Oncotice

PACKAGE LEAFLET

Package leaflet: information for the patient

OncoTICE powder for suspension for intravesical use

Bacillus Calmette-Guérin
(BCG, TICE strain)
Please read this leaflet carefully before this medicine is administered to you, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

1. What OncoTICE is and what it is used for
2. What you need to know before you are given OncoTICE
3. How OncoTICE is administered
4. Possible side effects
5. How to store OncoTICE
6. Contents of the pack and other information

1. What OncoTICE is and what it is used for

OncoTICE contains the active substance bacillus Calmette-Guérin, strain TICE, and belongs to a group of medicines known as “antineoplastic and immunostimulant agents”.
OncoTICE is indicated for:

• the treatment of flat-surfaced (flat urothelial) bladder tumours that are still confined within the bladder (carcinoma in situ);
• adjuvant treatment following endoscopic removal (transurethral resection) of primary tumours located in the bladder (primary bladder carcinoma);
• the treatment of recurrences of superficial papillary carcinomas (tumours with low malignancy grade characterised by small projections) at Stage T (non-invasive) or Stage T (those beginning to invade surrounding tissues). OncoTICE is recommended exclusively for the treatment of papillary tumours at Stage T when a high risk of tumour recurrence is suspected.

2. What you need to know before you are given OncoTICE

Do not use OncoTICE

• if you are allergic to the active substance or to any of the other components of this medicine (listed in section 6);
• if you have a bacterial urinary tract infection, including the bladder (cystitis). You may resume treatment with OncoTICE only when the urine bacterial culture is again negative and treatment with antibiotics and/or antiseptics has been completed;
• if you have a high amount of blood in your urine. You may start or resume treatment with OncoTICE only after this condition has resolved;
• if you have active tuberculosis. If the Mantoux test (a screening test for diagnosis of tuberculosis, see also section “Warnings and precautions”) is positive, active tuberculosis must be ruled out;
• if you are taking medicines for the treatment of tuberculosis such as streptomycin, para-aminosalicylic acid, isoniazid, rifampicin and ethambutol (see section “Other medicines and OncoTICE”);
• if you have a reduced immune response, regardless of its origin (congenital or caused by diseases, drugs or other therapies);
• if you are HIV-positive (human immunodeficiency virus);
• if you are pregnant or breastfeeding (see section “Pregnancy, breastfeeding and fertility”).

Warnings and precautions
Talk to your doctor, pharmacist or nurse before you are given this medicine.

• Before starting treatment with OncoTICE, a tuberculin skin test (Mantoux test) must be performed. If the test is positive and there is additional clinical evidence of active tuberculosis infection, OncoTICE must not be administered.
• If you have lesions of the urinary tract, for example due to catheter insertion, administration of OncoTICE should be postponed until the lesion has healed, in order to avoid a systemic infection with Calmette-Guérin bacillus.
• If you think you may be at risk of HIV infection, your doctor will recommend that you undergo an appropriate test before starting treatment.
• After each treatment, you will undergo medical check-ups to monitor for symptoms of Calmette-Guérin bacillus infection and any signs of treatment-related toxicity.
• OncoTICE will be administered exclusively into the bladder (intravesical use). Intravenous, subcutaneous or intramuscular administration is not indicated.
• As a precaution for your partner, abstain from sexual intercourse during the first week after administration of OncoTICE, or use contraceptive precautions such as a condom or another barrier method.
• Contamination with Calmette-Guérin bacillus may occur following accidental spillage of the medicine. In such an event, healthcare personnel will clean up the spilled suspension by covering it for at least 10 minutes with paper towels soaked in tuberculocidal disinfectants, and dispose of all cleaning materials as special waste.
• Accidental exposure to OncoTICE may occur during self-administration without trained personnel, through contact with open wounds, inhalation or ingestion. Exposure to OncoTICE is not expected to cause significant reactions in healthy individuals. However, if your doctor suspects accidental self-administration, you will be advised to immediately undergo a specific test to assess tuberculosis infection (Mantoux test), and repeat it after six weeks to evaluate whether the test has become negative.
• The use of OncoTICE may make you test positive in tuberculosis screening tests.
• If you experience symptoms such as fever and unexplained weight loss, contact your doctor, as these may indicate a late reactivation of BCG infection. These symptoms may appear months or even years after the last dose of OncoTICE.

Other medicines and OncoTICE
Inform your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
Healthcare professionals will pay particular attention before starting treatment with OncoTICE if you are taking the following medicines:

• antibiotics. The Calmette-Guérin bacillus is sensitive to antibiotics, which may interfere with the anti-tumour activity of OncoTICE (see section “Do not use OncoTICE”). If you are undergoing antibiotic treatment, your doctor will advise you to postpone administration of OncoTICE until completion of the antibiotic course;
• anti-tuberculosis medicines commonly used, such as streptomycin, para-aminosalicylic acid, isoniazid, rifampicin and ethambutol;
• medicines that suppress the immune system and/or reduce bone marrow function and/or radiation therapy, which may interfere with the anti-tumour efficacy of OncoTICE and therefore should not be used concomitantly with OncoTICE.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor, pharmacist or nurse before you are given this medicine.
OncoTICE must not be used for the treatment of bladder cancer during pregnancy and breastfeeding.

Effects on the ability to drive and use machines
OncoTICE does not affect the ability to drive or operate machinery.

3. How OncoTICE should be administered

The powder is reconstituted and diluted before use. The suspension will be administered directly into your bladder by a healthcare professional, such as a doctor or nurse.

Initial therapy (induction therapy)
The recommended dose is one weekly administration of OncoTICE for the first 6 weeks.

When used as adjuvant therapy following surgical removal of bladder tumour (transurethral resection), treatment with OncoTICE should begin between Day 10 and Day 15 after surgery. Treatment must not be started until mucosal lesions caused by tumour removal have healed.

Maintenance therapy
During the three weeks following the third, sixth, and twelfth months after the first administration of OncoTICE, maintenance treatment is scheduled for all patients, consisting of weekly administrations of OncoTICE.

Your doctor will advise you whether to continue maintenance treatment every 6 months beyond the first year of therapy, based on the severity of the tumour and your response to treatment.

If more OncoTICE is administered than recommended
In case of overdose, i.e. if more than one vial of OncoTICE is administered, your doctor will monitor you closely and may initiate anti-tuberculosis medications should symptoms of Bacillus Calmette-Guérin infection occur.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The toxicity and adverse effects of OncoTICE appear to be directly related to the dose of
Bacillus Calmette-Guerin administered.
Approximately 90% of patients experience localized bladder irritation after
administration of OncoTICE.
Very commonly reported are urinary difficulties and disturbances (frequency and
dysuria). Urinary tract infections (cystitis) and typical inflammatory reactions (granulomas) occurring
in the bladder following OncoTICE administration, which cause these
symptoms, may be an essential part of OncoTICE’s antitumour activity. In most
cases, symptoms disappear within 2 days of treatment and do not require further therapy.
During maintenance therapy, cystitis symptoms may be more pronounced and longer-lasting. If you
experience worsening symptoms, your doctor may advise you to take
medicines for the treatment of tuberculosis, such as isoniazid (300 mg daily), and medicines to
relieve pain and inflammation (analgesics), until symptoms resolve.
During treatment with OncoTICE, malaise, increased body temperature, and/or influenza-like symptoms (fever, chills, malaise, and muscle pain) have also been commonly observed.
These symptoms usually occur within 4 hours after administration and last for
24–48 hours. Fever above 39 °C generally resolves within 24–48 hours when treated with
medicines that reduce body temperature (antipyretics, preferably paracetamol) and adequate fluid intake. However, it is not always possible to determine whether such symptoms are due solely to fever and not to infection with Bacillus Calmette-Guerin; in such cases, treatment with antituberculosis medicines may be required.
A fever exceeding 39 °C that does not resolve within 12 hours after taking
antipyretic medicines should be considered indicative of Bacillus Calmette-Guerin infection.
The presence of the bacillus will be confirmed by laboratory tests and will require appropriate treatment.
Systemic Bacillus Calmette-Guerin infection may result from the mode of administration of
OncoTICE, particularly if trauma occurred during catheter insertion or bladder perforation, or from early administration of the medicine after surgical intervention (transurethral resection) to remove bladder tumour. These systemic infections may initially present as pneumonia, hepatitis and/or cytopenia (reduction in certain blood cells), following a period of fever and malaise during which symptoms progressively worsen. Symptoms may be delayed by months or years after the last dose, and patients should be instructed to seek medical attention if symptoms such as unexplained fever and weight loss occur. Patients with symptoms of systemic Bacillus Calmette-Guerin infection induced by therapy must be adequately treated with antituberculosis medicines according to the treatment regimen used for tuberculosis infections. In such cases, further treatment with OncoTICE is contraindicated.
Other side effects reported with OncoTICE after its marketing are listed below by frequency:
Very common (may affect more than 1 in 10 people)

• inflammation of the bladder (cystitis), urinary disturbances and difficulties (dysuria and frequency);
• presence of blood in the urine (haematuria);
• influenza-like symptoms, fever, malaise, fatigue.

Common (may affect up to 1 in 10 people)

• decrease in red blood cells (anaemia);
• inflammation of the lungs (pneumonia);
• abdominal pain, nausea, vomiting, diarrhoea;
• joint and muscle pain (arthralgia and myalgia), and joint inflammation (arthritis);
• urinary incontinence, urinary tract infection, urgency to urinate, abnormal urine test;
• chills.

Uncommon (may affect up to 1 in 100 people)

• BCG infection in the body (tuberculosis-like infections) with possible late reactivation. Symptoms may be delayed by months or years after the last dose;
• decrease in the number of red blood cells, platelets, and white blood cells in the blood (pancytopenia), which may be associated with fatigue; decrease in the number of platelets in the blood (thrombocytopenia), which may manifest as bruising;
• inflammation of the liver (hepatitis);
• skin reactions with appearance of blisters and vesicles (rash, exanthema);
• painful contractions of the bladder, presence of pus in the urine (pyuria), residual urine in the bladder due to inability to empty completely (urinary retention), obstruction of the ducts (ureters) carrying urine to the bladder;
• abnormal liver function tests.

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

• cough;
• inflammation of certain parts of the male genital tract (epididymitis).

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

• inflammation of the throat (pharyngitis), inflammation of the testicles (orchitis), Reiter's syndrome presenting with inflammation of the eyes, joints, and urogenital system;
• forms of cutaneous tuberculosis (lupus vulgaris);
• swollen lymph nodes (lymphadenopathy);
• loss or reduction of appetite (anorexia);
• confusion;
• dizziness (sensation of spinning), altered sensitivity to stimuli (dysesthesia, hyperesthesia, paresthesia), somnolence, headache, increased muscle tone (hypertonia), pain affecting various tissues due to inflammation of the trigeminal nerve (neuralgia);
• inflammation of the eye (conjunctivitis);
• low blood pressure (hypotension);
• inflammation of the bronchi (bronchitis) and nasal mucosa (rhinitis), difficulty breathing (dyspnoea);
• digestive difficulties (dyspepsia), excessive intestinal gas (flatulence);
• reduction in hair quantity (alopecia), increased sweating;
• back pain;
• severe kidney problems (acute renal failure);
• inflammation of the glans and foreskin (balanoposthitis) and of the prostate (prostatitis), discomfort (burning, itching, irritation) in female genital organs (vulvovaginal discomfort);
• chest pain, swelling of feet, legs, and ankles due to fluid accumulation in tissues (peripheral oedema), lesions caused by inflammation (granulomas). Granulomas have been observed in various organs including aorta, bladder, epididymis (part of the male genital tract), gastrointestinal tract, kidney, liver, lungs, lymph nodes, peritoneum, prostate;
• increase in an enzyme produced by prostate cells (Prostate-Specific Antigen, PSA);
• weight loss.

Not known (frequency cannot be estimated from available data):

• Inflammation of blood vessels, including those in the brain (vasculitis);
• Inflammation of the eye (infectious endophthalmitis);
• Haemophagocytic lymphohistiocytosis, a condition in which the immune system produces an excessive number of cells normally responsible for fighting infections, called histiocytes and lymphocytes. Symptoms may include fever, rash, swollen lymph nodes, difficulty breathing, and easy bruising.

Other side effects observed are:

• allergic reactions;
• BCG infection in the blood (sepsis);
• abnormal dilation of arteries due to Bacillus Calmette-Guerin infection (infectious aneurysm).

Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your
doctor, pharmacist, or nurse. You can also report side effects directly via
the national reporting system: reactions-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store OncoTICE

Keep this medicine out of the sight and reach of children.
OncoTICE has a shelf life of 1 year, provided it is stored under the prescribed conditions.
Store in the refrigerator (2 °C-8 °C).
Keep in the original packaging to protect the medicine from light.
The reconstituted and diluted suspension can be stored for a maximum of 2 hours at a temperature
between 2 °C and 8 °C, protected from light.
Do not use this medicine after the expiry date stated on the container after "Exp.:". The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What OncoTICE contains

• The active substance in OncoTICE is Bacillus Calmette-Guérin.
• The other components are: lactose, asparagine, citric acid (E330), potassium phosphate (dibasic), magnesium sulfate, ammonium ferric citrate, glycerol (E422), ammonium hydroxide (E527), zinc formate. Each 2 mL vial of OncoTICE powder contains 2–8 x 10^6 Colony Forming Units (CFU) of Bacillus Calmette-Guérin (BCG), TICE strain. After reconstitution with 50 mL of saline solution, the suspension contains 0.4–1.6 x 10^5 CFU/mL.

Description of the appearance of OncoTICE and contents of the pack
Powder for suspension for intravesical use.
OncoTICE is available in packs of 3 vials, each containing 2–8 x 10^6 CFU of TICE BCG.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
MSD Italia S.r.l.
Via Vitorchiano, 151
00189 Rome, Italy

Manufacturer
N.V. Organon
Kloosterstraat 6
5349 AB Oss
The Netherlands

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

The following information is intended exclusively for physicians or healthcare professionals:
OncoTICE contains live attenuated mycobacteria. Due to the potential risk of transmission, it must be prepared, handled, and disposed of as hazardous material (special waste).
Perform the following procedures under aseptic conditions:

Reconstitution
Using a sterile syringe, add 1 mL of sterile physiological saline solution to the contents of one OncoTICE vial. Ensure that the needle penetrates the center of the vial’s rubber stopper. Allow to stand for a few minutes.
Then gently shake to obtain a homogeneous suspension: do not shake vigorously.

Preparation of the suspension for instillation
Transfer the reconstituted suspension from the vial into a separate, sterile 50 mL container and dilute with sterile physiological saline solution up to a volume of 49 mL. Rinse the empty vial with 1 mL of sterile physiological saline solution and add the rinse liquid to the reconstituted suspension to achieve a final volume of 50 mL. Mix the suspension thoroughly.
The suspension is now ready for use: it contains a total of 2–8 x 10^6 CFU (Colony Forming Units) of Bacillus Calmette-Guérin (BCG), TICE strain.

Administration
The administration of the OncoTICE suspension must be performed under sterile conditions. Follow the instructions below:

• Insert a catheter into the bladder via the urethra and allow complete emptying;
• Instill the 50 mL OncoTICE suspension into the bladder through the catheter by gravity (i.e., using a natural flow without added force or pressure);
• Once the OncoTICE suspension has been introduced into the bladder, remove the catheter. The instilled OncoTICE suspension must be retained in the bladder for 2 hours. During this period, ensure adequate contact between the administered suspension and the entire bladder mucosa. To facilitate this contact, the patient should not remain immobile; if the patient is confined to bed, turn them from supine to prone position, and vice versa, every 15 minutes. After 2 hours from instillation, the patient should empty the bladder while sitting. After treatment, the patient should continue to empty the bladder while sitting for the next six hours. Two cups of household sodium hypochlorite solution should be poured into the toilet bowl, allowing it to remain in contact with the urine for 15 minutes before flushing. From 4 hours before instillation of the OncoTICE suspension until the first bladder emptying (i.e., 2 hours after instillation), the patient must not consume any fluids.