Talk to your doctor or pharmacist before taking Irinotecan.

-    If you have heart problems.

-    If you smoke, have high blood pressure or high cholesterol as these can increase the risk of heart problems during treatment with this medicine

-    If you have had or are due to have any vaccinations

1)    The first 24 hours after administration of irinotecan

During administration of irinotecan (30 - 90 minutes) and up to 24 hours after administration you may experience some of the following symptoms:

-    diarrhoea

-    sweating

-    abdominal pain

-    watering eyes

-    visual disturbance

-    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.

2)    From the day after treatment with irinotecan until next treatment

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

These can be:

Diarrhoea

If your diarrhoea starts more than 24 hours after administration of irinotecan (“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:

a) Take any antidiarrhoeal treatment that the doctor has given you,

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

Instruction for use - Cytotoxic Handling of Irinotecan

As with all neoplastic agents, caution should be exercised when handling irinotecan.

Dilution should be carried out under asceptic conditions by trained personnel in a designated area. Precautions should be taken to avoid contact with skin and mucouds membranes.

Protection instruction forpreparation of Irinotecan 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. ¹

exactly as he/she has told you. The treatment must not be changed without consulting the doctor.

Recommended antidiarrhoeal 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 must not be taken for more than 48 hours.

b)    Drink large amounts of water and rehydration fluids, immediately (i.e. water, soda water, fizzy drinks, soup or oral rehydration therapy).

c)    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 hospital unit supervising the irinotecan treatment. It is very important that they are aware of the diarrhoea.

Hospitalisation is recommended for the management of the diarrhoea, in the following cases, if

-    you have severe diarrhoea (and vomiting) with excessive loss of the water requiring intravenous hydration

-    you have fever as well as the diarrhea

-    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 antidiarrhoeal treatment should not be used to prevent a further episode of diarrhoea, even though 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 hospital unit immediately so that they can give you any treatment necessary.

Nausea (feeling sick) and vomiting

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

Neutropenia

Irinotecan 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.

Breathing difficulties

If you have any breathing difficulties contact your doctor immediately. Impaired liver function

Before treatment with irinotecan is started and before every following treatment cycle your doctor will monitor your liver function (by blood tests).

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.

Heart disease

If you have a heart disease or known risk factors, your doctor will monitor you closely.

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

Other medicines and Irinotecan

Tell your doctor or pharmacist if you are taking or have recently taken, any other medicines, including medicines obtained without a prescription.

The following medications can alter the effects of irinotecan:

-    Suxamethonium (muscle relaxant)

-    carbamazepine, phenobarbital or phenytoin (drugs used in the management of epilepsy)

-    ketoconazole (used for the treatment of fungal infections)

-    rifampicin (used for the treatment of tuberculosis)

-    the natural remedy St. John’s Wort (a treatment for depression)

-    Atazanavir (used to treat HIV)

-    Vaccines. Tell your doctor if you have had or are due to have any vaccinations.

-    Ciclosporin or tacromilus (used to dampen down your body's immune system)

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

Pregnancy and breast feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicines.

You must not be given irinotecan if you are pregnant.

If you or your partner is being treated with irinotecan you must avoid becoming pregnant during and for at least three months after cessation of therapy. Still, if you become pregnant, during this period you must immediately inform your doctor.

You must not breast-feed while you are being treated with irinotecan. Driving and using machines

Irinotecan may make you feel dizzy or cause visual disturbances within 24 hours after administration of the product. If this happens to you do not drive or use any tools or machines.

Irinotecan contains sorbitol. If you have been told by your doctor that you have intolerance to some sugars (e.g. fructose intolerance), contact your doctor before you are given this medicinal product.

3. How to use Irinotecan

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

For adults only

Irinotecan will be given as an infusion into your veins over a period of 30-90 minutes.

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3.    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 copius amounts of cold water.

-    the flushed surfaces should then be wiped thoroughly and the materials used for wiping should be disposed as HAZARDOUS WASTE.

4.    In the event of irinotecan contact with skin,the areas 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.

5.    In case of contact of irinotecan with eyes,wash them thoroughly with plenty of water contact an ophthalmologist immediately.

The amount of irintotecan you are given will depend on your age, height, weight and general medical condition. Your doctor will calculate your body surface area in square meters (m¹) from your height and weight. The dosage will also depend on any other treatment you may have received for your cancer.

-    if you have previously been treated with 5-fluorouracil you will normally be treated with irinotecan alone starting with a dose of 350 mg/m¹ every 3 weeks.

-    if you have not had previous chemotherapy you will normally receive 180 mg/m¹ irinotecan every two weeks. This will be followed by folinic acid and 5-fluorouracil.

If you receive irinotecan in combination with cetuximab, irinotecan must not be administered earlier than one hour after the end of the cetuximab infusion.

Please follow the advice of your doctor regarding your current treatment.

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

If you use more Irinotecan than you should

Irinotecan will be given to you by a doctor or nurse who is familliar with this type of treatment so the chances is very small to be given an overdose. If you were given a higher dosage of irinotecan than required or an overdose, the side effects could be severe. If you think you have been administered an overdose please contact your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

4. Possible side effects

Like all medicines, irinotecan 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 treatment.

Some of these side effects must be treated immediately. These are:

-    diarrhoea

-    a decrease in the number of neutrophil granulocytes, a type of white blood cell, which plays an important role in fighting infections.

-    fever

-    nausea and vomiting

-    breathing difficulties (possible symptom of severe allergic reactions)

Please read instructions described in section “Warnings and precautions” carefully and follow them if you have any of the side effects listed above.

Other side effects include:

Very common side effects (may affect more than 1 in 10 people)

-    Blood disorders including abnormally low number of neutrophil granulocytes, a type of white blood cell (neutropenia) which may make you more susceptible to infections and reduction of the quantity of red blood cells which can make you feel tired, weak and look pale (anaemia)

-    In combination therapy (when irinotecan is used with other medicines to treat your cancer), thrombocytopenia (reduction in the number of blood platelets) causing bruises, tendency to bleed and abnormal bleeding, short term increases in levels of liver enzymes (SGPT, SGOT, alkaline phosphatase) or bilirubin.

-    In monotherapy (when irinotecan is used alone to treat your cancer), fever, infections, severe nausea (feeling sick) and vomiting (being sick).

-    Delayed severe diarrhoea

-    Hair loss (the hair grows again after end of treatment)

Common side effects (may affect up to 1 in 10 people)

-    Severe short term acute cholinergic syndrome: the main symptoms are early diarrhoea and various other symptoms such as abdominal pain; red, sore, itching or weeping eyes (conjunctivitis); running nose (rhinitis); low blood pressure; flushing due to widening of the blood vessels (vasodilation); 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

-    In monotherapy, decreased number of blood platelets (thrombocytopenia) which increases the risk of bruising and bleeding, increased levels of some liver enzymes (transaminases, alkaline phosphatase) or bilirubin

-    In combination therapy, fever, infections, severe nausea (feeling sick) and vomiting (being sick), transient pronounced (grade 3) increase in serum levels of bilirubin.

-    Infections associated with a severe decrease in the number of some white blood cells (neutropenia) resulting in death in 3 cases

-    Fever associated with a severe decrease in the number of some white blood cells (febrile neutropenia)

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

-    Constipation

-    Feeling weak (asthenia)

-    Increase of creatinine in the blood

Uncommon side effects (may affect up to 1 in 100 people)

-    Mild allergic reaction (skin rash , sore and itchy eyes, runny nose)

-    Pain or redness at or close to the injection sits during the infusion

-    Early effects such as breathing difficulties

-    Lung disease causing shortness of breath, dry cough and crackly breathing (interstitial pulmonary disease)

-    Partial or complete blockage of the bowel

-    Bleeding in the stomach and bowel which may cause you to vomit blood or pass dark tarry stools

-    Bowel inflammation causing abdominal pain and/or diarrhoea (a condition known as pseudo-membraneous colitis)

-    Dehydration, often associated with diarrhoea and vomiting, which can lead to kidney problems, low blood pressure or collapse

-    Sepsis (a severe, whole body response to infection), which can lead to kidney problems, low blood pressure or collapse.

Rare side effects (may affect up to 1 in 1,000 people)

-    Severe allergic reactions (anaphylatic/ anaphylactoid reaction), including swelling of the hands, feet, ankles, face, lips, mouth or throat which may cause difficulty in swallowing or extreme difficulty breathing. If this happens you should tell your doctor immediately

-    Muscular contraction or cramps and numbness (paraesthesia)

-    Inflammation of the large bowel causing abdominal pain (colitis)

-    Intestinal perforation causing severe abdominal pain, nausea and vomiting

-    Loss of appetite

-    Abdominal pain

-    Inflammation of the mucous membranes

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

-    Inflammation of the pancreas causing upper abdominal pain

-    Increased blood pressure during and following administration

Very rare effects (may affect up to 1 in 10,000 people)

-    Short-term speech disorders

-    increase in levels of some digestive enzymes which break down sugars (amylase) and fats (lipase)

-    Bruising or bleeding easily due to your body destroying its own blood platelets (one case)

If you receive irinotecan in combination with cetuximab, some of the side effects you may experience can also be related to this combination. Such side effects may include an acne-like rash. Therefore, please make sure that you also read the package leaflet for cetuximab.

If you receive irinotecan 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 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.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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

5. How to store Irinotecan

-    Keep this medicine out of the sight and reach of children.

-    Do not use irinotecan after the expiry date which is stated on the vial and carton after EXP. The expiry date refers to the last day of that month.

-    Keep the vial below 25^oC and protect from light.

-    After dilution the solution should be used immediately. If this is not possible, the diluted solution should not be kept longer than 24 hours at 2-8°C

-    Do not use irinotecan if you notice any particles or cloudyness in the solution or if there are any other visible signs of deterioration.

-    Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment

6. Contents of the pack and other information

What irinotecan contains

The active substance is irinotecan (as hydrochloride trihydrate).

Each vial filled with 2ml Irinotecan hydrochloride trihydrate 20mg/ml contains 40 mg irinotecan hydrochloride trihydrate to 34.66 mg irinotecan.

Each vial filled with 5ml Irinotecan hydrochloride trihydrate 20mg/ml contains 100 mg irinotecan hydrochloride trihydrate to 86.65 mg irinotecan.

Each vial filled with 15 ml Irinotecan hydrochloride trihydrate 20mg/ml contains 300 mg irinotecan hydrochloride trihydrate to 259.95 mg irinotecan.

Each vial filled with 25 ml Irinotecan hydrochloride trihydrate 20mg/ml contains 500 mg irinotecan hydrochloride trihydrate to 433.25 mg irinotecan.

The other ingredients are sorbitol (E420), lactic acid, sodium hydroxide or hydrochloric acid and water for injection.

What irinotecan looks like and contents of the pack

Irinotecan Concentrate for solution for infusion is a clear, colourless pale yellow solution packaged in 5 ml ,15 ml and 25 ml Type I amber coloured glass vials with rubber stopper and aluminium flip-off tear-off seal.

Pack size:

2 ml fill volume 5 ml fill volume 15 ml fill volume 25 ml fill volume

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Cipla (EU) Limited,

Hillbrow House, Hillbrow Road, Esher, Surrey KT10 9NW United Kingdom

Manufacturer:

Cipla (EU) Limited, 4^th Floor,

1 Kingdom Street, London,

W2 6BY, United Kingdom

This leaflet was last revised in 04/2015

Cipla

Preparation of infusion solution

As with any other injectable drugs, the irinotecan concentrate solution for infusion must be prepared aseptically.

If any precipitate is observed in the vials or after reconstitution, the product should be discarded according to standard procedures for cytotoxic agents.

Aseptically withdraw the required amount of irinotecan concentrate for solution from the vial with a calibrated syringe and inject into a 250 ml infusion bag or bottle containing either 0.9% (w/v) sodium chloride or 5% (w/v) glucose solution.

The infusion should then be thoroughly mixed by manual rotation.

It is recommended, that in order to reduce microbiological hazard, the infusion solutions should be prepared immediately prior to use and infusion commenced as soon as practicable after preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution / dilution (etc) has taken place in controlled and validated aseptic conditions.

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

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

Disposal

All materials used for dilution and administration should be disposed of according to hospital standard procedures applicable to cytotoxic agents.

1

   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.