ONCOTICE POWDER FOR INSTILLATION FLUID FOR INTRAVESICAL USE CONTAINING 2-8 X 10^8 CFU TICE BCG

36273.100 36273.BR RA 8900 UK P6 (ref. 3.0)

RA 8900 UK S5 (ref. 3.0)

OncoTICE powder for suspension
2-8 X 108 CFU Tice BCG Information for the patient 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, please 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 effect not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Oncotice is and what it is used for 2. Before you are given Oncotice 3. How Oncotice is given 4. Possible side effects 5. How to store Oncotice 6. Further information 1. What Oncotice is and what it is used for Oncotice contains something called BCG (Bacillus Calmette-Gurin). This is a bacteria which has been specially altered, so that it can be used as a medicine. Oncotice is used to: treat bladder cancer prevent bladder cancer from coming back after bladder surgery. It comes as a powder which is mixed with saline (salt water). It is then run into your bladder through a tube. BCG is also used as a vaccine for TB (tuberculosis). Oncotice is a much stronger sort of BCG that cant be used as a vaccine. 2. Before you are given Oncotice Oncotice should not be given if: You have a urinary tract infection (UTI). This must be treated first. You have blood in your urine. You have or think you have TB (tuberculosis). Before you have Oncotice, your doctor may do a skin reaction test, to see if you have TB. This is called a Tuberculin Test. If you have had Oncotice before, this may give you a positive result in this test. You are HIV-positive. You may need to have a blood test for HIV. Tell your doctor if any of the following apply to you: you have been a drug user and have shared a needle you have had unsafe sex you have had a blood transfusion. You have problems with your immune system. This could be something which runs in the family, or is caused by an illness or other medicines you are taking. Do not have Oncotice if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before being given Oncotice. Take special care with Oncotice Check with your doctor or pharmacist before being given the medicine if: Your bladder wall or the tube coming into your bladder from your kidneys (called the ureter) have been damaged during previous treatment. Treatment with Oncotice will not be given until this has healed. If you are not sure if any of the above apply to you talk to your doctor or pharmacist before being given Oncotice. Taking other medicines Please tell your doctor or pharmacist if you are taking, or have recently taken any other medicine. This includes medicines obtained without a prescription, including herbal medicines. Do not have Oncotice and talk to your doctor straight away if: You are taking medicines for TB. The following can lower the effect of Oncotice: antibiotics medicines which affect the immune system (immuno-suppressants) medicines which affect the production of bone marrow cells (bone marrow suppressants) radiation treatment. If you are having any of these medicines or are having radiation treatment, your doctor will probably delay giving you Oncotice. Using Oncotice with food and drink Do not drink any liquid for 4 hours before you are given Oncotice. Do not drink any liquid for 2 hours after you have been given Oncotice. Pregnancy and breast-feeding Do not have Oncotice if you are pregnant or breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast-feeding. Driving and using machines Oncotice will not affect your being able to drive or use any tools or machines. Important information about some of the ingredients of Oncotice Oncotice contains lactose (a type of sugar). If you have been told by your doctor that you cannot tolerate or digest some sugars, talk to your doctor before being given this medicine. This medicine contains a very small amount of potassium (less than 1mmol or 39mg per dose). This means it is essentially potassium-free. 3. How Oncotice is given You will always be given Oncotice by a doctor or nurse. Before it is given Do not drink any liquid the 4 hours before Oncotice is given to you. You will be asked to pass water immediately before Oncotice is given to you. Being given your medicine First your genital area will be cleaned with a sterile solution. A nurse will then pass a small flexible tube into your bladder. This will remove any urine that is still in your bladder. Oncotice is then run into your bladder through this tube. This will only take a few minutes. The tube will then be removed.

OncoTICE (Tice BCG)
Information for the doctor 1. Trade name of the medicinal product OncoTICE powder for instillation fluid for intravesical use containing 28 x 108 CFU Tice BCG. 2. Qualitative and quantitative composition OncoTICE BCG 12.5 mg per vial containing 28 x 108 CFU Tice BCG. After reconstitution in 50 ml saline the suspension contains 0.41.6 x 107 CFU/ml. OncoTICE is a freeze-dried preparation containing attenuated bacilli of Mycobacterium bovis, prepared from a culture of Bacillus Calmette-Gurin (BCG). For excipients, see section 6.1. 3. Pharmaceutical form Powder for instillation fluid for intravesical use. 4. Clinical particulars 4.1 Therapeutic indications OncoTICE is indicated for treatment of primary or concurrent carcinoma-in-situ of the urinary bladder and for the prevention of recurrence of high grade and/or relapsing superficial papillary transitional cell carcinoma of the urinary bladder (Stage Ta (grade 2 or 3) or T1 (grade 1,2 or 3)) after transurethral resection. OncoTICE is only recommended for stage Ta grade 1 papillary tumours, when there is judged to be a high risk of tumour recurrence. 4.2 Posology and method of administration For preparation of the OncoTICE suspension see section 6.6. Dosage Adults and the elderly The contents of one vial of OncoTICE, reconstituted and diluted as indicated, are instilled into the urinary bladder. Induction treatment Weekly instillation with OncoTICE during the first 6 weeks. When used as an adjuvant therapy after TUR of a superficial urothelial cell carcinoma of the bladder (see Therapeutic indications), treatment with OncoTICE should be started between 10 and 15 days after performing the TUR. Treatment should not be started until mucosal lesions after TUR have healed. Treatment should also be delayed in cases of gross haematuria or major bladder irritability. Maintenance treatment Maintenance treatment consists of weekly instillation with OncoTICE during 3 consecutive weeks at months 3, 6 and 12 after initiation of the treatment. The need for maintenance every 6 months beyond the first year of treatment should be evaluated on the basis of tumour classification and clinical response. Children Not recommended. Intravesical instillation Insert a catheter via the urethra into the bladder and drain the bladder completely. Connect the 50 ml syringe containing the prepared OncoTICE suspension to the catheter, and instil the suspension into the bladder. After instillation, remove the catheter. The instilled OncoTICE suspension must remain in the bladder for a period of 2 hours. During this period care should be taken that the instilled OncoTICE suspension has sufficient contact with the whole mucosal surface of the bladder. Therefore the patient should not be immobilised or, in case of a bedridden patient, should be turned over from back to abdomen and vice versa every 15 minutes. After two hours, have the patient void the instilled suspension in a sitting position. Urine should be voided in a sitting position for 6 hours after treatment and two cups of household bleach should be added to the toilet before flushing. The bleach and urine should be left to stand in the toilet for 15 minutes before flushing. NOTE: The patient must not ingest any fluid for a period starting 4 hours prior to instillation, until bladder evacuation is permitted (i.e. 2 hours after instillation). 4.3 Contra-indications Urinary tract infections. Therapy with OncoTICE should be interrupted until the bacterial culture from urine becomes negative and therapy with antibiotics and/or urinary antiseptics is stopped. Gross haematuria. In these cases OncoTICE therapy should be stopped or postponed until the haematuria has been successfully treated or resolved. In patients with a positive Tuberculin test, OncoTICE instillations are contraindicated only if there is supplementary medical evidence for an active tuberculous infection. Treatment with anti-tuberculosis drugs like streptomycin, para-amino-salicylic acid (PAS), isoniazid (INH), rifampicin and ethambutol. Impaired immune response irrespective of whether this impairment is congenital or caused by disease, drugs or other therapy. Positive HIV serology. Pregnancy and lactation. 4.4 Special warnings and special precautions for use Before the first intravesical instillation of OncoTICE, a Tuberculin test (PPD) should be performed. If the test is positive, OncoTICE instillations are contraindicated only if there is supplementary medical evidence for an active tuberculous infection. Traumatic catheterisation or other injuries to the urethra or bladder mucosa can promote systemic BCG infection. Administration of OncoTICE should be delayed in such patients until mucosal damage has healed. It is recommended that patients known to be at risk of HIV infection be adequately screened prior to commencing therapy. Patients should be monitored for the presence of symptoms of systemic BCG infection and signs of toxicity after each intravesical treatment. OncoTICE should not be administered intravenously, subcutaneously or intramuscularly. In order to protect the partner, the patient should be recommended to either refrain from intercourse within one week after OncoTICE instillation, or to use a condom. The use of OncoTICE may sensitise patients to tuberculin resulting in a positive reaction to PPD. Reconstitution and preparation of the OncoTICE suspension for instillation and administration should be performed under aseptic conditions. Spillage of OncoTICE suspension may cause Tice BCG contamination. Any spilled OncoTICE suspension should be cleaned by covering with paper towels soaked with tuberculocidal disinfectant, such as household bleach, for at least 10 minutes. All waste materials should be disposed of as biohazard material. Accidental exposure to Tice BCG could occur through self-inoculation, by dermal exposure through an open wound, or by inhalation or ingestion of OncoTICE suspension. Tice BCG exposure should not produce significant adverse health outcomes in healthy individuals. However, in case of suspected, accidental self-inoculation, PPD skin testing is advised at the time of the accident and six weeks later to detect skin test conversion. 4.5 Interactions with other medicaments and other forms of interaction Tice BCG is sensitive to most antibiotics and in particular to the routinely used anti-tuberculosis drugs like streptomycin, para-amino salicylic acid (PAS), isoniazid (INH), rifampicin and ethambutol. Therefore the anti-tumour activity of OncoTICE may be influenced by concomitant therapy with antibiotics. If a patient is being treated with an antibiotic it is recommended to postpone the intravesical instillation
Very common (>1/10) Renal and urinary disorders General disorders and administration site conditions Common (>1/100, <1/10) Infections and infestations Blood and lymphatic system disorders Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Musculoskeletal and connective tissue disorders Renal and urinary disorders General disorders and administration site conditions Uncommon (>1/1,000, <1/100) Infections and infestations Blood and lymphatic system disorders Hepatobiliary disorders Skin and subcutaneous tissue disorders Renal and urinary disorders Investigations Rare (>1/10,000, <1/1,000) Respiratory, thoracic and mediastinal disorders Reproductive system and breast disorders Very rare (<1/10,000) Infections and infestations Blood and lymphatic system disorders Metabolism and nutrition disorders Psychiatric disorders Nervous system disorders Eye disorders Ear and labyrinth disorders Vascular disorders Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Renal and urinary disorders Reproductive system and breast disorders General disorders and administration site conditions Investigations

until the end of the antibiotic-treatment (see also Contra-indications). Immunosuppressants and/or bone marrow depressants and/or radiation may interfere with the development of the immune response and thus with the antitumour efficacy and should therefore not be used in combination with OncoTICE. 4.6 Pregnancy and lactation OncoTICE instillation for carcinoma of the bladder is contraindicated during pregnancy and lactation (see section 4.3). 4.7 Effects on ability to drive and use machines Not applicable 4.8 Undesirable effects The side effects of intravesical OncoTICE therapy are generally mild and transient. Toxicity and side-effects appear to be directly related to the cumulative CFU count of BCG administered with the various instillations. Approximately 90% of patients develop local irritative symptoms in the bladder. Pollakiuria

Cystitis, dysuria, pollakiuria, haematuria Influenza-like illness, pyrexia, malaise, fatigue Urinary tract infection Anaemia Pneumonitis Abdominal pain, nausea, vomiting, diarrhoea Arthralgia, arthritis, myalgia Urinary incontinence, micturition urgency, urine analysis abnormal Rigors Tuberculous infections1 Pancytopenia, thrombocytopenia Hepatitis Rashes, eruptions and exanthems NEC1 Bladder constriction, pyuria, urinary retention, ureteric obstruction Hepatic enzyme increased Cough Epididymitis Pharyngitis, orchitis, Reiters syndrome, Lupus vulgaris Lymphadenopathy Anorexia Confusional state Dizziness, dysaesthesia3, hyperaesthesia3, paraesthesia, somnolence, headache, hypertonia, neuralgia3 Conjunctivitis Vertigo3 Hypotension Bronchitis, dyspnoea, rhinitis Dyspepsia3, flatulence3 Alopecia, hyperhidrosis Back pain Renal failure acute Balanoposthitis, prostatitis, vulvovaginal discomfort3 Chest pain, oedema peripheral, granuloma2 Prostatic specific antigen increased, weight decreased

NEC = not elsewhere classified 1 High Level Term instead of Preferred Term 2 Granuloma NOS has been observed in various organs including the aorta, bladder, epididymis, gastrointestinal tract, kidney, liver, lungs, lymphnodes, peritoneum, prostate 3 Only isolated cases reported during post-marketing surveillance



OncoTICE (Tice BCG)
Information for the doctor and dysuria are reported very frequently. The cystitis and typical inflammatory reactions (granulomas) which occur in the mucosa of the bladder after instillation of BCG, and which cause these symptoms, may be an essential part of the anti-tumour activity of the BCG. In most cases, the symptoms disappear within two days after instillation and the cystitis does not require treatment. During maintenance treatment with BCG, the symptoms of cystitis may be more pronounced and prolonged. In these cases, when severe symptoms are present, isoniazid (300 mg daily) and analgesics can be given until disappearance of symptoms. Also commonly observed are malaise, a low to medium grade fever and/or influenza-like symptoms (fever, rigors, malaise and myalgia). These symptoms usually appear within 4 hours after instillation and last for 24 to 48 hours. Fever higher than 39 C typically resolves within 24 to 48 hours when treated with antipyretics (preferably paracetamol) and fluids. However, it is frequently not possible to distinguish these uncomplicated febrile reactions from early systemic BCG infection and antituberculosis treatment may be indicated. Fever above 39 C that does not resolve within 12 hours despite antipyretic therapy must be considered as systemic BCG-infection, necessitating clinical confirmatory diagnostics and treatment. Systemic BCG infections could be due to traumatic catheterisation, bladder perforation or premature BCG instillation after extensive TUR of a superficial carcinoma of the bladder. These systemic infections may be manifested initially by pneumonitis, hepatitis and/or cytopenia after a period of fever and malaise during which symptoms progressively increase. Patients with symptoms of therapyinduced systemic BCG infection should be adequately treated with anti-tuberculosis drugs according to treatment schedules used for tuberculosis infections. In these cases, further treatment with Tice BCG is contraindicated. 4.9 Overdose Overdosage occurs when more than one vial of OncoTICE is administered per instillation. In case of overdosage, the patient should be closely monitored for signs of systemic BCG infection and if necessary treated with anti-tuberculosis drugs. 5.0 Pharmacological properties 5.1 Pharmacodynamic properties OncoTICE is an immunostimulating agent (ATC code L 03 A). It has anti-tumor activity, but the exact mechanism of action is not known. Study data suggest that an active nonspecific immune response takes place. BCG invokes a local inflammatory response involving a variety of immune cells, such as macrophages, natural killer cells and T cells. 5.2 Pharmacokinetic Properties For the treatment and recurrence prophylaxis of bladder cancer, the attachment of BCG to the bladder wall after voiding has been shown to be important. This allows a targeted pharmacological effect at the site of application. 5.3 Preclinical safety data As a result of the wide clinical application of BCG vaccination in the preceding decades the risks of BCG in human subjects are well-characterised. Intra-vesical administration to dogs has been found to be safe and without significant toxicity. No evidence of birth defects, genetic damage or carcinogenecity in humans are available from the extensive adverse reaction literature of BCG used as a vaccine. 6. Pharmaceutical particulars 6.1 List of excipients Lactose Asparagine Citric Acid (E330) Dibasic Potassium Phosphate Magnesium Sulfate Iron Ammonium Citrate Glycerol (E422) Zinc formate Ammonium Hydroxide (E527) 6.2 Incompatibilities OncoTICE is incompatible with hypo and hypertonic solutions. OncoTICE should only be mixed with physiological saline as described in section 6.6. Other incompatibility studies have not been performed. 6.3 Shelf-life 12 months In-use stability of the reconstituted product has been demonstrated for 2 hours at 28 C protected from light. From a microbiological point of view, unless the method of Preparation of the solution for instillation Transfer the reconstituted contents of the vial back into the container. Rinse the vial by transfering 1 ml from the container back into the vial, then add back to the container. Mix the suspension carefully. The suspension, with a total volume of 50 ml is now ready for instillation; it contains a total of 28 x 108 CFU of Tice BCG. 7. Marketing authorisation holder N.V. Organon, Kloosterstraat 6, PO Box 20, 5340 BH, Oss, The Netherlands 8. Marketing authorisation number PL 05003/0046 9. Date of first authorisation/renewal of authorisation 4 August 2000/19 March 2004 10. Date of (partial) revision of the text June 2004 REF: USoncviV5.2 opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. 6.4 Special precautions for storage Store at 28 C, protect from light. 6.5 Nature and contents of containers 2 ml Type 1 glass vials in packs of 1 and 3. 6.6 Instruction for use/handling OncoTICE contains live, attenuated mycobacteria. Because of the potential risk for transmission, it should be prepared, handled and disposed of as a biohazard material (see section 4.4). Perform the following procedures under aseptic conditions using sterile physiological saline solution as the diluent and suitable techniques to ensure protection of the health care worker: Reconstitution Transfer 50 ml of the diluent into a sterile container and add 1 ml from the sterile container to the vial. Allow to stand for a few minutes then gently swirl until a homogenous suspension is obtained. Forceful agitation should be avoided.

OncoTICE powder for suspension
2-8 X 108 CFU Tice BCG Information for the patient After it has been given Oncotice will be left in your bladder for 2 hours. During this time you should move around a little. This makes sure that the Oncotice is spread around all of your bladder. Do not drink any liquid for 2 hours after you have been given Oncotice. After 2 hours you will be asked to pass water, to empty your bladder. You should do this while sitting down to avoid splashing your urine around the toilet. During the next 6 hours If you need to pass water again, also do this while sitting down. Every time you pass water, add two cups of household bleach to the toilet. Leave the bleach and urine to stand in the toilet for 15 minutes before flushing. How often Oncotice is given Oncotice is usually given once a week for 6 weeks. After this some people have maintenance therapy, where you may be given more doses. Your doctor will talk to you about this. Having sex in the week after having Oncotice If you have sexual intercourse during the week after being given the medicine, you must use a condom. This will lower the chance of the BCG bacteria being passed to your partner. If you have more Oncotice than you should Oncotice is made up from a standard bottle by your doctor, pharmacist or nurse. It is unlikely that you will receive too much Oncotice. If you do have too much, your doctor will check carefully to see whether you have BCG infection. If necessary you will need to have treatment for TB. 4. Possible side effects Like all medicines, Oncotice can cause side effects, although not everybody gets them. If you notice the following side effects, see your doctor straight away: a high temperature (fever) above 39 C that lasts for more than 12 hours, even after taking medicines like paracetamol to lower your temperature. signs of a BCG or TB infection: cough or bronchitis chest pain or tightness sweating sore throat cold in the nose swelling of your lymph glands. See your doctor straight away if you notice any of these side effects. Other side effects include: Very common (affects more than 1 in 10 people) bladder infection, pain when passing water, having to pass water often, feeling the need to pass water and bloody urine. Usually this goes away within two days. flu-like symptoms such as fever and feeling off-colour and tired (malaise). This usually happens about 4 hours after treatment and last for 24 to 48 hours. Common (affects less than 1 in 10 people) painful joints or arthritis muscle pain or stiffness feeling sick (nausea) and being sick (vomiting)

36273.BRA 36273.A



abdominal pain or diarrhoea chest infection anaemia problems with passing water or having a large amount of blood in your urine shivering with a high temperature (fever). Uncommon (affects less than 1 in 100 people) skin rash jaundice (yellow colour of your skin or eyes) pus in your urine difficulty passing water low blood count (shown in blood tests) Rare (affects less than 1 in every 1,000 people) inflammation of the genitals or prostate. Very Rare (affects less than 1 in every 10,000 people) headache back pain increased muscle tension swollen legs or arms low blood pressure blood problems (shown in blood tests) flatulence or discomfort following meals loss of appetite or weight loss hair loss prickling or itching skin open sores on your skin eye infection feeling confused, sleepy or dizzy kidney problems Tell your doctor if any side effect is severe or lasts longer than 48 hours. If you notice any side effects not listed in this leaflet, tell your doctor or pharmacist. 5. How to store Oncotice Keep Oncotice out of the reach and sight of children. Oncotice will be stored in the hospital according to the instructions given by the manufacturer on the packaging. Store at 2 C to 8 C (in a refrigerator). Do not use Oncotice after the expiry date which is stated on the carton and label. 6. Further information What Oncotice contains The active substance is Bacillus Calmette-Gurin (BCG). It is a specially treated bacteria to be used as a medicine. The other ingredients are: lactose, asparagine, citric acid (E330), potassium phosphate, magnesium sulfate, iron ammonium citrate, glycerol (E422), ammonium hydroxide (E527), zinc formate. What Oncotice looks like and contents of the pack Oncotice is a freeze-dried powder, packed in 2 ml glass vials (available in packs of 1), each containing 1 dose of 12.5 mg (equivalent to 2 to 8 x 108 CFU) of BCG. The Marketing authorisation holder is: N.V. Organon PO Box 20, 5340 BH, Oss The Netherlands The Manufacturer is: Organon Teknika Corporation 100 Rodolphe Street Building 1300, Durham, NC27712 USA This leaflet was last updated in December 2007. To listen to or request a copy of this leaflet in braille, large print or audio please call, free of charge: 0800 198 5000 (UK Only) Please be ready to give the following information: Product name: Oncotice Reference Number: PL 05003/0046 This is a service provided by the Royal National Institute for Blind People