IRINOTECAN HYDROCHLORIDE 20 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

PACKAGE LEAFLET: INFORMATION FOR THE USER

SZ00000LT000

Irinotecan Hydrochloride 20mg/ml Concentrate for Solution for Infusion
Irinotecan hydrochloride trihydrate
If you require an operation, please tell your doctor or anesthetist that you are using this medicine, as it may alter the effect of some medicines used during surgery (muscle relaxants).

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 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 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. In this leaflet: 1. What Irinotecan Hydrochloride is and what it is used for 2. Before you use Irinotecan Hydrochloride 3. How to use Irinotecan Hydrochloride 4. Possible side effects 5. How to store Irinotecan Hydrochloride 6. Further information

Caution: You may know some of the medicines listed above by another name, often the trade name. In this leaflet, only the main ingredient or therapeutic group of the medicine is named and not the trade name. This is why you should always carefully examine the packaging and the patient information leaflet of the medicines you are already taking for the name of the active substance or therapeutic group of that product. Pregnancy and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine. Pregnancy: Do not use irinotecan during pregnancy. You must not become pregnant during and up to 3 months after treatment with irinotecan has ended. If you become pregnant anyway, you must tell your doctor immediately. Breast-feeding: You must stop breast-feeding during the time you are having treatment with irinotecan. Driving and using machines Side effects such as dizziness and disturbances of sight (visual disturbances) can occur within 24 hours after treatment. They can have a negative effect on the ability to drive or use machines. If you get these side effects, do not drive or use machinery Important information about certain ingredients of Irinotecan Hydrochloride Irinotecan Hydrochloride contains sorbitol. If your doctor has told you that you cannot tolerate certain sugars, contact your doctor before taking this medicine.

1.

What Irinotecan Hydrochloride is and what it is used for

Irinotecan Hydrochloride belongs to the group of medicines called cytostatics (anti-cancer medicines). Irinotecan Hydrochloride is used for the treatment of advanced cancer of the colon and rectum in adults, either in combination with other medicines or alone.

2.

Before you use Irinotecan Hydrochloride

Do not use Irinotecan Hydrochloride: if you are allergic (hypersensitive) to irinotecan hydrochloride or one of the other ingredients of Irinotecan Hydrochloride (See section 6: Further information) if you have chronic bowel inflammation and/or a blockage of the bowel (bowel obstruction) if you are pregnant or breast-feeding if you have increased levels of bilirubin in the blood (more than 3 times the upper limit of normal) if your bone marrow function is extremely poor if the state of your health is very poor if you are using the natural remedy St. Johns Wort (see Using other medicines) Read the package leaflet for cetuximab or bevacizumab to find out in which cases you cannot use these medicines. If any of the above applies to you, do not use this medicine; talk to your doctor. Take special care with Irinotecan Hydrochloride: Tell your doctor if you have liver problems. You must be monitored carefully before and during treatment. If you have an extremely high level of bilirubin in the blood, you may not be treated with Irinotecan Hydrochloride. Your doctor will check this. This medicine is intended for adults only. Check with your doctor if this medicine has been prescribed for use in a child. Since, for older people, it is more likely for their bodies to work less well than younger people, particularly the liver, the doctor who will give you this medicine would have to choose the dosage very carefully. Tell your doctor if you have kidney problems. The use of irinotecan is not recommended, as there is no experience of its use in people with kidney problems. You should use contraceptives if you have sex while you are having this treatment and for at least three months after the course of this medicine. This applies to both male and female patients. As with all chemotherapies, the use of Irinotecan Hydrochloride is associated with a number of side-effects which may be serious. These side-effects require special management to lower 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 section 4 (Possible side effects) and follow the instructions carefully if you get any of the symptoms described. Using 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. Some medicines for the treatment of epilepsy (carbamazepine, phenobarbital, phenytoin), medicines for fungal infections (ketoconazole) and a medicine used to fight bacteria, particularly TB (rifampicin) can affect how well Irinotecan Hydrochloride works in your body. St. Johns Wort preparations must not be used together with Irinotecan Hydrochloride, as this can have an effect on how well the infusion works. If you were already taking St. John's Wort before you started on Irinotecan Hydrochloride, you must tell your doctor beforehand.

3.

How to use Irinotecan Hydrochloride

A specialist will give you Irinotecan Hydrochloride. The dosage 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. Your doctor will calculate your body surface area in metres squared (m 2). Dosage: Treatment with Irinotecan Hydrochloride as a single drug: The recommended dosage is 350 mg per m2 every 3 weeks. Irinotecan Hydrochloride in combination with 5-fluorouracil and folinic acid: The recommended dosage is 180 mg per m2 once every 2 weeks, followed by 5-fluorouracil and folinic acid through an infusion.

Please read the package leaflet of cetuximab or bevacizumab for dosage and use, in case you receive Irinotecan Hydrochloride in combination with one of these medicines. If you have side effects, your doctor may alter these dosages if necessary. How you will be given the infusion: Irinotecan Hydrochloride is given as an infusion into a vein over 30 to 90 minutes. How long you will have this treatment: Your doctor will decide on the duration of treatment. This will depend on your situation. If you notice that the effect of Irinotecan Hydrochloride is too strong or possibly not strong enough, tell your doctor or pharmacist. If you have any further questions on the use of this product, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some side effects may be slightly less frequent depending on whether you have Irinotecan Hydrochloride as a single drug or if you have it together with other drugs. Serious side effects: The following are all serious side effects. You may need urgent medical attention if you have any of them. Diarrhoea There are two types of diarrhoea, which can be distinguished by when they start. "Early diarrhoea starts less than 24 hours after the infusion and "late diarrhoea starts more than 24 hours after the infusion. If you have any diarrhoea, it is important that you follow these instructions carefully.
Please turn over



THE FOLLOWING INFORMATION IS ONLY INTENDED FOR HEALTH CARE PROFESSIONALS
QUALITATIVE AND QUANTITATIVE COMPOSITION

SZ00000LT000

One millilitre of the concentrate for solution for infusion contains 20 mg irinotecan hydrochloride trihydrate, equivalent to 17.33 mg irinotecan. One vial of 2 ml contains 40 mg of irinotecan hydrochloride trihydrate. One vial of 5 ml contains 100 mg of irinotecan hydrochloride trihydrate. One vial of 7.5 ml contains 150 mg of irinotecan hydrochloride trihydrate. Children One vial of 15 ml contains 300 mg of irinotecan hydrochloride trihydrate. Irinotecan should not be used in children One vial of 25 ml contains 500 mg of irinotecan hydrochloride trihydrate. Method of administration Excipients: Also includes Sorbitol E420 (45 mg/ml) and Sodium (less Irinotecan is cytotoxic, see Special precautions for disposal and than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium- free). other handling. Therapeutic indications Irinotecan Hydrochloride 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 Hydrochloride in combination with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of irinotecan-including cytotoxic therapy. Irinotecan Hydrochloride 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. Posology and method of administration For adults only. Irinotecan Hydrochloride solution for infusion should be infused into a peripheral or central vein.

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 Special warnings and precautions for use).

Irinotecan should not be delivered as an intravenous bolus or an intravenous infusion shorter than 30 minutes or longer than 90 minutes. Treatment duration Treatment with irinotecan should be continued until there is an objective progression of the disease or unacceptable toxicity. Contraindications History of severe hypersensitivity to irinotecan hydrochloride trihydrate or one of the excipients; Chronic inflammatory bowel disease and/or bowel obstruction (see Special warnings and precautions for use); Pregnancy and breast-feeding (see Special warnings and precautions for use); Bilirubin level > 3 times the upper limit of the normal range (see Special warnings and precautions for use); Severe bone marrow failure; WHO performance status > 2; Concomitant use of St. Johns Wort preparations (see Interaction with other medicinal products and other forms of interaction).

Recommended dosage For additional contraindications of cetuximab or bevacizumab, refer In monotherapy (for previously treated patients): to the product information for these medicinal products. The recommended dosage of Irinotecan Hydrochloride is 350 mg/m2 administered as an intravenous infusion over 30 to 90 minutes every Special warnings and precautions for use three weeks (see Special warnings and precautions for use). The use of irinotecan should be confined to units specialised in In combination therapy (for previously untreated patients): the administration of cytotoxic chemotherapy and it should only The safety and efficacy of irinotecan in combination with be administered under the supervision of a physician qualified in 5-fluorouracil (5FU) and folinic acid (FA) has been assessed with the the use of anticancer chemotherapy. following schedule: Given the nature and incidence of adverse events, irinotecan will only be prescribed in the following cases after the expected benefits have been weighed against the possible therapeutic risks: in patients presenting a risk factor, particularly those with a WHO performance status = 2. For the posology and method of administration of concomitant in the few rare instances where patients are deemed unlikely to cetuximab, refer to the product information for this medicinal product. observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrhoeal treatment Normally, the same dose of irinotecan is used as administered in the combined with high fluid intake at onset of delayed diarrhoea). last cycles of the prior irinotecan-containing regimen. Irinotecan Strict supervision in hospital is recommended for such patients. must not be administered earlier than 1 hour after the end of the cetuximab infusion. When irinotecan is used in monotherapy, it is usually prescribed with For the posology and method of administration of bevacizumab, refer to the bevacizumab summary product of characteristics. Dosage adjustments Irinotecan should be administered after appropriate recovery of all adverse events to grade 0 or 1 of the NCI-CTC grading (National Cancer Institute Common Toxicity Criteria) and when treatment-related diarrhoea is fully resolved. At the start of a subsequent infusion 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 dosage reduction of 15 to 20% should be applied for irinotecan and/or 5FU when applicable: haematological toxicity (neutropenia grade 4, neutropenia with fever (neutropenia grade 3-4 and fever grade 2-4), thrombocytopenia and leucopenia (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. Refer to the bevacizumab summary of product characteristics for dose modifications of bevacizumab when administered in combination with irinotecan/5FU/FA. the every-3-week-dosage schedule. However, a weekly dosage schedule 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 the 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. As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate anti-diarrhoeal therapy must be initiated immediately. This anti-diarrhoeal 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. Irinotecan plus 5 FU/FA in every 2 weeks schedule The recommended dosage of irinotecan is 180 mg/m2 administered once every 2 weeks as an intravenous infusion over 30 to 90 minutes, followed by an infusion with folinic acid and 5-fluorouracil.

The currently recommended anti-diarrhoeal treatment consists of high doses of loperamide (4 mg for the first intake and then 2 mg every 2 hours). This therapy should continued for 12 hours after the Special populations last liquid stool and should not be modified. In no instance should Patients with impaired liver function loperamide be administered for more than 48 consecutive hours at In monotherapy: Blood bilirubin levels (up to three times the upper these doses, because of the risk of paralytic ileus, nor for less than limit of the normal range (ULN) in patients with performance status 2 should determine the starting dose of irinotecan. In these patients 12 hours. with hyperbilirubinaemia and with a prothrombin time greater than 50%, the clearance of irinotecan is decreased and therefore, the risk In addition to the anti-diarrhoeal treatment, a prophylactic of haematotoxicity is increased. Thus, weekly monitoring of complete broad-spectrum antibiotic should be given when diarrhoea is associated with severe neutropenia (neutrophil count < 500 cells/mm). blood counts should be conducted in this patient population. In patients with a bilirubin level up to 1.5 times the upper limit of the normal range (ULN) the recommended dosage of irinotecan is 350 mg/m2. In patients with a bilirubin level ranging from 1.5 to 3 times the ULN, the recommended dosage of irinotecan is 200 mg/m2. Patients with a bilirubin level of more than 3 times ULN should not be treated with irinotecan (see Contraindications and Special warnings and precautions for use). 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 rehydration); 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 Posology and method of administration). Haematology Weekly monitoring of complete blood cell counts is recommended during irinotecan treatment. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature > 38C and neutrophils 1000 cells/mm) should be urgently treated in hospital with broad-spectrum intravenous antibiotics.
Please turn over



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 Special warnings and precautions for use).





Rare (affects less than 1 in 1000 patients) serious inflammation of the large bowel causing abdominal pain and/or diarrhoea (colitis, ischaemic colitis and ulcerative colitis); inflammation of the appendix; perforations in the intestines inflammation of the pancreas with severe upper abdominal pain and radiation to the back, also nausea and vomiting stomach ache inflammation of the mucous membranes (mucositis) mild forms of lack of appetite if your diarrhoea starts more than 24 hours after the infusion raised blood pressure (hypertension) during or after treatment ("late diarrhoea") as soon as you have had the first liquid stool, spasms or cramping of the muscles and sensations of tickling, do the following without delay: itching or tingling without an apparent cause (paresthesia) 1. Start the diarrhoea medicine prescribed for you by the doctor low blood levels of potassium and sodium which can cause who is treating you with irinotecan immediately. muscle weakness, twitching, tiredness and confusion or abnormal The medicine currently recommended to treat diarrhoea is heart rhythm. It is usually related to diarrhoea and vomiting. loperamide (4 mg as the start dose and thereafter 2 mg every 2 hours). You must continue this treatment for 12 hours after Very rare (affects less than 1 in 10,000 patients): the last liquid stool and this dosage may not be altered. You shortage of blood platelets caused by antibodies must not take loperamide for longer than 48 consecutive increase in levels of some digestive enzymes, which break down hours or for less than 12 hours. You must not alter the sugars and fats recommended dose of loperamide. temporary problems with speech. 2. Drink large volumes of water and/or drinks that contain salts (soda water, carbonated drinks or soups). If any of the side effects gets serious or if you notice any side effects 3. Tell the doctor who is treating you with irinotecan about the not listed in this leaflet, please tell your doctor or pharmacist. diarrhoea as soon as possible. If he/she is not available, tell the department staff where you were given this medicine. How to store Irinotecan Hydrochloride Late diarrhoea affects more than 1 in 10 patients.

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. Do not use any treatment that your doctor has given you for "late diarrhoea". This "early diarrhoea" affects less than 1 in 10 patients. You may feel other symptoms such as - sweating, chills - stomach cramps - runny nose - red, sore, or watery eyes - visual disturbance, pupil contraction - dizziness - low blood pressure, widening of blood vessels - feeling unwell - excessive mouth watering Tell your doctor or nurse about all your symptoms.



bleeding in the stomach and intestines (gastrointestinal bleeding) diarrhoea that is serious, lasts a long time or has blood in it, with stomach pain or fever (pseudomembranous colitis) renal insufficiency, low blood pressure and cardio-circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting or sepsis.

5.



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 the fluids described above.

Keep out of the reach and sight of children. For single use only. Before opening Keep the vial in the outer carton in order to protect from light. Do not use this medicinal product after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month. After opening The product should be diluted and used immediately after opening. After dilution From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally be not longer than 24 hours at 2-8C, unless dilution has taken place in controlled and validated aseptic conditions. Chemical and physical in-use stability have been demonstrated for 28 days at 2-8C as well as at room temperature (20-25C) with light protection and for 48 hours without light protection. Do not use Irinotecan Hydrochloride if you notice particles in the solution. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

Shortage of white blood cells (neutropenia): Neutropenia is a reduction of certain white blood cells which play an important role in fighting infections. Neutropenia and infections affect more than 1 in 10 patients after having Irinotecan Hydrochloride. For this reason, your own doctor (e.g. GP) must regularly monitor the number of cells in your blood during treatment with Irinotecan Hydrochloride. The doctor who prescribes Irinotecan Hydrochloride must know the results of these tests. If you have any fever this may be an indication of infection associated with this neutropenia. This may become a life-threatening condition and requires immediate treatment. Neutropenic fever affects less than 1 in 10 patients. If you have a fever (if your temperature is over 38C), and particularly if you also have diarrhoea, tell your doctor or nurse immediately, as direct and appropriate treatment is necessary. Nausea and vomiting: You should take a drug for vomiting before every treatment with Irinotecan Hydrochloride. Nausea and vomiting (feeling and being sick) affects more than 1 in 10 patients. If you have vomiting and delayed (late) diarrhoea, you should contact the doctor or the ward where you were given the treatment as quickly as possible. Serious allergic reaction Following symptoms of a serious allergic reaction affect less than 1 in 1000 patients: rapid drop in blood pressure, weak rapid pulse pale complexion, clammy skin restlessness, reduced level of consciousness swelling of the face or throat which may cause difficulty in swallowing, or extreme difficulty in breathing. If you have any of these symptoms contact your doctor or nurse immediately. Breathing difficulties Interstitial lung disease presenting as shortness of breath, dry cough and inspiratory crackles affects less than 1 in 100 patients. If you have breathing difficulties contact your doctor or nurse immediately.

6.

Further information

What Irinotecan Hydrochloride 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 2 ml vial contains 40 mg irinotecan hydrochloride trihydrate. One 5 ml vial contains 100 mg irinotecan hydrochloride trihydrate. One 7.5 ml vial contains 150 mg irinotecan hydrochloride trihydrate. One 15 ml vial contains 300 mg irinotecan hydrochloride trihydrate. One 25 ml vial contains 500 mg irinotecan hydrochloride trihydrate. The other ingredients are sorbitol E420, lactic acid, sodium hydroxide and water for injections What Irinotecan Hydrochloride looks like and contents of the pack Amber class I glass vial with rubber stopper (fluoropolymer coated bromobutyl rubber stopper), with or without a protective plastic overwrap (Onco-Safe). Onco-Safe does not come into contact with the medicinal product and provides additional transport protection, which increases the safety for the medical and pharmaceutical personnel. The vials are sealed with aluminium crimp caps.

Other possible side effects: Tell your doctor if any of the following side effects become troublesome. Clear, colourless to slightly yellow solution. Very common (affects more than 1 in 10 patients): shortage of red blood cells which can make the skin pale and cause weakness or breathlessness shortage of blood platelets which increases risk of bruising and bleeding fever without infection reversible hair loss blood tests which show changes in the way the liver is working (ALT, AST, alkaline phosphatase, bilirubin). Common (affects less than 1 in 10 patients): weakness (asthenia) constipation dehydration, commonly associated with diarrhoea and/or vomiting abnormal kidney function test results (creatinine). Uncommon (affects less than 1in 100 patients) mild allergic reactions such as rash and itching mild skin reactions, mild reactions at the site of infusion blockage of the bowel (bowel obstruction, ileus) Pack sizes: 40 mg/2 ml: 1 vial, 5 vials, 10 vials 100 mg/5 ml: 1 vial, 5 vials, 10 vials 150 mg/7.5 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 Sandoz UK Ltd, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, UK. Manufacturer Lek Pharmaceuticals d.d., Verovkova 57, 1526 Ljubljana, Slovenia or Salutas Pharma GmbH, Otto-von-Guericke-Allee 1, 39179 Barleben, Germany or EBEWE Pharma Ges.m.b.H. Nfg. KG, Mondseestrae 11, A-4866 Unterach, Austria. This leaflet was last approved in 11/2010 (tbaaa).
SZ00000LT000

In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration (see Posology and method of administration). There is an increased risk of infection and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, complete blood cell count should be performed. Liver function 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 the decrease of the clearance of irinotecan and thus increasing the risk of haematotoxicity in this population . For patients with a bilirubin > 3 times ULN, see Contraindications. Nausea and vomiting Prophylactic therapy with anti-emetics 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 If acute cholinergic syndrome appears (defined as early diarrhoea and various other symptoms such as sweating, abdominal cramping, lacrimation, myosis and salivation), atropine sulphate (250 micrograms subcutaneously) should be administered unless clinically contraindicated. 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, radiotherapy and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy. Elderly Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with Irinotecan Hydrochloride should be cautious in this population (see Posology and method of administration). Patients with bowel obstruction Patients must not be treated with irinotecan until resolution of the bowel obstruction (see Contraindications). Patients with impaired renal function Studies in this population have not been conducted (see Posology and method of administration). Other Since this medicinal product contains sorbitol, it is patients with rare unsuitable inhereditary fructose problems of fructose intolerance should not take this medicine. 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 by women of child bearing age, and also by male patients, during and for at least three months after cessation of therapy. Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducers (e.g. rifampicin, carbamazepine, phenobarbital, St John's Wort) of CYP3A4 may alter the metabolism of irinotecan and should be avoided (see Interaction with other medicinal products and other forms of interaction). Interaction with other medicinal products and other forms of interaction Interaction between irinotecan and neuromuscular muscle relaxants 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 CYP3A4-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 effect of such anticonvulsant drugs was reflected by a decrease in AUC of SN-38 and SN-38G of 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) Cytochrome P450 3A. Concurrent administration of irinotecan with an inhibitor/inducer of this metabolic pathway may alter the metabolism of irinotecan and should be avoided (see Special warnings and precautions for use). In a small pharmacokinetic study (n=5), in which irinotecan 350 mg/m2 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 Contraindications). Co-administration of 5-fluorouracil/folinic acid in the combination regimen does not change the pharmacokinetics of irinotecan. There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa. In one study, irinotecan concentrations were similar in patients receiving irinotecan/5FU/FA alone and in combination with bevacizumab. Concentrations of SN-38, the active metabolite of irinotecan, were analyzed in a subset of patients (approximately 30 per treatment arm). Concentrations of SN-38 were on average 33% higher in patients receiving irinotecan /5FU/FA in combination with bevacizumab compared with irinotecan/5FU/FA alone. Due to high

inter-patient variability and limited sampling, it is uncertain if the increase in SN-38 levels observed was due to bevacizumab. There was a small increase in diarrhoea and leukopenia adverse events. More dose reductions of irinotecan were reported for patients receiving irinotecan/5FU/FA in combination with bevacizumab. Patients who develop severe diarrhoea, leukopenia, or neutropenia with the bevacizumab and irinotecan combination should have irinotecan dose modifications as specified in Posology and method of administration. List of excipients Sorbitol (E420), Lactic acid, Sodium hydroxide (for pH adjustment to pH 3.5), Water for injection Incompatibilities Irinotecan Hydrochloride must not be mixed with other medicinal products. Shelf life Vial before opening: 3 years. After opening: The content of the vial should be used immediately after the first opening of vial. After dilution: From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally be not longer than 24 hours at 2-8C, unless dilution has taken place in controlled and validated aseptic conditions. Chemical and physical in-use stability have been demonstrated for 28 days at 2-8C as well as at room temperature (20-25C) with light protection and for 48 hours without light protection. Special precautions for storage Keep vial in outer carton in order to protect from light. For storage conditions of the diluted medicinal product, see section 6.3. Nature and contents of container Amber class I glass vial with rubber stopper (fluoropolymer coated bromobutyl rubber stopper), with or without a protective plastic overwrap (Onco-Safe). Onco-Safe does not come into contact with the medicinal product and provides additional transport protection, which increases the safety for the medical and pharmaceutical personnel. The vials are sealed with aluminium crimp caps. Pack sizes: 40 mg/2 ml: 1 vial, 5 vials, 10 vials 100 mg/5 ml: 1 vial, 5 vials, 10 vials 150 mg/7.5 ml: 1 vial, 5 vials, 10 vials 300 mg/15 ml: 1 vial 500 mg/25 ml: 1 vial Not all pack size may be marketed. Special precautions for disposal (and other handling) Handling As with all antineoplastic agents, caution should be exercised when handling Irinotecan Hydrochloride. 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. Instructions for dilution Irinotecan Hydrochloride 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 Hydrochloride 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. Protection instructions for preparation of Irinotecan Hydrochloride 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. 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. 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 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 4. In the event of Irinotecan Hydrochloride 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. 5. In case of contact of Irinotecan Hydrochloride with eyes, wash them thoroughly with plenty of water. Contact an ophthalmologist immediately. Disposal All items used for preparation, administration or otherwise coming into contact with Irinotecan Hydrochloride should undergo disposal according to local guidelines for the handling of cytotoxic compounds.

SAP: 5135298840 P.h: 1130 C.V: 1 - 2 - 3 - 4 - 20

SZ00000LT000